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Study Of Letrozole With Or Without Palbociclib (PD-0332991) For The First-Line Treatment Of Hormone-Receptor Positive Advanced Breast Cancer

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT00721409
Recruitment Status : Completed
First Posted : July 24, 2008
Results First Posted : March 19, 2015
Last Update Posted : December 10, 2018
Sponsor:
Information provided by (Responsible Party):
Pfizer

Study Type Interventional
Study Design Allocation: Randomized;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Breast Cancer
Interventions Drug: PD 0332991
Drug: letrozole
Enrollment 177
Recruitment Details This Phase 1/2, open-label, randomized study enrolled a total of 12 participants at 3 sites in the United States for Phase 1. Phase 1 participants received Palbociclib + Letrozole. In Phase 2, a total of 165 participants were randomized (84 in palbociclib plus letrozole arm and 81 in letrozole alone arm) at 50 sites in 12 countries.
Pre-assignment Details Phase 2 portion has 2 parts. Phase 2, Part 1 – ER positive, HER2 negative postmenopausal women with advanced breast cancer. Phase 2, Part 2- ER positive, HER2 negative postmenopausal women with tumors demonstrating CCND1 gene amplification and/or loss of CDKN2A gene.
Arm/Group Title Phase 1 (Palbociclib + Letrozole) Phase 2 (Palbociclib + Letrozole) Phase 2 (Letrozole)
Hide Arm/Group Description In Cycle 1 (3 weeks), participants received single agent palbociclib 125 mg/d orally for 2 weeks followed by 1 week off treatment. In Cycles 2 and beyond (4 weeks each), participants received letrozole 2.5 mg/d in a continuous regimen plus Palbociclib 125 mg/d orally for 3 weeks followed by 1 week off treatment. All participants who were randomized to letrozole plus palbociclib in both Phase 2 part 1 (Ph2P1) and Phase 2 part 2 (Ph2P2) are combined and presented. In Ph2P1 and Ph2P2, the participants received palbociclib 125 mg/d orally for 3 weeks followed by 1 week off treatment and letrozole 2.5 mg/d orally in a continuous regimen. All participants who were randomized to receive letrozole alone in both Phase 2 part 1 (Ph2P1) and Phase 2 part 2 (Ph2P2) are combined and presented. This was considered as control arm. Letrozole 2.5 mg/d was administered orally in a continuous regimen.
Period Title: Overall Study
Started 12 84 81
Treated 12 83 77
Completed 0 2 2
Not Completed 12 82 79
Reason Not Completed
Global deterioration of health status             2             6             3
Death             0             1             0
Randomized not Treated             0             1             4
Reason not specified             1             0             2
Adverse Event             0             13             2
Lost to Follow-up             0             0             1
Withdrawal by Subject             1             6             5
Objective progression or relapse             8             55             62
Arm/Group Title Phase 1 (Palbociclib + Letrozole) Phase 2 (Palbociclib + Letrozole) Phase 2 (Letrozole) Total
Hide Arm/Group Description In Cycle 1 (3 weeks), participants received single agent palbociclib 125 mg/d orally for 2 weeks followed by 1 week off treatment. In Cycles 2 and beyond (4 weeks each), participants received letrozole 2.5 mg/d in a continuous regimen plus Palbociclib 125 mg/d orally for 3 weeks followed by 1 week off treatment. All participants who were randomized to letrozole plus palbociclib in both Phase 2 part 1 (Ph2P1) and Phase 2 part 2 (Ph2P2) are combined and presented. In Ph2P1 and Ph2P2, the participants received palbociclib 125 mg/d orally for 3 weeks followed by 1 week off treatment and letrozole 2.5 mg/d orally in a continuous regimen. All participants who were randomized to receive letrozole alone in both Phase 2 part 1 (Ph2P1) and Phase 2 part 2 (Ph2P2) are combined and presented. This was considered as control arm. Letrozole 2.5 mg/d was administered orally in a continuous regimen. Total of all reporting groups
Overall Number of Baseline Participants 12 84 81 177
Hide Baseline Analysis Population Description
Analysis was done on participants who received at least one dose of study drug.
Age, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 12 participants 84 participants 81 participants 177 participants
<18 Years
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
18-44 Years
1
   8.3%
2
   2.4%
4
   4.9%
7
   4.0%
45-64 Years
6
  50.0%
45
  53.6%
38
  46.9%
89
  50.3%
>= 65 Years
5
  41.7%
37
  44.0%
39
  48.1%
81
  45.8%
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 12 participants 84 participants 81 participants 177 participants
Female
12
 100.0%
84
 100.0%
81
 100.0%
177
 100.0%
Male
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 12 participants 84 participants 81 participants 177 participants
American Indian or Alaska Native
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Asian
0
   0.0%
6
   7.1%
4
   4.9%
10
   5.6%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Black or African American
0
   0.0%
1
   1.2%
1
   1.2%
2
   1.1%
White
11
  91.7%
76
  90.5%
72
  88.9%
159
  89.8%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Unknown or Not Reported
1
   8.3%
1
   1.2%
4
   4.9%
6
   3.4%
1.Primary Outcome
Title Number of Participants With Treatment-Emergent Adverse Events (TEAEs; All Causalities) at Phase 1
Hide Description An adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly.
Time Frame Maximum treatment duration (approximately 55 months)
Hide Outcome Measure Data
Hide Analysis Population Description
Safety analysis set included all participants who received at least 1 dose of any agent of the combination.
Arm/Group Title Phase 1 (Palbociclib + Letrozole)
Hide Arm/Group Description:
In Cycle 1 (3 weeks), participants received single agent palbociclib 125 mg/d orally for 2 weeks followed by 1 week off treatment. In Cycles 2 and beyond (4 weeks each), participants received letrozole 2.5 mg/d in a continuous regimen plus Palbociclib 125 mg/d orally for 3 weeks followed by 1 week off treatment.
Overall Number of Participants Analyzed 12
Measure Type: Number
Unit of Measure: Participants
Participants with AEs 12
Participants with SAEs 2
Participants with Grade 3 or 4 AEs 11
Participants with Grade 5 AEs 0
2.Primary Outcome
Title Number of Participants With Treatment-Related Adverse Events at Phase 1
Hide Description An AE was any untoward medical occurrence attributed to study drug in a participant who received study drug. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly.
Time Frame Maximum treatment duration (approximately 55 months)
Hide Outcome Measure Data
Hide Analysis Population Description
Safety analysis set included all participants who received at least 1 dose of any agent of the combination.
Arm/Group Title Phase 1 (Palbociclib + Letrozole)
Hide Arm/Group Description:
In Cycle 1 (3 weeks), participants received single agent palbociclib 125 mg/d orally for 2 weeks followed by 1 week off treatment. In Cycles 2 and beyond (4 weeks each), participants received letrozole 2.5 mg/d in a continuous regimen plus Palbociclib 125 mg/d orally for 3 weeks followed by 1 week off treatment.
Overall Number of Participants Analyzed 12
Measure Type: Number
Unit of Measure: Participants
Participants with AEs 12
Participants with SAEs 0
Participants with Grade 3 or 4 AEs 11
Participants with Grade 5 AEs 0
3.Primary Outcome
Title Number of Participants With Dose Limiting Toxicities at Phase 1
Hide Description Dose limiting toxicity was defined as any of the following TEAEs occurring during the second cycle of treatment and possibly attributable to the combination of letrozole plus Palbociclib: 1. Grade 4 hematologic toxicity (including platelets <25,000/μL, ANC <500/μL). 2. Grade 3 neutropenia associated with a documented infection or fever ≥38.5°C. 3. Grade ≥3 non-hematologic toxicities, except those that have not been maximally treated (eg, nausea, vomiting, diarrhea, hypertension). 4. Delay by ≥1 week in receiving the next scheduled dose of either study treatment due to persisting treatment-related toxicities (platelet count <50,000/μL; ANC <1,000/μL; nonhematologic toxicities of Grade ≥3 severity). 5. Inability to deliver at least 80% of the planned Palbociclib or letrozole doses during Cycle 2 due to toxicity possibly attributable to the study treatment.
Time Frame Cycle 2 (4 weeks)
Hide Outcome Measure Data
Hide Analysis Population Description
Safety analysis set included all participants who received at least 1 dose of any agent of the combination.
Arm/Group Title Phase 1 (Palbociclib + Letrozole)
Hide Arm/Group Description:
In Cycle 1 (3 weeks), participants received single agent palbociclib 125 mg/d orally for 2 weeks followed by 1 week off treatment. In Cycles 2 and beyond (4 weeks each), participants received letrozole 2.5 mg/d in a continuous regimen plus Palbociclib 125 mg/d orally for 3 weeks followed by 1 week off treatment.
Overall Number of Participants Analyzed 12
Measure Type: Number
Unit of Measure: Participants
Grade 4 Neutropenia 2
<80% of doses due to elevated creatinine 1
4.Primary Outcome
Title Progression-Free Survival (PFS) at Phase 2 - Investigator Assessment
Hide Description PFS was defined as the time from randomization (or the first dose of study treatment for non-randomized studies) to the first documentation of objective tumor progression or to death due to any cause, whichever occurred first. PFS calculated as (Weeks or Months) = (first event date minus randomization or the first dose date plus 1) divided by 7 (or 30.44 if in months). PFS is usually characterized by the median, 25% percentile,75% percentile and their 95% Confidence Intervals (CIs).
Time Frame From randomization date to date of first documentation of progression or death (assessed up to 41 months)
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-Treat (ITT) was used. This represented all randomized participants from Ph2P1 or Ph2P2 or Ph2P1+Ph2P2, where participants were classified according to the randomized treatment regardless of what treatment, if any, was received.
Arm/Group Title Phase 2 (Palbociclib + Letrozole) Phase 2 (Letrozole) Ph2P1 (Palbociclib + Letrozole) Ph2P1 (Letrozole) Ph2P2 (Palbociclib + Letrozole) Ph2P2 (Letrozole)
Hide Arm/Group Description:
All participants who were randomized to letrozole plus palbociclib in both Phase 2 part 1 (Ph2P1) and Phase 2 part 2 (Ph2P2) are combined and presented. In Ph2P1 and Ph2P2, the participants received palbociclib 125 mg/d orally for 3 weeks followed by 1 week off treatment and letrozole 2.5 mg/d orally in a continuous regimen.
All participants who were randomized to receive letrozole alone in both Phase 2 part 1 (Ph2P1) and Phase 2 part 2 (Ph2P2) are combined and presented. This was considered as control arm. Letrozole 2.5 mg/d was administered orally in a continuous regimen.
All participants were randomized to receive Letrozole plus Palbociclib. Palbociclib 125 mg/d orally for 3 weeks followed by 1 week off treatment and Letrozole 2.5 mg/d orally in a continuous regimen.
Participants were randomized to receive Letrozole alone. Letrozole 2.5 mg/d was administered orally in a continuous regimen. This was considered as control arm.
Participants were randomized to receive Letrozole plus Palbociclib. Palbociclib 125 mg/d orally for 3 weeks followed by 1 week off treatment and Letrozole 2.5 mg/d orally in a continuous regimen.
Participants were randomized to receive Letrozole. Letrozole 2.5 mg/d was administered orally in a continuous regimen. This was considered as control arm.
Overall Number of Participants Analyzed 84 81 34 32 50 49
Median (95% Confidence Interval)
Unit of Measure: Months
20.2
(13.8 to 27.5)
10.2
(5.7 to 12.6)
26.1 [1] 
(11.2 to NA)
5.7
(2.6 to 10.5)
18.1
(13.1 to 27.5)
11.1
(7.1 to 16.4)
[1]
Not reached
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Phase 2 (Palbociclib + Letrozole), Phase 2 (Letrozole)
Comments The primary hypothesis to be tested was H0: λ=1 versus. HA: λ<1, where λ was the palbociclib plus letrozole:letrozole alone hazard ratio (HR). A HR less than 1 indicates a reduction in hazard rate in favor of Palbociclib + Letrozole. Stratified analysis was presented above.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0004
Comments 1-sided p-value from the log-rank test stratified by stratification factors per randomization and Part.
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.488
Confidence Interval (2-Sided) 95%
0.319 to 0.748
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Ph2P1 (Palbociclib + Letrozole), Ph2P1 (Letrozole)
Comments The primary hypothesis to be tested was H0: λ=1 versus. HA: λ<1, where λ was the palbociclib plus letrozole:letrozole alone hazard ratio (HR). A HR less than 1 indicates a reduction in hazard rate in favor of Palbociclib + Letrozole. Unstratified analysis was presented above.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments 1-sided p-value from the log-rank test.
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.299
Confidence Interval (2-Sided) 95%
0.156 to 0.572
Estimation Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Ph2P2 (Palbociclib + Letrozole), Ph2P2 (Letrozole)
Comments The primary hypothesis to be tested was H0: λ=1 versus. HA: λ<1, where λ was the palbociclib plus letrozole:letrozole alone hazard ratio (HR). A HR less than 1 indicates a reduction in hazard rate in favor of Palbociclib + Letrozole. Unstratified analysis was presented above.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0046
Comments 1-sided p-value from the log-rank test.
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.508
Confidence Interval (2-Sided) 95%
0.303 to 0.853
Estimation Comments [Not Specified]
5.Secondary Outcome
Title Objective Response Rate - Percentage of Participants With Confirmed Objective Tumor Response at Phase 1
Hide Description Percentage of participants with objective response based assessment of confirmed complete response (CR) or confirmed partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST). Confirmed responses are those that persist on repeat imaging study at least 4 weeks after initial documentation of response. Per RECIST v1.0: CR defined as disappearance of all target lesions and non-target lesions. PR defined as ≥30% decrease in sum of the longest diameters (LD) of the target lesions taking as a reference the baseline sum LD according to RECIST associated to non-progressive disease response for non target lesions.
Time Frame From Baseline up to end of study (assessed up to 55 months)
Hide Outcome Measure Data
Hide Analysis Population Description
Efficacy analysis set included all enrolled participants with the disease under study, adequate baseline disease assessment, and who started study treatment.
Arm/Group Title Phase 1 (Palbociclib + Letrozole)
Hide Arm/Group Description:
In Cycle 1 (3 weeks), participants received single agent palbociclib 125 mg/d orally for 2 weeks followed by 1 week off treatment. In Cycles 2 and beyond (4 weeks each), participants received letrozole 2.5 mg/d in a continuous regimen plus Palbociclib 125 mg/d orally for 3 weeks followed by 1 week off treatment.
Overall Number of Participants Analyzed 12
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of participants
33.3
(9.9 to 65.1)
6.Secondary Outcome
Title Percentage of Participants With Clinical Benefit Response (CBR) at Phase 1
Hide Description CBR is defined as a confirmed CR, confirmed PR, or stable disease (SD) for at least 24 weeks on study according to RECIST. Confirmed responses are those that persisted on repeat imaging >= 4 weeks after initial response.
Time Frame From Baseline up to end of study (assessed up to 55 months)
Hide Outcome Measure Data
Hide Analysis Population Description
Efficacy analysis set included all enrolled participants with the disease under study, adequate baseline disease assessment, and who started study treatment.
Arm/Group Title Phase 1 (Palbociclib + Letrozole)
Hide Arm/Group Description:
In Cycle 1 (3 weeks), participants received single agent palbociclib 125 mg/d orally for 2 weeks followed by 1 week off treatment. In Cycles 2 and beyond (4 weeks each), participants received letrozole 2.5 mg/d in a continuous regimen plus Palbociclib 125 mg/d orally for 3 weeks followed by 1 week off treatment.
Overall Number of Participants Analyzed 12
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of participants
83.3
(51.6 to 97.9)
7.Secondary Outcome
Title Summary of Plasma Palbociclib Steady-state Pharmacokinetic Parameter Following Palbociclib Alone and in Combination With Letrozole: Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours (AUC24) at Phase 1
Hide Description On Cycle 1 Day 14, plasma pharmacokinetic samples were collected prior to and 1, 2, 4, 8, 12, 24, 48, 96 and 120 hours after Palbociclib dosing. On Cycle 2 Day 14, plasma pharmacokinetic samples for Palbociclib and letrozole were collected prior to and 1, 2, 4, 8, 12 and 24 hours after Palbociclib and letrozole dosing.
Time Frame Cycle 1 Day 14, and Cycle 2 Day 14
Hide Outcome Measure Data
Hide Analysis Population Description
The pharmacokinetic concentration set included all participants who were treated and had at least 1 concentration measurement in at least 1 pharmacokinetic assessment day. The pharmacokinetic parameter analysis set consisted of all participants treated who had at least 1 of the pharmacokinetic parameters of primary interest.
Arm/Group Title Palbociclib Alone (Cycle 1 Day 14) Palbociclib + Letrozole (Cycle 2 Day 14)
Hide Arm/Group Description:
In Cycle 1 (3 weeks), participants received single agent palbociclib 125 mg/d orally for 2 weeks followed by 1 week off treatment.
In Cycles 2 and beyond (4 weeks each), participants received letrozole 2.5 mg/d in a continuous regimen plus palbociclib 125 mg/d orally for 3 weeks followed by 1 week off treatment.
Overall Number of Participants Analyzed 12 12
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng·hr/mL
1982
(29%)
1933
(31%)
8.Secondary Outcome
Title Summary of Plasma Palbociclib Steady-state Pharmacokinetic Parameter Following Palbociclib Alone and in Combination With Letrozole: Maximum Observed Plasma Concentration (Cmax) at Phase 1
Hide Description On Cycle 1 Day 14, plasma pharmacokinetic samples were collected prior to and 1, 2, 4, 8, 12, 24, 48, 96 and 120 hours after Palbociclib dosing. On Cycle 2 Day 14, plasma pharmacokinetic samples for Palbociclib and letrozole were collected prior to and 1, 2, 4, 8, 12 and 24 hours after Palbociclib and letrozole dosing.
Time Frame Cycle 1 Day 14, and Cycle 2 Day 14
Hide Outcome Measure Data
Hide Analysis Population Description
The pharmacokinetic concentration set included all participants who were treated and had at least 1 concentration measurement in at least 1 pharmacokinetic assessment day. The pharmacokinetic parameter analysis set consisted of all participants treated who had at least 1 of the pharmacokinetic parameters of primary interest.
Arm/Group Title Palbociclib Alone (Cycle 1 Day 14) Palbociclib + Letrozole (Cycle 2 Day 14)
Hide Arm/Group Description:
In Cycle 1 (3 weeks), participants received single agent palbociclib 125 mg/d orally for 2 weeks followed by 1 week off treatment.
In Cycles 2 and beyond (4 weeks each), participants received letrozole 2.5 mg/d in a continuous regimen plus palbociclib 125 mg/d orally for 3 weeks followed by 1 week off treatment.
Overall Number of Participants Analyzed 12 12
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng/mL
115.8
(28%)
108.4
(29%)
9.Secondary Outcome
Title Summary of Plasma Palbociclib Steady-state Pharmacokinetic Parameter Following Palbociclib Alone and in Combination With Letrozole: Time to Maximum Plasma Concentration (Tmax) at Phase 1
Hide Description On Cycle 1 Day 14, plasma pharmacokinetic samples were collected prior to and 1, 2, 4, 8, 12, 24, 48, 96 and 120 hours after Palbociclib dosing. On Cycle 2 Day 14, plasma pharmacokinetic samples for Palbociclib and letrozole were collected prior to and 1, 2, 4, 8, 12 and 24 hours after Palbociclib and letrozole dosing.
Time Frame Cycle 1 Day 14, and Cycle 2 Day 14
Hide Outcome Measure Data
Hide Analysis Population Description
The pharmacokinetic concentration set included all participants who were treated and had at least 1 concentration measurement in at least 1 pharmacokinetic assessment day. The pharmacokinetic parameter analysis set consisted of all participants treated who had at least 1 of the pharmacokinetic parameters of primary interest.
Arm/Group Title Palbociclib Alone (Cycle 1 Day 14) Palbociclib + Letrozole (Cycle 2 Day 14)
Hide Arm/Group Description:
In Cycle 1 (3 weeks), participants received single agent palbociclib 125 mg/d orally for 2 weeks followed by 1 week off treatment.
In Cycles 2 and beyond (4 weeks each), participants received letrozole 2.5 mg/d in a continuous regimen plus palbociclib 125 mg/d orally for 3 weeks followed by 1 week off treatment.
Overall Number of Participants Analyzed 12 12
Median (Full Range)
Unit of Measure: Hour
7.92
(2.17 to 8.20)
7.92
(2.00 to 8.08)
10.Secondary Outcome
Title Summary of Plasma Palbociclib Steady-state Pharmacokinetic Parameter Following Palbociclib Alone and in Combination With Letrozole: Terminal Plasma Half-life (t1/2) at Phase 1
Hide Description On Cycle 1 Day 14, plasma pharmacokinetic samples were collected prior to and 1, 2, 4, 8, 12, 24, 48, 96 and 120 hours after Palbociclib dosing. On Cycle 2 Day 14, plasma pharmacokinetic samples for Palbociclib and letrozole were collected prior to and 1, 2, 4, 8, 12 and 24 hours after Palbociclib and letrozole dosing.
Time Frame Cycle 1 Day 14, and Cycle 2 Day 14
Hide Outcome Measure Data
Hide Analysis Population Description
The pharmacokinetic concentration set included all participants who were treated and had at least 1 concentration measurement in at least 1 pharmacokinetic assessment day. The pharmacokinetic parameter analysis set consisted of all participants treated who had at least 1 of the pharmacokinetic parameters of primary interest.
Arm/Group Title Palbociclib Alone (Cycle 1 Day 14) Palbociclib + Letrozole (Cycle 2 Day 14)
Hide Arm/Group Description:
In Cycle 1 (3 weeks), participants received single agent palbociclib 125 mg/d orally for 2 weeks followed by 1 week off treatment.
In Cycles 2 and beyond (4 weeks each), participants received letrozole 2.5 mg/d in a continuous regimen plus palbociclib 125 mg/d orally for 3 weeks followed by 1 week off treatment.
Overall Number of Participants Analyzed 12 12
Mean (Standard Deviation)
Unit of Measure: Hour
28.81  (5.0462) NA [1]   (NA)
[1]
Not calculated
11.Secondary Outcome
Title Summary of Plasma Palbociclib Steady-state Pharmacokinetic Parameter Following Palbociclib Alone and in Combination With Letrozole: Apparent Clearance (CL/F) at Phase 1
Hide Description On Cycle 1 Day 14, plasma pharmacokinetic samples were collected prior to and 1, 2, 4, 8, 12, 24, 48, 96 and 120 hours after Palbociclib dosing. On Cycle 2 Day 14, plasma pharmacokinetic samples for Palbociclib and letrozole were collected prior to and 1, 2, 4, 8, 12 and 24 hours after Palbociclib and letrozole dosing.
Time Frame Cycle 1 Day 14, and Cycle 2 Day 14
Hide Outcome Measure Data
Hide Analysis Population Description
The pharmacokinetic concentration set included all participants who were treated and had at least 1 concentration measurement in at least 1 pharmacokinetic assessment day. The pharmacokinetic parameter analysis set consisted of all participants treated who had at least 1 of the pharmacokinetic parameters of primary interest.
Arm/Group Title Palbociclib Alone (Cycle 1 Day 14) Palbociclib + Letrozole (Cycle 2 Day 14)
Hide Arm/Group Description:
In Cycle 1 (3 weeks), participants received single agent palbociclib 125 mg/d orally for 2 weeks followed by 1 week off treatment.
In Cycles 2 and beyond (4 weeks each), participants received letrozole 2.5 mg/d in a continuous regimen plus palbociclib 125 mg/d orally for 3 weeks followed by 1 week off treatment.
Overall Number of Participants Analyzed 12 12
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: L/hr
63.08
(2.17% to 8.20%)
NA [1] 
(2.00% to 8.08%)
[1]
Not calculated
12.Secondary Outcome
Title Summary of Plasma Palbociclib Steady-state Pharmacokinetic Parameter Following Palbociclib Alone and in Combination With Letrozole: Apparent Volume of Distribution (Vz/F) at Phase 1
Hide Description On Cycle 1 Day 14, plasma pharmacokinetic samples were collected prior to and 1, 2, 4, 8, 12, 24, 48, 96 and 120 hours after Palbociclib dosing. On Cycle 2 Day 14, plasma pharmacokinetic samples for Palbociclib and letrozole were collected prior to and 1, 2, 4, 8, 12 and 24 hours after Palbociclib and letrozole dosing.
Time Frame Cycle 1 Day 14, and Cycle 2 Day 14
Hide Outcome Measure Data
Hide Analysis Population Description
The pharmacokinetic concentration set included all participants who were treated and had at least 1 concentration measurement in at least 1 pharmacokinetic assessment day. The pharmacokinetic parameter analysis set consisted of all participants treated who had at least 1 of the pharmacokinetic parameters of primary interest.
Arm/Group Title Palbociclib Alone (Cycle 1 Day 14) Palbociclib + Letrozole (Cycle 2 Day 14)
Hide Arm/Group Description:
In Cycle 1 (3 weeks), participants received single agent palbociclib 125 mg/d orally for 2 weeks followed by 1 week off treatment.
In Cycles 2 and beyond (4 weeks each), participants received letrozole 2.5 mg/d in a continuous regimen plus palbociclib 125 mg/d orally for 3 weeks followed by 1 week off treatment.
Overall Number of Participants Analyzed 12 12
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: L
2583
(2.17% to 8.20%)
NA [1] 
(2.00% to 8.08%)
[1]
Not calculated
13.Secondary Outcome
Title Summary of Plasma Letrozole Pharmacokinetic Parameter Following Letrozole Alone and in Combination With Palbociclib: AUC24 at Phase 1
Hide Description On Cycle 2 Day 14, plasma pharmacokinetic samples for Palbociclib and letrozole were collected prior to and 1, 2, 4, 8, 12 and 24 hours after Palbociclib and letrozole dosing. On Cycle 2 Day 28, plasma pharmacokinetic samples were collected prior to and 1, 2, 4, 8, 12, and 24 hours after letrozole dosing.
Time Frame Cycle 2 Day 14, Cycle 2 Day 28
Hide Outcome Measure Data
Hide Analysis Population Description
The pharmacokinetic concentration set included all participants who were treated and had at least 1 concentration measurement in at least 1 pharmacokinetic assessment day. The pharmacokinetic parameter analysis set consisted of all participants treated who had at least 1 of the pharmacokinetic parameters of primary interest.
Arm/Group Title Palbociclib + Letrozole (Cycle 2 Day 14) Letrozole Alone (Cycle 2 Day 28)
Hide Arm/Group Description:
Participants received 125 mg oral doses of palbociclib with daily 2.5 mg doses of letrozole.
Participants received daily 2.5 mg doses of letrozole alone.
Overall Number of Participants Analyzed 12 12
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng·hr/mL
1739
(2.17% to 8.20%)
1936
(2.00% to 8.08%)
14.Secondary Outcome
Title Summary of Plasma Letrozole Pharmacokinetic Parameter Following Letrozole Alone and in Combination With Palbociclib: Cmax at Phase 1
Hide Description On Cycle 2 Day 14, plasma pharmacokinetic samples for Palbociclib and letrozole were collected prior to and 1, 2, 4, 8, 12 and 24 hours after Palbociclib and letrozole dosing. On Cycle 2 Day 28, plasma pharmacokinetic samples were collected prior to and 1, 2, 4, 8, 12, and 24 hours after letrozole dosing.
Time Frame Cycle 2 Day 14, and Cycle 2 Day 28
Hide Outcome Measure Data
Hide Analysis Population Description
The pharmacokinetic concentration set included all participants who were treated and had at least 1 concentration measurement in at least 1 pharmacokinetic assessment day. The pharmacokinetic parameter analysis set consisted of all participants treated who had at least 1 of the pharmacokinetic parameters of primary interest.
Arm/Group Title Palbociclib + Letrozole (Cycle 2 Day 14) Letrozole Alone (Cycle 2 Day 28)
Hide Arm/Group Description:
Participants received 125 mg oral doses of palbociclib with daily 2.5 mg doses of letrozole.
Participants received daily 2.5 mg doses of letrozole alone.
Overall Number of Participants Analyzed 12 12
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng/mL
94.95
(2.17% to 8.20%)
104.0
(2.00% to 8.08%)
15.Secondary Outcome
Title Summary of Plasma Letrozole Pharmacokinetic Parameter Following Letrozole Alone and in Combination With Palbociclib: Tmax at Phase 1
Hide Description On Cycle 2 Day 14, plasma pharmacokinetic samples for Palbociclib and letrozole were collected prior to and 1, 2, 4, 8, 12 and 24 hours after Palbociclib and letrozole dosing. On Cycle 2 Day 28, plasma pharmacokinetic samples were collected prior to and 1, 2, 4, 8, 12, and 24 hours after letrozole dosing.
Time Frame Cycle 2 Day 14, and Cycle 2 Day 28
Hide Outcome Measure Data
Hide Analysis Population Description
The pharmacokinetic concentration set included all participants who were treated and had at least 1 concentration measurement in at least 1 pharmacokinetic assessment day. The pharmacokinetic parameter analysis set consisted of all participants treated who had at least 1 of the pharmacokinetic parameters of primary interest.
Arm/Group Title Palbociclib + Letrozole (Cycle 2 Day 14) Letrozole Alone (Cycle 2 Day 28)
Hide Arm/Group Description:
Participants received 125 mg oral doses of palbociclib with daily 2.5 mg doses of letrozole.
Participants received daily 2.5 mg doses of letrozole alone.
Overall Number of Participants Analyzed 12 12
Median (Full Range)
Unit of Measure: Hour
2.00
(0.833 to 4.13)
1.04
(0.00 to 4.42)
16.Secondary Outcome
Title Number of Participants With Increase From Baseline in Corrected QT (QTc) Interval at Phase 1
Hide Description Triplicate 12-lead ECG measurements (each recording separated by approximately 2 minutes) were performed and average was calculated. The time corresponding to beginning of depolarization to repolarization of the ventricles (QT interval) was adjusted for RR interval using QT and RR from each ECG by Fridericia’s formula (QTcF = QT divided by cube root of RR), by Bazette’s formula (QTcB = QT divided by square root of RR) and corrected QT interval according to study-specific criteria (QTcS). Participants with maximum increase from baseline of 30 to less than (<) 60 msec(borderline) and greater than or equal to (>=) 60 msec (prolonged) were summarized.
Time Frame Cycle 1 Day 1 prior to dosing, Cycle 1 Day 14 (2, 4 [prior to meal], 8, 24, 48, and 96 hours after dosing of Palbociclib), Cycle 2 Day 1 and Day 14 (prior to and 4 hours after dosing of letrozole)
Hide Outcome Measure Data
Hide Analysis Population Description
Safety analysis set included all participants who received at least 1 dose of any agent of the combination.
Arm/Group Title Phase 1 (Palbociclib + Letrozole)
Hide Arm/Group Description:
In Cycle 1 (3 weeks), participants received single agent palbociclib 125 mg/d orally for 2 weeks followed by 1 week off treatment. In Cycles 2 and beyond (4 weeks each), participants received letrozole 2.5 mg/d in a continuous regimen plus Palbociclib 125 mg/d orally for 3 weeks followed by 1 week off treatment.
Overall Number of Participants Analyzed 12
Measure Type: Number
Unit of Measure: Participants
QTcB - Change <30 9
QTcB - 30 ≤ change <60 3
QTcB - Change ≥60 0
QTcF - Change <30 11
QTcF - 30 ≤ change <60 1
QTcF - Change ≥60 0
QTcS - Change <30 8
QTcS - 30 ≤ change <60 4
QTcS - Change ≥60 0
17.Secondary Outcome
Title Overall Survival (OS) at Phase 2
Hide Description Time in weeks or months from randomization to date of death due to any cause. OS was calculated as (the death date or last known alive date (if death date unavailable) minus the date of randomization plus 1) divided by 7 or 30.44 if in months.
Time Frame From randomization until death (assessed up to 86 months)
Hide Outcome Measure Data
Hide Analysis Population Description
ITT was used. This represented all randomized participants from Ph2P1or Ph2P2 or Ph2P1+Ph2P2, where participants were classified according to the randomized treatment regardless of what treatment, if any, was received.
Arm/Group Title Phase 2 (Palbociclib + Letrozole) Phase 2 (Letrozole) Ph2P1 (Palbociclib + Letrozole) Ph2P1 (Letrozole) Ph2P2 (Palbociclib + Letrozole) Ph2P2 (Letrozole)
Hide Arm/Group Description:
All participants who were randomized to letrozole plus palbociclib in both Phase 2 part 1 (Ph2P1) and Phase 2 part 2 (Ph2P2) are combined and presented. In Ph2P1 and Ph2P2, the participants received palbociclib 125 mg/d orally for 3 weeks followed by 1 week off treatment and letrozole 2.5 mg/d orally in a continuous regimen.
All participants who were randomized to receive letrozole alone in both Phase 2 part 1 (Ph2P1) and Phase 2 part 2 (Ph2P2) are combined and presented. This was considered as control arm. Letrozole 2.5 mg/d was administered orally in a continuous regimen.
All participants were randomized to receive Letrozole plus Palbociclib. Palbociclib 125 mg/d orally for 3 weeks followed by 1 week off treatment and Letrozole 2.5 mg/d orally in a continuous regimen.
Participants were randomized to receive Letrozole alone. Letrozole 2.5 mg/d was administered orally in a continuous regimen. This was considered as control arm.
Participants were randomized to receive Letrozole plus Palbociclib. Palbociclib 125 mg/d orally for 3 weeks followed by 1 week off treatment and Letrozole 2.5 mg/d orally in a continuous regimen.
Participants were randomized to receive Letrozole. Letrozole 2.5 mg/d was administered orally in a continuous regimen. This was considered as control arm.
Overall Number of Participants Analyzed 84 81 34 32 50 49
Median (95% Confidence Interval)
Unit of Measure: Months
37.5
(31.4 to 47.8)
34.5
(27.4 to 42.6)
37.5
(27.6 to 58.8)
33.3
(26.0 to 54.3)
35.1
(28.1 to 47.8)
35.7
(26.6 to 46.7)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Phase 2 (Palbociclib + Letrozole), Phase 2 (Letrozole)
Comments Stratified analysis was presented above. Hazard ratio was assuming proportional hazards, a hazard ratio less than 1 indicated a reduction in hazard rate in favor of palbociclib + letrozole.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2812
Comments 1-sided p-value from the log-rank test stratified by Part (α = 0.10).
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.897
Confidence Interval (2-Sided) 95%
0.623 to 1.294
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Ph2P1 (Palbociclib + Letrozole), Ph2P1 (Letrozole)
Comments Unstratified analysis was presented above.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2803
Comments 1-sided p-value from the unstratified log-rank test (α=0.10).
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.837
Confidence Interval (2-Sided) 95%
0.458 to 1.527
Estimation Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Ph2P2 (Palbociclib + Letrozole), Ph2P2 (Letrozole)
Comments Unstratified analysis was presented above.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.3875
Comments 1-sided p-value from the unstratified log-rank test (α=0.10).
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.935
Confidence Interval (2-Sided) 95%
0.590 to 1.480
Estimation Comments [Not Specified]
18.Secondary Outcome
Title Objective Response Rate - Percentage of Participants With Confirmed Objective Response at Phase 2- Investigator Assessment
Hide Description Percentage of participants with objective response based assessment of confirmed CR or confirmed PR according to RECIST. Confirmed responses are those that persist on repeat imaging study at least 4 weeks after initial documentation of response. Per RECIST v1.0: CR defined as disappearance of all target lesions and non-target lesions. PR defined as ≥30% decrease in sum of the longest diameters (LD) of the target lesions taking as a reference the baseline sum LD according to RECIST associated to non-progressive disease response for non target lesions.
Time Frame From randomization up to the end of treatment (approximately 41 months)
Hide Outcome Measure Data
Hide Analysis Population Description
ITT was used. This represented all randomized participants from Ph2P1or Ph2P2 or Ph2P1+Ph2P2, where participants were classified according to the randomized treatment regardless of what treatment, if any, was received.
Arm/Group Title Phase 2 (Palbociclib + Letrozole) Phase 2 (Letrozole) Ph2P1 (Palbociclib + Letrozole) Ph2P1 (Letrozole) Ph2P2 (Palbociclib + Letrozole) Ph2P2 (Letrozole)
Hide Arm/Group Description:
All participants who were randomized to letrozole plus palbociclib in both Phase 2 part 1 (Ph2P1) and Phase 2 part 2 (Ph2P2) are combined and presented. In Ph2P1 and Ph2P2, the participants received palbociclib 125 mg/d orally for 3 weeks followed by 1 week off treatment and letrozole 2.5 mg/d orally in a continuous regimen.
All participants who were randomized to receive letrozole alone in both Phase 2 part 1 (Ph2P1) and Phase 2 part 2 (Ph2P2) are combined and presented. This was considered as control arm. Letrozole 2.5 mg/d was administered orally in a continuous regimen.
All participants were randomized to receive Letrozole plus Palbociclib. Palbociclib 125 mg/d orally for 3 weeks followed by 1 week off treatment and Letrozole 2.5 mg/d orally in a continuous regimen.
Participants were randomized to receive Letrozole alone. Letrozole 2.5 mg/d was administered orally in a continuous regimen. This was considered as control arm.
Participants were randomized to receive Letrozole plus Palbociclib. Palbociclib 125 mg/d orally for 3 weeks followed by 1 week off treatment and Letrozole 2.5 mg/d orally in a continuous regimen.
Participants were randomized to receive Letrozole. Letrozole 2.5 mg/d was administered orally in a continuous regimen. This was considered as control arm.
Overall Number of Participants Analyzed 84 81 34 32 50 49
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of participants
42.9
(32.1 to 54.1)
33.3
(23.2 to 44.7)
44.1
(27.2 to 62.1)
25.0
(11.5 to 43.4)
42.0
(28.2 to 56.8)
38.8
(25.2 to 53.8)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Phase 2 (Palbociclib + Letrozole), Phase 2 (Letrozole)
Comments Objective Response CI was calculated using the exact Clopper-Pearson method. The stratified analysis presented above was based on CMH test stratified by Part. An Odds Ratio >1 means better response in favor of palbociclib + letrozole arm.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1347
Comments 1-sided p-value is from the stratified exact test (1-sided, α =0.10)
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 1.50
Confidence Interval (2-Sided) 95%
0.76 to 2.97
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Ph2P1 (Palbociclib + Letrozole), Ph2P1 (Letrozole)
Comments Unstratified analysis was presented above. Exact CI was based on Clopper-Pearson method.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0849
Comments Chi-square test was used (1-sided, α=0.10)
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 2.37
Confidence Interval (2-Sided) 95%
0.74 to 7.84
Estimation Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Ph2P2 (Palbociclib + Letrozole), Ph2P2 (Letrozole)
Comments Unstratified analysis was presented above. Exact CI was based on Clopper-Pearson method.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.4515
Comments Chi-square test was used (1-sided, α=0.10)
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 1.14
Confidence Interval (2-Sided) 95%
0.48 to 2.76
Estimation Comments [Not Specified]
19.Secondary Outcome
Title Objective Response Rate - Percentage of Participants With Confirmed Objective Response in Participants With Measurable Disease at Phase 2- Investigator Assessment
Hide Description Percentage of participants with objective response based assessment of confirmed CR or PR according to RECIST. Confirmed responses are those that persist on repeat imaging study at least 4 weeks after initial documentation of response. Per RECIST v1.0: CR defined as disappearance of all target lesions and non-target lesions. PR defined as ≥30% decrease in sum of the LD of the target lesions taking as a reference the baseline sum LD according to RECIST associated to non-progressive disease response for non target lesions. Measurable disease referred to the lesions that was accurately measured in at least 1 dimension (longest diameter to be recorded) as ≥20 mm with conventional techniques or as ≥10-16 mm with spiral computer tomography scan (depending on reconstruction interval). Clinical lesions were only be considered measurable when they were superficial (eg, skin nodules, palpable lymph nodes).
Time Frame From randomization up to the end of treatment (approximately 41 months)
Hide Outcome Measure Data
Hide Analysis Population Description
Participants in ITT population with measurable disease were used.
Arm/Group Title Phase 2 (Palbociclib + Letrozole) Phase 2 (Letrozole) Ph2P1 (Palbociclib + Letrozole) Ph2P1 (Letrozole) Ph2P2 (Palbociclib + Letrozole) Ph2P2 (Letrozole)
Hide Arm/Group Description:
All participants who were randomized to letrozole plus palbociclib in both Phase 2 part 1 (Ph2P1) and Phase 2 part 2 (Ph2P2) are combined and presented. In Ph2P1 and Ph2P2, the participants received palbociclib 125 mg/d orally for 3 weeks followed by 1 week off treatment and letrozole 2.5 mg/d orally in a continuous regimen.
All participants who were randomized to receive letrozole alone in both Phase 2 part 1 (Ph2P1) and Phase 2 part 2 (Ph2P2) are combined and presented. This was considered as control arm. Letrozole 2.5 mg/d was administered orally in a continuous regimen.
All participants were randomized to receive Letrozole plus Palbociclib. Palbociclib 125 mg/d orally for 3 weeks followed by 1 week off treatment and Letrozole 2.5 mg/d orally in a continuous regimen.
Participants were randomized to receive Letrozole alone. Letrozole 2.5 mg/d was administered orally in a continuous regimen. This was considered as control arm.
Participants were randomized to receive Letrozole plus Palbociclib. Palbociclib 125 mg/d orally for 3 weeks followed by 1 week off treatment and Letrozole 2.5 mg/d orally in a continuous regimen.
Participants were randomized to receive Letrozole. Letrozole 2.5 mg/d was administered orally in a continuous regimen. This was considered as control arm.
Overall Number of Participants Analyzed 65 66 27 23 21 43
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of participants
55.4
(42.5 to 67.7)
39.4
(27.6 to 52.2)
55.6
(35.3 to 74.5)
34.8
(16.4 to 57.3)
55.3
(38.3 to 71.4)
41.9
(27.0 to 57.9)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Phase 2 (Palbociclib + Letrozole), Phase 2 (Letrozole)
Comments Objective Response CI was calculated using the exact Clopper-Pearson method. The stratified analysis presented above was based on CMH test stratified by Part. An Odds Ratio >1 means better response in favor of palbociclib + letrozole arm.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0471
Comments 1-sided p-value is from the stratified exact test (1-sided, α =0.10)
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 1.93
Confidence Interval (2-Sided) 95%
0.91 to 4.08
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Ph2P1 (Palbociclib + Letrozole), Ph2P1 (Letrozole)
Comments Unstratified analysis was presented above. Exact CI was based on Clopper-Pearson method.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1180
Comments Chi-square test was used (1-sided, α=0.10)
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 2.34
Confidence Interval (2-Sided) 95%
0.65 to 8.66
Estimation Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Ph2P2 (Palbociclib + Letrozole), Ph2P2 (Letrozole)
Comments Unstratified analysis was presented above. Exact CI was based on Clopper-Pearson method.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1631
Comments Chi-square test was used (1-sided, α=0.10)
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 1.72
Confidence Interval (2-Sided) 95%
0.65 to 4.54
Estimation Comments [Not Specified]
20.Secondary Outcome
Title Duration of Response at Phase 2 - Investigator Assessment
Hide Description Time in weeks, (months or years) from randomization or (start of study treatment for non-randomized studies) to first documentation of objective tumor progression. TTP was calculated as (first event date or last known progression-free date minus the date of randomization [or first dose of study medication for non-randomized studies] plus 1) divided by 7 or 30.44 if in months. Tumor progression was determined from oncologic assessment data (where data meet the criteria for progressive disease [PD] per RECIST).
Time Frame From randomization up to the end of treatment (approximately 41 months)
Hide Outcome Measure Data
Hide Analysis Population Description
A subset of ITT population i.e., participants who had response was used for this analysis.
Arm/Group Title Phase 2 (Palbociclib + Letrozole) Phase 2 (Letrozole) Ph2P1 (Palbociclib + Letrozole) Ph2P1 (Letrozole) Ph2P2 (Palbociclib + Letrozole) Ph2P2 (Letrozole)
Hide Arm/Group Description:
All participants who were randomized to letrozole plus palbociclib in both Phase 2 part 1 (Ph2P1) and Phase 2 part 2 (Ph2P2) are combined and presented. In Ph2P1 and Ph2P2, the participants received palbociclib 125 mg/d orally for 3 weeks followed by 1 week off treatment and letrozole 2.5 mg/d orally in a continuous regimen.
All participants who were randomized to receive letrozole alone in both Phase 2 part 1 (Ph2P1) and Phase 2 part 2 (Ph2P2) are combined and presented. This was considered as control arm. Letrozole 2.5 mg/d was administered orally in a continuous regimen.
All participants were randomized to receive Letrozole plus Palbociclib. Palbociclib 125 mg/d orally for 3 weeks followed by 1 week off treatment and Letrozole 2.5 mg/d orally in a continuous regimen.
Participants were randomized to receive Letrozole alone. Letrozole 2.5 mg/d was administered orally in a continuous regimen. This was considered as control arm.
Participants were randomized to receive Letrozole plus Palbociclib. Palbociclib 125 mg/d orally for 3 weeks followed by 1 week off treatment and Letrozole 2.5 mg/d orally in a continuous regimen.
Participants were randomized to receive Letrozole. Letrozole 2.5 mg/d was administered orally in a continuous regimen. This was considered as control arm.
Overall Number of Participants Analyzed 36 27 15 8 21 19
Median (95% Confidence Interval)
Unit of Measure: Months
20.3
(13.4 to 25.8)
11.1
(9.3 to 31.6)
20.9
(6.2 to 25.8)
10.8
(3.7 to 31.6)
20.2 [1] 
(13.0 to NA)
14.8 [1] 
(7.4 to NA)
[1]
Not reached
21.Secondary Outcome
Title Number of Participants With CBR at Phase 2 - Investigator Assessment
Hide Description CBR is defined as a confirmed complete response (CR), confirmed partial response (PR), or stable disease (SD) for at least 24 weeks on study according to RECIST.
Time Frame From randomization up to the end of treatment (approximately 41 months)
Hide Outcome Measure Data
Hide Analysis Population Description
ITT was used. This represented all randomized patients from Ph2P1or Ph2P2 or Ph2P1+Ph2P2, where participants were classified according to the randomized treatment regardless of what treatment, if any, was received.
Arm/Group Title Phase 2 (Palbociclib + Letrozole) Phase 2 (Letrozole) Ph2P1 (Palbociclib + Letrozole) Ph2P1 (Letrozole) Ph2P2 (Palbociclib + Letrozole) Ph2P2 (Letrozole)
Hide Arm/Group Description:
All participants who were randomized to letrozole plus palbociclib in both Phase 2 part 1 (Ph2P1) and Phase 2 part 2 (Ph2P2) are combined and presented. In Ph2P1 and Ph2P2, the participants received palbociclib 125 mg/d orally for 3 weeks followed by 1 week off treatment and letrozole 2.5 mg/d orally in a continuous regimen.
All participants who were randomized to receive letrozole alone in both Phase 2 part 1 (Ph2P1) and Phase 2 part 2 (Ph2P2) are combined and presented. This was considered as control arm. Letrozole 2.5 mg/d was administered orally in a continuous regimen.
All participants were randomized to receive Letrozole plus Palbociclib. Palbociclib 125 mg/d orally for 3 weeks followed by 1 week off treatment and Letrozole 2.5 mg/d orally in a continuous regimen.
Participants were randomized to receive Letrozole alone. Letrozole 2.5 mg/d was administered orally in a continuous regimen. This was considered as control arm.
Participants were randomized to receive Letrozole plus Palbociclib. Palbociclib 125 mg/d orally for 3 weeks followed by 1 week off treatment and Letrozole 2.5 mg/d orally in a continuous regimen.
Participants were randomized to receive Letrozole. Letrozole 2.5 mg/d was administered orally in a continuous regimen. This was considered as control arm.
Overall Number of Participants Analyzed 84 81 34 32 50 49
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of participants
81.0
(70.9 to 88.7)
58.0
(46.5 to 68.9)
76.5
(58.8 to 89.3)
43.8
(26.4 to 62.3)
84.0
(70.9 to 92.8)
67.3
(52.5 to 80.1)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Phase 2 (Palbociclib + Letrozole), Phase 2 (Letrozole)
Comments CBR CI was calculated using the exact Clopper-Pearson method. The stratified analysis presented above was based on CMH test stratified by Part. An Odds Ratio >1 means better response in favor of palbociclib + letrozole arm.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0009
Comments 1-sided p-value is from the stratified exact test (1-sided, α =0.10).
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 3.18
Confidence Interval (2-Sided) 95%
1.48 to 6.98
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Ph2P1 (Palbociclib + Letrozole), Ph2P1 (Letrozole)
Comments Unstratified analysis was presented above. Exact CI was based on Clopper-Pearson method.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0065
Comments Chi-square test was used (1-sided, α=0.10)
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 4.18
Confidence Interval (2-Sided) 95%
1.30 to 13.90
Estimation Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Ph2P2 (Palbociclib + Letrozole), Ph2P2 (Letrozole)
Comments Unstratified analysis was presented above. Exact CI was based on Clopper-Pearson method.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0442
Comments Chi-square test was used (1-sided, α=0.10)
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 2.55
Confidence Interval (2-Sided) 95%
0.89 to 7.70
Estimation Comments [Not Specified]
22.Secondary Outcome
Title Time to Tumor Progression (TTP) at Phase 2-Investigator Assessment
Hide Description Time in weeks, (months or years) from randomization or (start of study treatment for non-randomized studies) to first documentation of objective tumor progression. TTP was calculated as (first event date or last known progression-free date minus the date of randomization [or first dose of study medication for non-randomized studies] plus 1) divided by 7 or 30.44 if in months. Tumor progression was determined from oncologic assessment data (where data meet the criteria for progressive disease [PD] per RECIST).
Time Frame From randomization up to the end of treatment (approximately 41 months)
Hide Outcome Measure Data
Hide Analysis Population Description
ITT was used. This represented all randomized participants from Ph2P1or Ph2P2 or Ph2P1+Ph2P2, where participants were classified according to the randomized treatment regardless of what treatment, if any, was received.
Arm/Group Title Phase 2 (Palbociclib + Letrozole) Phase 2 (Letrozole) Ph2P1 (Palbociclib + Letrozole) Ph2P1 (Letrozole) Ph2P2 (Palbociclib + Letrozole) Ph2P2 (Letrozole)
Hide Arm/Group Description:
All participants who were randomized to letrozole plus palbociclib in both Phase 2 part 1 (Ph2P1) and Phase 2 part 2 (Ph2P2) are combined and presented. In Ph2P1 and Ph2P2, the participants received palbociclib 125 mg/d orally for 3 weeks followed by 1 week off treatment and letrozole 2.5 mg/d orally in a continuous regimen.
All participants who were randomized to receive letrozole alone in both Phase 2 part 1 (Ph2P1) and Phase 2 part 2 (Ph2P2) are combined and presented. This was considered as control arm. Letrozole 2.5 mg/d was administered orally in a continuous regimen.
All participants were randomized to receive Letrozole plus Palbociclib. Palbociclib 125 mg/d orally for 3 weeks followed by 1 week off treatment and Letrozole 2.5 mg/d orally in a continuous regimen.
Participants were randomized to receive Letrozole alone. Letrozole 2.5 mg/d was administered orally in a continuous regimen. This was considered as control arm.
Participants were randomized to receive Letrozole plus Palbociclib. Palbociclib 125 mg/d orally for 3 weeks followed by 1 week off treatment and Letrozole 2.5 mg/d orally in a continuous regimen.
Participants were randomized to receive Letrozole. Letrozole 2.5 mg/d was administered orally in a continuous regimen. This was considered as control arm.
Overall Number of Participants Analyzed 84 81 34 32 50 49
Median (95% Confidence Interval)
Unit of Measure: Months
20.2
(13.8 to 27.5)
10.2
(5.7 to 12.6)
26.1 [1] 
(11.2 to NA)
5.7
(2.6 to 10.5)
18.8
(13.1 to 27.5)
11.1
(7.1 to 16.4)
[1]
Not reached
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Phase 2 (Palbociclib + Letrozole), Phase 2 (Letrozole)
Comments Kaplan-Meier method was applied for median and 95% CI. Hazard ratio was based on assuming proportional hazards, a hazard ratio less than 1 indicates a reduction in hazard rate in favor of palbociclib + letrozole.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments 1-sided p-value is from the stratified log-rank test (α =0.10).
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.399
Confidence Interval (2-Sided) 95%
0.265 to 0.601
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Ph2P1 (Palbociclib + Letrozole), Ph2P1 (Letrozole)
Comments Unstratified analysis was presented above. Kaplan-Meier method was applied for median and 95% CI.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments 1-sided p-value is from unstratified log-rank test (α=0.10).
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.299
Confidence Interval (2-Sided) 95%
0.156 to 0.572
Estimation Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Ph2P2 (Palbociclib + Letrozole), Ph2P2 (Letrozole)
Comments Unstratified analysis was presented above. Kaplan-Meier method was applied for median and 95% CI.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0030
Comments 1-sided p-value is from unstratified log-rank test (α=0.10).
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.486
Confidence Interval (2-Sided) 95%
0.288 to 0.822
Estimation Comments [Not Specified]
23.Secondary Outcome
Title Change From Baseline in Modified Brief Pain Inventory in Pain Severity Scale (mBPI-sf) Questionnaire at Phase 2
Hide Description The mBPI-sf is a validated and reliable self-report questionnaire which consists of 13 questions that assess the severity and impact of pain on daily function. The 13 items of the questionnaire make up two scales and two single items. The scales include the 4-item Pain Severity Scale (worst pain, least pain, average pain, and pain right now) and the 7-item Pain Interference Scale (general activity, mood, walking ability, normal work, relations with other people, sleep, and enjoyment of life). Each item of the pain severity and pain interference scales are based on a 11-point numeric rating scale from 0 (“no pain” or “does not interfere”) to 10 (“pain as bad as you can imagine” or “completely interferes”).
Time Frame Baseline, End of treatment (approximately 41 months)
Hide Outcome Measure Data
Hide Analysis Population Description
Patient reported outcome evaluable participants included participants who had received at least 1 dose of study medication, had baseline data, and at least one post-baseline measurement.
Arm/Group Title Phase 2 (Palbociclib + Letrozole) Phase 2 (Letrozole) Ph2P1 (Palbociclib + Letrozole) Ph2P1 (Letrozole) Ph2P2 (Palbociclib + Letrozole) Ph2P2 (Letrozole)
Hide Arm/Group Description:
All participants who were randomized to letrozole plus palbociclib in both Phase 2 part 1 (Ph2P1) and Phase 2 part 2 (Ph2P2) are combined and presented. In Ph2P1 and Ph2P2, the participants received palbociclib 125 mg/d orally for 3 weeks followed by 1 week off treatment and letrozole 2.5 mg/d orally in a continuous regimen.
All participants who were randomized to receive letrozole alone in both Phase 2 part 1 (Ph2P1) and Phase 2 part 2 (Ph2P2) are combined and presented. This was considered as control arm. Letrozole 2.5 mg/d was administered orally in a continuous regimen.
All participants were randomized to receive Letrozole plus Palbociclib. Palbociclib 125 mg/d orally for 3 weeks followed by 1 week off treatment and Letrozole 2.5 mg/d orally in a continuous regimen.
Participants were randomized to receive Letrozole alone. Letrozole 2.5 mg/d was administered orally in a continuous regimen. This was considered as control arm.
Participants were randomized to receive Letrozole plus Palbociclib. Palbociclib 125 mg/d orally for 3 weeks followed by 1 week off treatment and Letrozole 2.5 mg/d orally in a continuous regimen.
Participants were randomized to receive Letrozole. Letrozole 2.5 mg/d was administered orally in a continuous regimen. This was considered as control arm.
Overall Number of Participants Analyzed 76 74 29 27 47 47
Mean (Standard Error)
Unit of Measure: Units on a scale
Pain at its worst in the last 24 hours 0.6  (0.42) 0.1  (0.42) 0.2  (0.60) 0.0  (0.89) 1.2  (0.55) 0.1  (0.43)
Pain at its least in the last 24 hours 0.4  (0.27) 0.4  (0.27) 0.3  (0.31) 0.7  (0.50) 0.5  (0.40) 0.2  (0.31)
Pain on the average 0.2  (0.33) 0.2  (0.34) -0.1  (0.48) 0.2  (0.64) 0.4  (0.45) 0.3  (0.40)
Pain right now 0.3  (0.35) 0.1  (0.36) 0.1  (0.31) 0.3  (0.66) 0.3  (0.55) 0.0  (0.43)
Pain Severity Scale 0.4  (0.29) 0.2  (0.32) 0.0  (0.36) 0.3  (0.62) 0.6  (0.41) 0.1  (0.36)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Phase 2 (Palbociclib + Letrozole), Phase 2 (Letrozole)
Comments Statistical analysis presented above is for Pain Severity Scale.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.6900
Comments P-values are based on 2-sample t-test.
Method t-test, 2 sided
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.2
Confidence Interval (2-Sided) 95%
-0.7 to 1.0
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Ph2P1 (Palbociclib + Letrozole), Ph2P1 (Letrozole)
Comments Statistical analysis presented above is for Pain Severity Scale.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.7125
Comments P-values are based on 2-sample t-test.
Method t-test, 2 sided
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.3
Confidence Interval (2-Sided) 95%
-1.8 to 1.2
Estimation Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Ph2P2 (Palbociclib + Letrozole), Ph2P2 (Letrozole)
Comments Statistical analysis presented above is for Pain Severity Scale.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.4012
Comments P-values are based on 2-sample t-test.
Method t-test, 2 sided
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.5
Confidence Interval (2-Sided) 95%
-0.6 to 1.5
Estimation Comments [Not Specified]
24.Secondary Outcome
Title Change From Baseline in Modified Brief Pain Inventory in Pain Interference Scale (mBPI-sf) Questionnaire at Phase 2
Hide Description The mBPI-sf is a validated and reliable self-report questionnaire which consists of 13 questions that assess the severity and impact of pain on daily function. The 13 items of the questionnaire make up two scales and two single items. The scales include the 4-item Pain Severity Scale (worst pain, least pain, average pain, and pain right now) and the 7-item Pain Interference Scale (general activity, mood, walking ability, normal work, relations with other people, sleep, and enjoyment of life). Each item of the pain severity and pain interference scales are based on a 11-point numeric rating scale from 0 (“no pain” or “does not interfere”) to 10 (“pain as bad as you can imagine” or “completely interferes”).
Time Frame Baseline, End of treatment (approximately 41 months)
Hide Outcome Measure Data
Hide Analysis Population Description
Patient reported outcome evaluable participants included participants who had received at least 1 dose of study medication, had baseline data, and at least one post-baseline measurement.
Arm/Group Title Phase 2 (Palbociclib + Letrozole) Phase 2 (Letrozole) Ph2P1 (Palbociclib + Letrozole) Ph2P1 (Letrozole) Ph2P2 (Palbociclib + Letrozole) Ph2P2 (Letrozole)
Hide Arm/Group Description:
All participants who were randomized to letrozole plus palbociclib in both Phase 2 part 1 (Ph2P1) and Phase 2 part 2 (Ph2P2) are combined and presented. In Ph2P1 and Ph2P2, the participants received palbociclib 125 mg/d orally for 3 weeks followed by 1 week off treatment and letrozole 2.5 mg/d orally in a continuous regimen.
All participants who were randomized to receive letrozole alone in both Phase 2 part 1 (Ph2P1) and Phase 2 part 2 (Ph2P2) are combined and presented. This was considered as control arm. Letrozole 2.5 mg/d was administered orally in a continuous regimen.
All participants were randomized to receive Letrozole plus Palbociclib. Palbociclib 125 mg/d orally for 3 weeks followed by 1 week off treatment and Letrozole 2.5 mg/d orally in a continuous regimen.
Participants were randomized to receive Letrozole alone. Letrozole 2.5 mg/d was administered orally in a continuous regimen. This was considered as control arm.
Participants were randomized to receive Letrozole plus Palbociclib. Palbociclib 125 mg/d orally for 3 weeks followed by 1 week off treatment and Letrozole 2.5 mg/d orally in a continuous regimen.
Participants were randomized to receive Letrozole. Letrozole 2.5 mg/d was administered orally in a continuous regimen. This was considered as control arm.
Overall Number of Participants Analyzed 76 74 29 27 47 47
Mean (Standard Error)
Unit of Measure: Units on a scale
General Activity 1.1  (0.40) 0.2  (0.31) 1.0  (0.66) 0.2  (0.58) 1.2  (0.51) 0.3  (0.37)
Mood 0.8  (0.50) 0.2  (0.36) 0.6  (0.72) -0.2  (0.62) 1.0  (0.69) 0.4  (0.44)
Walking ability 0.8  (0.46) 0.1  (0.35) 1.0  (0.55) 0.3  (0.63) 0.7  (0.67) 0.0  (0.43)
Normal work 0.7  (0.48) 0.3  (0.39) 1.0  (0.53) 0.2  (0.74) 0.5  (0.71) 0.4  (0.45)
Relations 0.8  (0.32) 0.8  (0.32) 0.6  (0.34) 0.6  (0.60) 0.9  (0.47) 0.8  (0.37)
Sleep 0.6  (0.43) 0.3  (0.35) 0.1  (0.53) 0.5  (0.63) 0.9  (0.61) 0.1  (0.42)
Enjoyment of life 0.8  (0.46) 0.6  (0.41) 0.4  (0.34) 0.2  (0.69) 1.1  (0.71) 0.8  (0.52)
Pain Interference Scale 0.8  (0.34) 0.4  (0.30) 0.7  (0.42) 0.3  (0.56) 0.9  (0.48) 0.4  (0.36)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Phase 2 (Palbociclib + Letrozole), Phase 2 (Letrozole)
Comments Statistical analysis presented above is for Pain Interference Scale.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.3346
Comments P-values are based on 2-sample t-test.
Method t-test, 2 sided
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.4
Confidence Interval (2-Sided) 95%
-0.5 to 1.3
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Ph2P1 (Palbociclib + Letrozole), Ph2P1 (Letrozole)
Comments Statistical analysis presented above is for Pain Interference Scale.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.5630
Comments P-values are based on 2-sample t-test.
Method t-test, 2 sided
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.4
Confidence Interval (2-Sided) 95%
-1.0 to 1.9
Estimation Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Ph2P2 (Palbociclib + Letrozole), Ph2P2 (Letrozole)
Comments Statistical analysis presented above is for Pain Severity Scale.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.4427
Comments P-values are based on 2-sample t-test.
Method t-test, 2 sided
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.5
Confidence Interval (2-Sided) 95%
-0.7 to 1.6
Estimation Comments [Not Specified]
25.Secondary Outcome
Title Presence or Absence of Tumor Tissue Biomarkers at Phase 2 - p16/INK4A, CCND1
Hide Description Tissue samples were used for retrospective biomarker analyses. For Phase 2 Part 2, the tissue samples were sent to a central laboratory for the assessment of participant selection biomarkers. For Phase 2 Part 1, the assessment of the biomarkers (CCND1 amplification and/or loss of p16) were performed retrospectively from the available samples.
Time Frame Screening visit (≤ 28 Days prior to dosing)
Hide Outcome Measure Data
Hide Analysis Population Description
Copy number analysis set included participants in the Safety Analysis Set who had at least 1 of the biomarker assessments.
Arm/Group Title Ph2P1 (Palbociclib + Letrozole) Ph2P1 (Letrozole) Ph2P2 (Palbociclib + Letrozole) Ph2P2 (Letrozole)
Hide Arm/Group Description:
All participants were randomized to receive Letrozole plus Palbociclib. Palbociclib 125 mg/d orally for 3 weeks followed by 1 week off treatment and Letrozole 2.5 mg/d orally in a continuous regimen.
Participants were randomized to receive Letrozole alone. Letrozole 2.5 mg/d was administered orally in a continuous regimen. This was considered as control arm.
Participants were randomized to receive Letrozole plus Palbociclib. Palbociclib 125 mg/d orally for 3 weeks followed by 1 week off treatment and Letrozole 2.5 mg/d orally in a continuous regimen.
Participants were randomized to receive Letrozole. Letrozole 2.5 mg/d was administered orally in a continuous regimen. This was considered as control arm.
Overall Number of Participants Analyzed 22 24 50 48
Measure Type: Number
Unit of Measure: Participants
CCND1>=1.5 12 9 39 44
p16/INK4A<0.8 0 2 19 12
CCND1>=1.5 and p16/INK4A<0.8 0 2 8 8
26.Secondary Outcome
Title Presence or Absence of Tumor Tissue Biomarkers at Phase 2 - Ki67
Hide Description Frequency of tumor tissue biomarker Ki67 was evaluated in across treatment groups.
Time Frame Screening visit (≤ 28 Days prior to dosing)
Hide Outcome Measure Data
Hide Analysis Population Description
All participants in the Safety Analysis set who had a Ki67 protein biomarker assessment.
Arm/Group Title Phase 2 (Palbociclib + Letrozole) Phase 2 (Letrozole) Ph2P1 (Palbociclib + Letrozole) Ph2P1 (Letrozole) Ph2P2 (Palbociclib + Letrozole) Ph2P2 (Letrozole)
Hide Arm/Group Description:
All participants who were randomized to letrozole plus palbociclib in both Phase 2 part 1 (Ph2P1) and Phase 2 part 2 (Ph2P2) are combined and presented. In Ph2P1 and Ph2P2, the participants received palbociclib 125 mg/d orally for 3 weeks followed by 1 week off treatment and letrozole 2.5 mg/d orally in a continuous regimen.
All participants who were randomized to receive letrozole alone in both Phase 2 part 1 (Ph2P1) and Phase 2 part 2 (Ph2P2) are combined and presented. This was considered as control arm. Letrozole 2.5 mg/d was administered orally in a continuous regimen.
All participants were randomized to receive Letrozole plus Palbociclib. Palbociclib 125 mg/d orally for 3 weeks followed by 1 week off treatment and Letrozole 2.5 mg/d orally in a continuous regimen.
Participants were randomized to receive Letrozole alone. Letrozole 2.5 mg/d was administered orally in a continuous regimen. This was considered as control arm.
Participants were randomized to receive Letrozole plus Palbociclib. Palbociclib 125 mg/d orally for 3 weeks followed by 1 week off treatment and Letrozole 2.5 mg/d orally in a continuous regimen.
Participants were randomized to receive Letrozole. Letrozole 2.5 mg/d was administered orally in a continuous regimen. This was considered as control arm.
Overall Number of Participants Analyzed 74 71 24 26 50 45
Measure Type: Number
Unit of Measure: Participants
<=20% 26 31 7 16 19 15
>20% 48 40 17 10 31 30
27.Secondary Outcome
Title Presence or Absence of Tumor Tissue Biomarkers at Phase 2 - Tumor Retinoblastoma (RB) and CyclinD1
Hide Description Presence or absence of tumor RB and CyclinD1 were evaluated. The following definitions of expression applied in the below table: Positive: any expression >0 and Negative: any expression=0.
Time Frame Screening visit (≤ 28 Days prior to dosing)
Hide Outcome Measure Data
Hide Analysis Population Description
Protein biomarkers analysis set included all participants in the safety analysis set who had at least protein biomarker assessment.
Arm/Group Title Phase 2 (Palbociclib + Letrozole) Phase 2 (Letrozole) Ph2P1 (Palbociclib + Letrozole) Ph2P1 (Letrozole) Ph2P2 (Palbociclib + Letrozole) Ph2P2 (Letrozole)
Hide Arm/Group Description:
All participants who were randomized to letrozole plus palbociclib in both Phase 2 part 1 (Ph2P1) and Phase 2 part 2 (Ph2P2) are combined and presented. In Ph2P1 and Ph2P2, the participants received palbociclib 125 mg/d orally for 3 weeks followed by 1 week off treatment and letrozole 2.5 mg/d orally in a continuous regimen.
All participants who were randomized to receive letrozole alone in both Phase 2 part 1 (Ph2P1) and Phase 2 part 2 (Ph2P2) are combined and presented. This was considered as control arm. Letrozole 2.5 mg/d was administered orally in a continuous regimen.
All participants were randomized to receive Letrozole plus Palbociclib. Palbociclib 125 mg/d orally for 3 weeks followed by 1 week off treatment and Letrozole 2.5 mg/d orally in a continuous regimen.
Participants were randomized to receive Letrozole alone. Letrozole 2.5 mg/d was administered orally in a continuous regimen. This was considered as control arm.
Participants were randomized to receive Letrozole plus Palbociclib. Palbociclib 125 mg/d orally for 3 weeks followed by 1 week off treatment and Letrozole 2.5 mg/d orally in a continuous regimen.
Participants were randomized to receive Letrozole. Letrozole 2.5 mg/d was administered orally in a continuous regimen. This was considered as control arm.
Overall Number of Participants Analyzed 45 35 12 16 33 19
Measure Type: Number
Unit of Measure: Participants
CyclinD1 - Positive 41 32 10 16 31 16
CyclinD1 - Negative 3 3 2 0 1 3
RB - Positive 41 32 10 16 31 16
RB - Negative 2 2 2 0 0 2
28.Secondary Outcome
Title Summary of Copy Number for CCND1 (CCND1/CEP11) and p16/INK4A (p16/CEP9) at Phase 2
Hide Description Gene copy number for CCND1 (CCND1/CEP11) and p16/INK4A (p16/CEP9) were evaluated. This analysis was done for Phase 2 combined group.
Time Frame Screening visit (≤ 28 Days prior to dosing)
Hide Outcome Measure Data
Hide Analysis Population Description
Copy number analysis set included participants in the Safety Analysis Set who had at least 1 of the biomarker assessments.
Arm/Group Title Phase 2 (Palbociclib + Letrozole) Phase 2 (Letrozole)
Hide Arm/Group Description:
All participants who were randomized to letrozole plus palbociclib in both Phase 2 part 1 (Ph2P1) and Phase 2 part 2 (Ph2P2) are combined and presented. In Ph2P1 and Ph2P2, the participants received palbociclib 125 mg/d orally for 3 weeks followed by 1 week off treatment and letrozole 2.5 mg/d orally in a continuous regimen.
All participants who were randomized to receive letrozole alone in both Phase 2 part 1 (Ph2P1) and Phase 2 part 2 (Ph2P2) are combined and presented. This was considered as control arm. Letrozole 2.5 mg/d was administered orally in a continuous regimen.
Overall Number of Participants Analyzed 72 72
Mean (Standard Deviation)
Unit of Measure: Copy number
CCND1 2.76  (1.875) 2.73  (1.559)
p16/INK4A 0.83  (0.224) 0.87  (0.173)
29.Secondary Outcome
Title Percentage of Participants With Tumor Expression of CYP19A1 and CCND1 Genotypes at Phase 2
Hide Description One 2-mL blood specimen was collected for the analysis of germline polymorphism in CYP19A1 and CCND1 genes. A single nucleotide polymorphism (SNP) rs4646 as defined in the National Center for Biotechnology Information (NCBI) database in the aromatase gene (CYP19A1) was analyzed. A germline polymorphism G/A870 (rs9344) in the CCND1 gene was analyzed.
Time Frame Screening visit (≤ 28 Days prior to dosing)
Hide Outcome Measure Data
Hide Analysis Population Description
Polymorphism analysis set included participants in the safety analysis set who had at least 1 polymorphism assessment.
Arm/Group Title Phase 2 (Palbociclib + Letrozole) Phase 2 (Letrozole) Ph2P1 (Palbociclib + Letrozole) Ph2P1 (Letrozole) Ph2P2 (Palbociclib + Letrozole) Ph2P2 (Letrozole)
Hide Arm/Group Description:
All participants who were randomized to letrozole plus palbociclib in both Phase 2 part 1 (Ph2P1) and Phase 2 part 2 (Ph2P2) are combined and presented. In Ph2P1 and Ph2P2, the participants received palbociclib 125 mg/d orally for 3 weeks followed by 1 week off treatment and letrozole 2.5 mg/d orally in a continuous regimen.
All participants who were randomized to receive letrozole alone in both Phase 2 part 1 (Ph2P1) and Phase 2 part 2 (Ph2P2) are combined and presented. This was considered as control arm. Letrozole 2.5 mg/d was administered orally in a continuous regimen.
All participants were randomized to receive Letrozole plus Palbociclib. Palbociclib 125 mg/d orally for 3 weeks followed by 1 week off treatment and Letrozole 2.5 mg/d orally in a continuous regimen.
Participants were randomized to receive Letrozole alone. Letrozole 2.5 mg/d was administered orally in a continuous regimen. This was considered as control arm.
Participants were randomized to receive Letrozole plus Palbociclib. Palbociclib 125 mg/d orally for 3 weeks followed by 1 week off treatment and Letrozole 2.5 mg/d orally in a continuous regimen.
Participants were randomized to receive Letrozole. Letrozole 2.5 mg/d was administered orally in a continuous regimen. This was considered as control arm.
Overall Number of Participants Analyzed 76 74 30 28 46 46
Measure Type: Number
Unit of Measure: Percentage of participants
CYP19A1 - A/A Genotype 7.9 5.4 10.0 10.7 6.5 2.2
CYP19A1 - C/A Genotype 34.2 36.5 33.3 42.9 34.8 32.6
CYP19A1 - C/C Genotype 57.9 58.1 56.7 46.4 58.7 65.2
CCND1 - A/A Genotype 26.3 28.4 33.3 39.3 21.7 21.7
CCND1 - G/A Genotype 47.4 47.3 43.3 42.9 50.0 50.0
CCND1 - G/G Genotype 26.3 24.3 23.3 17.9 28.3 28.3
30.Secondary Outcome
Title Number of Participants With TEAEs (All Causalities) at Phase 2
Hide Description AE:any untoward medical occurrence in participant who received study drug without regard to possibility of causal relationship.AEs included both serious and non-serious AEs.SAE:AE resulting in any of following outcomes/deemed significant and jeopardized participants or required treatment to prevent other AE outcomes for any other reason:death;initial or prolonged inpatient hospitalization;life-threatening experience (immediate risk of dying);persistent or significant disability/incapacity;congenital anomaly.Treatment emergent AEs:events occurred between first dose of study drug and up to 28 days after last dose that were absent before treatment or worsened relative to pre-treatment state.AEs were graded as per the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 and coded using Medical Dictionary for Regulatory Activities (MedDRA). Participants with AE of grade 3 or 4 and grade 5 were reported as Grade 3:Severe, Grade 4:Life threatening, Grade 5:Death related to AE.
Time Frame Baseline up to 28 days after last dose of study drug (for a maximum of 86 months)
Hide Outcome Measure Data
Hide Analysis Population Description
All treated as treated set included all treated participants classified by the treatment actually received.
Arm/Group Title Phase 2 (Palbociclib + Letrozole) Phase 2 (Letrozole) Ph2P1 (Palbociclib + Letrozole) Ph2P1 (Letrozole) Ph2P2 (Palbociclib + Letrozole) Ph2P2 (Letrozole)
Hide Arm/Group Description:
All participants who were randomized to letrozole plus palbociclib in both Phase 2 part 1 (Ph2P1) and Phase 2 part 2 (Ph2P2) are combined and presented. In Ph2P1 and Ph2P2, the participants received palbociclib 125 mg/d orally for 3 weeks followed by 1 week off treatment and letrozole 2.5 mg/d orally in a continuous regimen.
All participants who were randomized to receive letrozole alone in both Phase 2 part 1 (Ph2P1) and Phase 2 part 2 (Ph2P2) are combined and presented. This was considered as control arm. Letrozole 2.5 mg/d was administered orally in a continuous regimen.
All participants were randomized to receive Letrozole plus Palbociclib. Palbociclib 125 mg/d orally for 3 weeks followed by 1 week off treatment and Letrozole 2.5 mg/d orally in a continuous regimen.
Participants were randomized to receive Letrozole alone. Letrozole 2.5 mg/d was administered orally in a continuous regimen. This was considered as control arm.
Participants were randomized to receive Letrozole plus Palbociclib. Palbociclib 125 mg/d orally for 3 weeks followed by 1 week off treatment and Letrozole 2.5 mg/d orally in a continuous regimen.
Participants were randomized to receive Letrozole. Letrozole 2.5 mg/d was administered orally in a continuous regimen. This was considered as control arm.
Overall Number of Participants Analyzed 83 77 33 29 50 48
Measure Type: Count of Participants
Unit of Measure: Participants
Participants with AEs
83
 100.0%
66
  85.7%
33
 100.0%
25
  86.2%
50
 100.0%
41
  85.4%
Participants with SAEs
22
  26.5%
6
   7.8%
10
  30.3%
2
   6.9%
12
  24.0%
4
   8.3%
Participants with Grade 3 or 4 AEs
70
  84.3%
19
  24.7%
29
  87.9%
5
  17.2%
41
  82.0%
14
  29.2%
Participants with Grade 5 AEs
1
   1.2%
0
   0.0%
0
   0.0%
0
   0.0%
1
   2.0%
0
   0.0%
31.Secondary Outcome
Title Number of Participants With Treatment-Related Adverse Events at Phase 2
Hide Description AE: any untoward medical occurrence in a participant who received study drug. AEs included both serious and non-serious adverse events. SAE: AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment emergent AEs: events occurred between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Treatment related AEs: all AEs with causality related to treatment. Relatedness to drug was assessed by the investigator. AEs were graded according to the CTCAE version 3.0 and coded using the MedDRA. Number of participants with AE of grade 3 or 4 and with AE of grade 5 were reported as Grade 3: Severe, Grade 4: Life threatening, Grade 5: Death related to AE.
Time Frame Baseline up to 28 days after last dose of study drug (for a maximum of 86 months)
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Hide Analysis Population Description
All treated as treated set included all treated participants classified by the treatment actually received.
Arm/Group Title Phase 2 (Palbociclib + Letrozole) Phase 2 (Letrozole) Ph2P1 (Palbociclib + Letrozole) Ph2P1 (Letrozole) Ph2P2 (Palbociclib + Letrozole) Ph2P2 (Letrozole)
Hide Arm/Group Description:
All participants who were randomized to letrozole plus palbociclib in both Phase 2 part 1 (Ph2P1) and Phase 2 part 2 (Ph2P2) are combined and presented. In Ph2P1 and Ph2P2, the participants received palbociclib 125 mg/d orally for 3 weeks followed by 1 week off treatment and letrozole 2.5 mg/d orally in a continuous regimen.
All participants who were randomized to receive letrozole alone in both Phase 2 part 1 (Ph2P1) and Phase 2 part 2 (Ph2P2) are combined and presented. This was considered as control arm. Letrozole 2.5 mg/d was administered orally in a continuous regimen.
All participants were randomized to receive Letrozole plus Palbociclib. Palbociclib 125 mg/d orally for 3 weeks followed by 1 week off treatment and Letrozole 2.5 mg/d orally in a continuous regimen.
Participants were randomized to receive Letrozole alone. Letrozole 2.5 mg/d was administered orally in a continuous regimen. This was considered as control arm.
Participants were randomized to receive Letrozole plus Palbociclib. Palbociclib 125 mg/d orally for 3 weeks followed by 1 week off treatment and Letrozole 2.5 mg/d orally in a continuous regimen.
Participants were randomized to receive Letrozole. Letrozole 2.5 mg/d was administered orally in a continuous regimen. This was considered as control arm.
Overall Number of Participants Analyzed 83 77 33 29 50 48
Measure Type: Count of Participants
Unit of Measure: Participants
Participants with AEs
78
  94.0%
33
  42.9%
32
  97.0%
13
  44.8%
46
  92.0%
20
  41.7%
Participants with SAEs
1
   1.2%
0
   0.0%
0
   0.0%
0
   0.0%
1
   2.0%
0
   0.0%
Participants with Grade 3 or 4 AEs
57
  68.7%
2
   2.6%
25
  75.8%
0
   0.0%
32
  64.0%
2
   4.2%
Participants with Grade 5 AEs
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Time Frame Baseline up to 28 days after last dose of study drug (for a maximum of 86 months)
Adverse Event Reporting Description An event may be categorized as serious in one participant and non serious in another participant, or one participant may experience both serious and non serious event. All treatment emergent AEs and SAEs were collected and reported. The same event may appear as both AE and SAE. All-cause mortality data included all anticipated and unanticipated deaths due to any cause. Analysis was done on participants who received at least one dose of study drug.
 
Arm/Group Title Phase 1 (Palbociclib + Letrozole) Phase 2 (Palbociclib + Letrozole) Phase 2 (Letrozole) Ph2P1 (Palbociclib + Letrozole) Ph2P1 (Letrozole) Ph2P2 (Palbociclib + Letrozole) Ph2P2 (Letrozole)
Hide Arm/Group Description In Cycle 1 (3 weeks), participants received single agent palbociclib 125 mg/d orally for 2 weeks followed by 1 week off treatment. In Cycles 2 and beyond (4 weeks each), participants received letrozole 2.5 mg/d in a continuous regimen plus Palbociclib 125 mg/d orally for 3 weeks followed by 1 week off treatment. All participants who were randomized to letrozole plus palbociclib in both Phase 2 part 1 (Ph2P1) and Phase 2 part 2 (Ph2P2) are combined and presented. In Ph2P1 and Ph2P2, the participants received palbociclib 125 mg/d orally for 3 weeks followed by 1 week off treatment and letrozole 2.5 mg/d orally in a continuous regimen. All participants who were randomized to receive letrozole alone in both Phase 2 part 1 (Ph2P1) and Phase 2 part 2 (Ph2P2) are combined and presented. This was considered as control arm. Letrozole 2.5 mg/d was administered orally in a continuous regimen. All participants were randomized to receive Letrozole plus Palbociclib. Palbociclib 125 mg/d orally for 3 weeks followed by 1 week off treatment and Letrozole 2.5 mg/d orally in a continuous regimen. Participants were randomized to receive Letrozole alone. Letrozole 2.5 mg/d was administered orally in a continuous regimen. This was considered as control arm. Participants were randomized to receive Letrozole plus Palbociclib. Palbociclib 125 mg/d orally for 3 weeks followed by 1 week off treatment and Letrozole 2.5 mg/d orally in a continuous regimen. Participants were randomized to receive Letrozole. Letrozole 2.5 mg/d was administered orally in a continuous regimen. This was considered as control arm.
All-Cause Mortality
Phase 1 (Palbociclib + Letrozole) Phase 2 (Palbociclib + Letrozole) Phase 2 (Letrozole) Ph2P1 (Palbociclib + Letrozole) Ph2P1 (Letrozole) Ph2P2 (Palbociclib + Letrozole) Ph2P2 (Letrozole)
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/12 (0.00%)      3/83 (3.61%)      1/77 (1.30%)      1/33 (3.03%)      0/29 (0.00%)      2/50 (4.00%)      1/48 (2.08%)    
Show Serious Adverse Events Hide Serious Adverse Events
Phase 1 (Palbociclib + Letrozole) Phase 2 (Palbociclib + Letrozole) Phase 2 (Letrozole) Ph2P1 (Palbociclib + Letrozole) Ph2P1 (Letrozole) Ph2P2 (Palbociclib + Letrozole) Ph2P2 (Letrozole)
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   2/12 (16.67%)      22/83 (26.51%)      6/77 (7.79%)      10/33 (30.30%)      2/29 (6.90%)      12/50 (24.00%)      4/48 (8.33%)    
Blood and lymphatic system disorders               
Anaemia * 1  0/12 (0.00%)  0/83 (0.00%)  1/77 (1.30%)  0/33 (0.00%)  0/29 (0.00%)  0/50 (0.00%)  1/48 (2.08%) 
Cardiac disorders               
Cardiac failure * 1  0/12 (0.00%)  0/83 (0.00%)  1/77 (1.30%)  0/33 (0.00%)  0/29 (0.00%)  0/50 (0.00%)  1/48 (2.08%) 
Gastrointestinal disorders               
Abdominal pain * 1  0/12 (0.00%)  1/83 (1.20%)  0/77 (0.00%)  0/33 (0.00%)  0/29 (0.00%)  1/50 (2.00%)  0/48 (0.00%) 
Colitis ischaemic * 1  0/12 (0.00%)  1/83 (1.20%)  0/77 (0.00%)  0/33 (0.00%)  0/29 (0.00%)  1/50 (2.00%)  0/48 (0.00%) 
Diarrhoea * 1  0/12 (0.00%)  1/83 (1.20%)  0/77 (0.00%)  0/33 (0.00%)  0/29 (0.00%)  1/50 (2.00%)  0/48 (0.00%) 
Gastrointestinal disorder * 1  0/12 (0.00%)  1/83 (1.20%)  0/77 (0.00%)  1/33 (3.03%)  0/29 (0.00%)  0/50 (0.00%)  0/48 (0.00%) 
Ileus * 1  0/12 (0.00%)  0/83 (0.00%)  1/77 (1.30%)  0/33 (0.00%)  1/29 (3.45%)  0/50 (0.00%)  0/48 (0.00%) 
Oesophageal achalasia * 1  0/12 (0.00%)  0/83 (0.00%)  1/77 (1.30%)  0/33 (0.00%)  0/29 (0.00%)  0/50 (0.00%)  1/48 (2.08%) 
Nausea * 1  1/12 (8.33%)  0/83 (0.00%)  0/77 (0.00%)  0/33 (0.00%)  0/29 (0.00%)  0/50 (0.00%)  0/48 (0.00%) 
Vomiting * 1  1/12 (8.33%)  0/83 (0.00%)  0/77 (0.00%)  0/33 (0.00%)  0/29 (0.00%)  0/50 (0.00%)  0/48 (0.00%) 
Gastritis * 1  0/12 (0.00%)  1/83 (1.20%)  0/77 (0.00%)  0/33 (0.00%)  0/29 (0.00%)  1/50 (2.00%)  0/48 (0.00%) 
Inguinal hernia * 1  0/12 (0.00%)  1/83 (1.20%)  0/77 (0.00%)  0/33 (0.00%)  0/29 (0.00%)  1/50 (2.00%)  0/48 (0.00%) 
General disorders               
Asthenia * 1  0/12 (0.00%)  1/83 (1.20%)  0/77 (0.00%)  1/33 (3.03%)  0/29 (0.00%)  0/50 (0.00%)  0/48 (0.00%) 
Chest pain * 1  0/12 (0.00%)  1/83 (1.20%)  0/77 (0.00%)  1/33 (3.03%)  0/29 (0.00%)  0/50 (0.00%)  0/48 (0.00%) 
Disease progression * 1  0/12 (0.00%)  1/83 (1.20%)  0/77 (0.00%)  0/33 (0.00%)  0/29 (0.00%)  1/50 (2.00%)  0/48 (0.00%) 
Pain * 1  1/12 (8.33%)  1/83 (1.20%)  0/77 (0.00%)  1/33 (3.03%)  0/29 (0.00%)  0/50 (0.00%)  0/48 (0.00%) 
Infections and infestations               
Erysipelas * 1  0/12 (0.00%)  0/83 (0.00%)  1/77 (1.30%)  0/33 (0.00%)  0/29 (0.00%)  0/50 (0.00%)  1/48 (2.08%) 
Gangrene * 1  0/12 (0.00%)  1/83 (1.20%)  0/77 (0.00%)  0/33 (0.00%)  0/29 (0.00%)  1/50 (2.00%)  0/48 (0.00%) 
Influenza * 1  0/12 (0.00%)  1/83 (1.20%)  0/77 (0.00%)  1/33 (3.03%)  0/29 (0.00%)  0/50 (0.00%)  0/48 (0.00%) 
Pneumonia * 1  0/12 (0.00%)  1/83 (1.20%)  0/77 (0.00%)  0/33 (0.00%)  0/29 (0.00%)  1/50 (2.00%)  0/48 (0.00%) 
Staphylococcal bacteraemia * 1  0/12 (0.00%)  1/83 (1.20%)  0/77 (0.00%)  1/33 (3.03%)  0/29 (0.00%)  0/50 (0.00%)  0/48 (0.00%) 
Upper respiratory tract infection * 1  0/12 (0.00%)  1/83 (1.20%)  0/77 (0.00%)  1/33 (3.03%)  0/29 (0.00%)  0/50 (0.00%)  0/48 (0.00%) 
Campylobacter infection * 1  0/12 (0.00%)  1/83 (1.20%)  0/77 (0.00%)  1/33 (3.03%)  0/29 (0.00%)  0/50 (0.00%)  0/48 (0.00%) 
Infective exacerbation of chronic obstructive airways disease * 1  0/12 (0.00%)  1/83 (1.20%)  0/77 (0.00%)  1/33 (3.03%)  0/29 (0.00%)  0/50 (0.00%)  0/48 (0.00%) 
Mastoiditis * 1  0/12 (0.00%)  1/83 (1.20%)  0/77 (0.00%)  1/33 (3.03%)  0/29 (0.00%)  0/50 (0.00%)  0/48 (0.00%) 
Injury, poisoning and procedural complications               
Fractured sacrum * 1  0/12 (0.00%)  1/83 (1.20%)  0/77 (0.00%)  0/33 (0.00%)  0/29 (0.00%)  1/50 (2.00%)  0/48 (0.00%) 
Hip fracture * 1  0/12 (0.00%)  0/83 (0.00%)  1/77 (1.30%)  0/33 (0.00%)  0/29 (0.00%)  0/50 (0.00%)  1/48 (2.08%) 
Humerus fracture * 1  0/12 (0.00%)  1/83 (1.20%)  0/77 (0.00%)  0/33 (0.00%)  0/29 (0.00%)  1/50 (2.00%)  0/48 (0.00%) 
Upper limb fracture * 1  0/12 (0.00%)  0/83 (0.00%)  1/77 (1.30%)  0/33 (0.00%)  0/29 (0.00%)  0/50 (0.00%)  1/48 (2.08%) 
Investigations               
Alanine aminotransferase increased * 1  0/12 (0.00%)  1/83 (1.20%)  0/77 (0.00%)  1/33 (3.03%)  0/29 (0.00%)  0/50 (0.00%)  0/48 (0.00%) 
Aspartate aminotransferase increased * 1  0/12 (0.00%)  1/83 (1.20%)  0/77 (0.00%)  1/33 (3.03%)  0/29 (0.00%)  0/50 (0.00%)  0/48 (0.00%) 
Blood alkaline phosphatase increased * 1  0/12 (0.00%)  1/83 (1.20%)  0/77 (0.00%)  1/33 (3.03%)  0/29 (0.00%)  0/50 (0.00%)  0/48 (0.00%) 
Gamma-glutamyltransferase increased * 1  0/12 (0.00%)  1/83 (1.20%)  0/77 (0.00%)  1/33 (3.03%)  0/29 (0.00%)  0/50 (0.00%)  0/48 (0.00%) 
Musculoskeletal and connective tissue disorders               
Back pain * 1  0/12 (0.00%)  2/83 (2.41%)  0/77 (0.00%)  1/33 (3.03%)  0/29 (0.00%)  1/50 (2.00%)  0/48 (0.00%) 
Bone pain * 1  0/12 (0.00%)  1/83 (1.20%)  0/77 (0.00%)  0/33 (0.00%)  0/29 (0.00%)  1/50 (2.00%)  0/48 (0.00%) 
Intervertebral disc protrusion * 1  0/12 (0.00%)  2/83 (2.41%)  0/77 (0.00%)  0/33 (0.00%)  0/29 (0.00%)  2/50 (4.00%)  0/48 (0.00%) 
Arthralgia * 1  0/12 (0.00%)  1/83 (1.20%)  0/77 (0.00%)  1/33 (3.03%)  0/29 (0.00%)  0/50 (0.00%)  0/48 (0.00%) 
Osteonecrosis of jaw * 1  0/12 (0.00%)  1/83 (1.20%)  0/77 (0.00%)  0/33 (0.00%)  0/29 (0.00%)  1/50 (2.00%)  0/48 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)               
Fallopian tube cancer * 1  0/12 (0.00%)  1/83 (1.20%)  0/77 (0.00%)  1/33 (3.03%)  0/29 (0.00%)  0/50 (0.00%)  0/48 (0.00%) 
Plasma cell myeloma * 1  0/12 (0.00%)  0/83 (0.00%)  1/77 (1.30%)  0/33 (0.00%)  0/29 (0.00%)  0/50 (0.00%)  1/48 (2.08%) 
Nervous system disorders               
Neuralgia * 1  0/12 (0.00%)  1/83 (1.20%)  0/77 (0.00%)  0/33 (0.00%)  0/29 (0.00%)  1/50 (2.00%)  0/48 (0.00%) 
Brain stem infarction * 1  0/12 (0.00%)  1/83 (1.20%)  0/77 (0.00%)  1/33 (3.03%)  0/29 (0.00%)  0/50 (0.00%)  0/48 (0.00%) 
Renal and urinary disorders               
Nephrolithiasis * 1  0/12 (0.00%)  1/83 (1.20%)  0/77 (0.00%)  0/33 (0.00%)  0/29 (0.00%)  1/50 (2.00%)  0/48 (0.00%) 
Renal disorder * 1  0/12 (0.00%)  1/83 (1.20%)  0/77 (0.00%)  0/33 (0.00%)  0/29 (0.00%)  1/50 (2.00%)  0/48 (0.00%) 
Urethral obstruction * 1  0/12 (0.00%)  1/83 (1.20%)  0/77 (0.00%)  0/33 (0.00%)  0/29 (0.00%)  1/50 (2.00%)  0/48 (0.00%) 
Acute kidney injury * 1  0/12 (0.00%)  1/83 (1.20%)  0/77 (0.00%)  0/33 (0.00%)  0/29 (0.00%)  1/50 (2.00%)  0/48 (0.00%) 
Respiratory, thoracic and mediastinal disorders               
Pulmonary embolism * 1  1/12 (8.33%)  4/83 (4.82%)  0/77 (0.00%)  4/33 (12.12%)  0/29 (0.00%)  0/50 (0.00%)  0/48 (0.00%) 
Dyspnoea * 1  0/12 (0.00%)  1/83 (1.20%)  0/77 (0.00%)  1/33 (3.03%)  0/29 (0.00%)  0/50 (0.00%)  0/48 (0.00%) 
Skin and subcutaneous tissue disorders               
Subcutaneous emphysema * 1  0/12 (0.00%)  0/83 (0.00%)  1/77 (1.30%)  0/33 (0.00%)  1/29 (3.45%)  0/50 (0.00%)  0/48 (0.00%) 
1
Term from vocabulary, MedDRA (v20.1)
*
Indicates events were collected by non-systematic assessment
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Phase 1 (Palbociclib + Letrozole) Phase 2 (Palbociclib + Letrozole) Phase 2 (Letrozole) Ph2P1 (Palbociclib + Letrozole) Ph2P1 (Letrozole) Ph2P2 (Palbociclib + Letrozole) Ph2P2 (Letrozole)
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   12/12 (100.00%)      83/83 (100.00%)      57/77 (74.03%)      33/33 (100.00%)      22/29 (75.86%)      50/50 (100.00%)      35/48 (72.92%)    
Blood and lymphatic system disorders               
Anaemia * 1  4/12 (33.33%)  29/83 (34.94%)  3/77 (3.90%)  13/33 (39.39%)  0/29 (0.00%)  16/50 (32.00%)  3/48 (6.25%) 
Leukopenia * 1  8/12 (66.67%)  36/83 (43.37%)  3/77 (3.90%)  16/33 (48.48%)  1/29 (3.45%)  20/50 (40.00%)  2/48 (4.17%) 
Lymphopenia * 1  0/12 (0.00%)  3/83 (3.61%)  0/77 (0.00%)  2/33 (6.06%)  0/29 (0.00%)  1/50 (2.00%)  0/48 (0.00%) 
Neutropenia * 1  11/12 (91.67%)  62/83 (74.70%)  4/77 (5.19%)  26/33 (78.79%)  1/29 (3.45%)  36/50 (72.00%)  3/48 (6.25%) 
Thrombocytopenia * 1  3/12 (25.00%)  16/83 (19.28%)  2/77 (2.60%)  8/33 (24.24%)  1/29 (3.45%)  8/50 (16.00%)  1/48 (2.08%) 
Ear and labyrinth disorders               
Vertigo * 1  1/12 (8.33%)  1/83 (1.20%)  2/77 (2.60%)  1/33 (3.03%)  0/29 (0.00%)  0/50 (0.00%)  2/48 (4.17%) 
Ear pain * 1  0/12 (0.00%)  2/83 (2.41%)  0/77 (0.00%)  2/33 (6.06%)  0/29 (0.00%)  0/50 (0.00%)  0/48 (0.00%) 
Endocrine disorders               
Hyperthyroidism * 1  1/12 (8.33%)  0/83 (0.00%)  1/77 (1.30%)  0/33 (0.00%)  1/29 (3.45%)  0/50 (0.00%)  0/48 (0.00%) 
Thyroid mass * 1  1/12 (8.33%)  0/83 (0.00%)  0/77 (0.00%)  0/33 (0.00%)  0/29 (0.00%)  0/50 (0.00%)  0/48 (0.00%) 
Eye disorders               
Dry eye * 1  1/12 (8.33%)  0/83 (0.00%)  1/77 (1.30%)  0/33 (0.00%)  1/29 (3.45%)  0/50 (0.00%)  0/48 (0.00%) 
Lacrimation increased * 1  2/12 (16.67%)  3/83 (3.61%)  0/77 (0.00%)  1/33 (3.03%)  0/29 (0.00%)  2/50 (4.00%)  0/48 (0.00%) 
Visual impairment * 1  1/12 (8.33%)  4/83 (4.82%)  1/77 (1.30%)  1/33 (3.03%)  1/29 (3.45%)  3/50 (6.00%)  0/48 (0.00%) 
Cataract * 1  1/12 (8.33%)  2/83 (2.41%)  0/77 (0.00%)  1/33 (3.03%)  0/29 (0.00%)  1/50 (2.00%)  0/48 (0.00%) 
Presbyopia * 1  1/12 (8.33%)  0/83 (0.00%)  0/77 (0.00%)  0/33 (0.00%)  0/29 (0.00%)  0/50 (0.00%)  0/48 (0.00%) 
Gastrointestinal disorders               
Abdominal discomfort * 1  1/12 (8.33%)  0/83 (0.00%)  2/77 (2.60%)  0/33 (0.00%)  0/29 (0.00%)  0/50 (0.00%)  2/48 (4.17%) 
Abdominal distension * 1  1/12 (8.33%)  0/83 (0.00%)  2/77 (2.60%)  0/33 (0.00%)  1/29 (3.45%)  0/50 (0.00%)  1/48 (2.08%) 
Abdominal pain * 1  0/12 (0.00%)  7/83 (8.43%)  4/77 (5.19%)  7/33 (21.21%)  0/29 (0.00%)  0/50 (0.00%)  4/48 (8.33%) 
Abdominal pain upper * 1  0/12 (0.00%)  2/83 (2.41%)  4/77 (5.19%)  1/33 (3.03%)  1/29 (3.45%)  1/50 (2.00%)  3/48 (6.25%) 
Constipation * 1  3/12 (25.00%)  13/83 (15.66%)  7/77 (9.09%)  8/33 (24.24%)  4/29 (13.79%)  5/50 (10.00%)  3/48 (6.25%) 
Diarrhoea * 1  6/12 (50.00%)  18/83 (21.69%)  9/77 (11.69%)  9/33 (27.27%)  2/29 (6.90%)  9/50 (18.00%)  7/48 (14.58%) 
Dry mouth * 1  1/12 (8.33%)  3/83 (3.61%)  4/77 (5.19%)  2/33 (6.06%)  2/29 (6.90%)  1/50 (2.00%)  2/48 (4.17%) 
Dyspepsia * 1  3/12 (25.00%)  4/83 (4.82%)  2/77 (2.60%)  1/33 (3.03%)  0/29 (0.00%)  3/50 (6.00%)  2/48 (4.17%) 
Flatulence * 1  0/12 (0.00%)  2/83 (2.41%)  1/77 (1.30%)  2/33 (6.06%)  0/29 (0.00%)  0/50 (0.00%)  1/48 (2.08%) 
Food poisoning * 1  1/12 (8.33%)  1/83 (1.20%)  1/77 (1.30%)  0/33 (0.00%)  0/29 (0.00%)  1/50 (2.00%)  1/48 (2.08%) 
Chronic gastritis * 1  1/12 (8.33%)  0/83 (0.00%)  0/77 (0.00%)  0/33 (0.00%)  0/29 (0.00%)  0/50 (0.00%)  0/48 (0.00%) 
Gastrooesophageal reflux disease * 1  1/12 (8.33%)  1/83 (1.20%)  1/77 (1.30%)  1/33 (3.03%)  1/29 (3.45%)  0/50 (0.00%)  0/48 (0.00%) 
Gingival pain * 1  1/12 (8.33%)  4/83 (4.82%)  0/77 (0.00%)  0/33 (0.00%)  0/29 (0.00%)  4/50 (8.00%)  0/48 (0.00%) 
Mouth ulceration * 1  1/12 (8.33%)  2/83 (2.41%)  1/77 (1.30%)  2/33 (6.06%)  1/29 (3.45%)  0/50 (0.00%)  0/48 (0.00%) 
Nausea * 1  6/12 (50.00%)  25/83 (30.12%)  11/77 (14.29%)  12/33 (36.36%)  7/29 (24.14%)  13/50 (26.00%)  4/48 (8.33%) 
Stomatitis * 1  2/12 (16.67%)  10/83 (12.05%)  2/77 (2.60%)  5/33 (15.15%)  1/29 (3.45%)  5/50 (10.00%)  1/48 (2.08%) 
Rectal haemorrhage * 1  1/12 (8.33%)  0/83 (0.00%)  1/77 (1.30%)  0/33 (0.00%)  0/29 (0.00%)  0/50 (0.00%)  1/48 (2.08%) 
Toothache * 1  1/12 (8.33%)  6/83 (7.23%)  2/77 (2.60%)  1/33 (3.03%)  1/29 (3.45%)  5/50 (10.00%)  1/48 (2.08%) 
Vomiting * 1  3/12 (25.00%)  15/83 (18.07%)  3/77 (3.90%)  9/33 (27.27%)  2/29 (6.90%)  6/50 (12.00%)  1/48 (2.08%) 
Oral disorder * 1  1/12 (8.33%)  1/83 (1.20%)  0/77 (0.00%)  1/33 (3.03%)  0/29 (0.00%)  0/50 (0.00%)  0/48 (0.00%) 
Gastritis * 1  0/12 (0.00%)  1/83 (1.20%)  4/77 (5.19%)  0/33 (0.00%)  2/29 (6.90%)  1/50 (2.00%)  2/48 (4.17%) 
General disorders               
Asthenia * 1  1/12 (8.33%)  11/83 (13.25%)  4/77 (5.19%)  2/33 (6.06%)  0/29 (0.00%)  9/50 (18.00%)  4/48 (8.33%) 
Chest pain * 1  0/12 (0.00%)  3/83 (3.61%)  4/77 (5.19%)  0/33 (0.00%)  2/29 (6.90%)  3/50 (6.00%)  2/48 (4.17%) 
Facial pain * 1  1/12 (8.33%)  0/83 (0.00%)  0/77 (0.00%)  0/33 (0.00%)  0/29 (0.00%)  0/50 (0.00%)  0/48 (0.00%) 
Fatigue * 1  10/12 (83.33%)  34/83 (40.96%)  18/77 (23.38%)  14/33 (42.42%)  7/29 (24.14%)  20/50 (40.00%)  11/48 (22.92%) 
Influenza like illness * 1  1/12 (8.33%)  5/83 (6.02%)  2/77 (2.60%)  3/33 (9.09%)  1/29 (3.45%)  2/50 (4.00%)  1/48 (2.08%) 
Mucosal inflammation * 1  0/12 (0.00%)  7/83 (8.43%)  2/77 (2.60%)  2/33 (6.06%)  0/29 (0.00%)  5/50 (10.00%)  2/48 (4.17%) 
Non-cardiac chest pain * 1  1/12 (8.33%)  0/83 (0.00%)  0/77 (0.00%)  0/33 (0.00%)  0/29 (0.00%)  0/50 (0.00%)  0/48 (0.00%) 
Oedema peripheral * 1  2/12 (16.67%)  6/83 (7.23%)  8/77 (10.39%)  3/33 (9.09%)  5/29 (17.24%)  3/50 (6.00%)  3/48 (6.25%) 
Pain * 1  2/12 (16.67%)  3/83 (3.61%)  3/77 (3.90%)  1/33 (3.03%)  2/29 (6.90%)  2/50 (4.00%)  1/48 (2.08%) 
Pyrexia * 1  0/12 (0.00%)  9/83 (10.84%)  2/77 (2.60%)  8/33 (24.24%)  0/29 (0.00%)  1/50 (2.00%)  2/48 (4.17%) 
Temperature intolerance * 1  1/12 (8.33%)  0/83 (0.00%)  0/77 (0.00%)  0/33 (0.00%)  0/29 (0.00%)  0/50 (0.00%)  0/48 (0.00%) 
Chills * 1  1/12 (8.33%)  1/83 (1.20%)  0/77 (0.00%)  1/33 (3.03%)  0/29 (0.00%)  0/50 (0.00%)  0/48 (0.00%) 
Face oedema * 1  1/12 (8.33%)  1/83 (1.20%)  0/77 (0.00%)  0/33 (0.00%)  0/29 (0.00%)  1/50 (2.00%)  0/48 (0.00%) 
Peripheral swelling * 1  1/12 (8.33%)  4/83 (4.82%)  2/77 (2.60%)  2/33 (6.06%)  0/29 (0.00%)  2/50 (4.00%)  2/48 (4.17%) 
Immune system disorders               
Seasonal allergy * 1  2/12 (16.67%)  1/83 (1.20%)  1/77 (1.30%)  1/33 (3.03%)  1/29 (3.45%)  0/50 (0.00%)  0/48 (0.00%) 
Infections and infestations               
Conjunctivitis * 1  0/12 (0.00%)  5/83 (6.02%)  0/77 (0.00%)  2/33 (6.06%)  0/29 (0.00%)  3/50 (6.00%)  0/48 (0.00%) 
Bronchitis * 1  1/12 (8.33%)  3/83 (3.61%)  2/77 (2.60%)  3/33 (9.09%)  1/29 (3.45%)  0/50 (0.00%)  1/48 (2.08%) 
Cystitis * 1  0/12 (0.00%)  3/83 (3.61%)  1/77 (1.30%)  0/33 (0.00%)  0/29 (0.00%)  3/50 (6.00%)  1/48 (2.08%) 
Diverticulitis * 1  0/12 (0.00%)  0/83 (0.00%)  2/77 (2.60%)  0/33 (0.00%)  2/29 (6.90%)  0/50 (0.00%)  0/48 (0.00%) 
Ear infection * 1  0/12 (0.00%)  2/83 (2.41%)  0/77 (0.00%)  2/33 (6.06%)  0/29 (0.00%)  0/50 (0.00%)  0/48 (0.00%) 
Gastroenteritis viral * 1  1/12 (8.33%)  1/83 (1.20%)  1/77 (1.30%)  0/33 (0.00%)  0/29 (0.00%)  1/50 (2.00%)  1/48 (2.08%) 
Herpes zoster * 1  1/12 (8.33%)  1/83 (1.20%)  1/77 (1.30%)  0/33 (0.00%)  1/29 (3.45%)  1/50 (2.00%)  0/48 (0.00%) 
Influenza * 1  1/12 (8.33%)  8/83 (9.64%)  1/77 (1.30%)  4/33 (12.12%)  1/29 (3.45%)  4/50 (8.00%)  0/48 (0.00%) 
Localised infection * 1  2/12 (16.67%)  0/83 (0.00%)  0/77 (0.00%)  0/33 (0.00%)  0/29 (0.00%)  0/50 (0.00%)  0/48 (0.00%) 
Nasopharyngitis * 1  1/12 (8.33%)  12/83 (14.46%)  7/77 (9.09%)  7/33 (21.21%)  3/29 (10.34%)  5/50 (10.00%)  4/48 (8.33%) 
Oral herpes * 1  1/12 (8.33%)  3/83 (3.61%)  0/77 (0.00%)  3/33 (9.09%)  0/29 (0.00%)  0/50 (0.00%)  0/48 (0.00%) 
Pneumonia * 1  1/12 (8.33%)  1/83 (1.20%)  2/77 (2.60%)  0/33 (0.00%)  2/29 (6.90%)  1/50 (2.00%)  0/48 (0.00%) 
Sinusitis * 1  2/12 (16.67%)  2/83 (2.41%)  2/77 (2.60%)  1/33 (3.03%)  2/29 (6.90%)  1/50 (2.00%)  0/48 (0.00%) 
Skin infection * 1  2/12 (16.67%)  2/83 (2.41%)  1/77 (1.30%)  2/33 (6.06%)  0/29 (0.00%)  0/50 (0.00%)  1/48 (2.08%) 
Tooth infection * 1  2/12 (16.67%)  2/83 (2.41%)  0/77 (0.00%)  1/33 (3.03%)  0/29 (0.00%)  1/50 (2.00%)