Pre-Operative Study of PF-4691502 With Letrozole Compared To Letrozole Alone In Patients With Early Breast Cancer

This study has been terminated.
(See termination reason in detailed description.)
Sponsor:
Information provided by (Responsible Party):
Pfizer
ClinicalTrials.gov Identifier:
NCT01430585
First received: August 18, 2011
Last updated: July 18, 2014
Last verified: July 2014
  Purpose

PF-04691502 is an inhibitor of PI3K and mTOR kinase. Published data support the hypothesis that a PI3K/mTOR antagonist in combination with letrozole might mitigate the intrinsic or acquired resistance to hormonal therapy and restore hormone sensitivity in high risk (high Ki-67) patient population of hormone-sensitive breast cancers. In addition, Ki-67, a marker of cellular proliferation, could be used to select those patients who benefit from treatment with a PI3K-pathway inhibitor.


Condition Intervention Phase
Early Breast Cancer (Phase 2)
Advanced Breast Cancer (Phase 1b)
Drug: PF-04691502
Drug: PF-04691502 in combination with Letrozole
Drug: Letrozole
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: An Open-Label, Randomised Phase 1b/2 Study Of PF-04691502 In Combination With Letrozole Compared With Letrozole Alone In Patients With Estrogen Receptor Positive, Her-2 Negative Early Breast Cancer

Resource links provided by NLM:


Further study details as provided by Pfizer:

Primary Outcome Measures:
  • Number of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs): Phase 1B [ Time Frame: Phase 1B: Baseline up to 28 days after last administration of study treatment ] [ Designated as safety issue: Yes ]
    An AE was any untoward medical occurrence in a participant who received study treatment without regard to possibility of causal relationship. SAE: 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. Treatment-emergent are events between first dose of study treatment and up to 28 days after last dose that were absent before treatment or that worsened relative to pretreatment state.

  • Change From Baseline in Ki-67 Percent Positive Tumor Cells in Biopsied Tumor Tissue at Week 6: Phase 2 [ Time Frame: Phase 2: Baseline, Week 6 ] [ Designated as safety issue: No ]
    Nuclear proliferation marker Ki-67 was to be assessed by immunohistochemistry technique in all specimens.


Secondary Outcome Measures:
  • Number of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs): Phase 2 [ Time Frame: Phase 2: Baseline up to 28 days after last administration of study treatment ] [ Designated as safety issue: Yes ]
    An AE was any untoward medical occurrence in a participant who received study treatment without regard to possibility of causal relationship. SAE: 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. Treatment-emergent are events between first dose of study treatment and up to 28 days after last dose that were absent before treatment or that worsened relative to pretreatment state.

  • Number of Participants With Clinically Significant Laboratory Tests Abnormalities: Phase 1B and 2 [ Time Frame: Phase 1B: Baseline up to end of treatment (Week 34); Phase 2: Baseline up to Week 16 or early termination (ET) ] [ Designated as safety issue: Yes ]
    Laboratory analysis planned to include blood chemistry, hematology and urinalysis.

  • Number of Participants With Clinically Significant Abnormalities in Vital Signs: Phase 1B and 2 [ Time Frame: Phase 1B: Baseline up to 28 days after last dose of study treatment (Week 34); Phase 2: Baseline up to Week 16 or ET ] [ Designated as safety issue: Yes ]
    Vital signs assessments planned to include measurement of blood pressure and heart rate.

  • Number of Participants With Clinically Significant Abnormalities in Corrected QT (QTc) Interval: Phase 1B [ Time Frame: Phase 1B: Baseline up to end of treatment (Week 34) ] [ Designated as safety issue: Yes ]
  • Number of Participants With Objective Response (OR): Phase 1B and 2 [ Time Frame: Phase 1B: Baseline, Week 12, end of treatment (Week 34); Phase 2: Baseline, Week 6, 16 or ET ] [ Designated as safety issue: No ]
    Number of participants with objective response based on assessment of complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST). CR was defined as complete disappearance of all target lesions and non-target lesions, with the exception of nodal disease. All nodes, both target and non-target, must decrease to normal (short axis less than [<] 10 millimeter [mm]). No appearance of new lesions and normalization of tumor marker levels. PR was defined as greater than or equal to (>=) 30 percent (%) decrease from baseline of the sum of diameters of all target lesions, using the short diameter in the sum for target nodes and the longest diameter in the sum for all other target lesions.

  • Pharmacokinetic (PK) Parameters of PF-04691502 and Letrozole: Phase 1B and 2 [ Time Frame: Phase 1B: 0 (pre-dose), 1, 2, 4, 6, 24 hours on Day 1 (letrozole alone), Day 2 (PF-0491502 alone), Day 12, Week 5 (PF-0491502 and letrozole in combination); Phase 2: 0 (pre-dose), 1, 2, 4, 6, 24 hours on Day 1, pre-dose on Week 2, 6 ] [ Designated as safety issue: No ]
    Phase 1B: Following PK parameters were planned to be calculated from the plasma concentration time data using standard non-compartmental methods. For PF-04691502: area under the curve from time zero to last quantifiable concentration (AUClast), area under the curve from time zero to end of dosing interval (AUCtau), maximum observed plasma concentration (Cmax), minimum observed plasma trough concentration (Cmin), average plasma concentration (Cavg), time to reach maximum observed plasma concentration (Tmax), observed accumulation ratio (Rac [obs]); for letrozole: AUClast, Cmax. Phase 2: Following PK parameters were planned to be calculated for PF-04691502 from the plasma concentration time data using standard non-compartmental methods- AUClast, Cmax and Tmax.

  • Change From Baseline in Pharmacodynamic, Cell Proliferation and Survival Biomarkers in Biopsied Tumor Tissue at Week 2 and 6: Phase 2 [ Time Frame: Phase 2: Baseline, Week 2, 6 ] [ Designated as safety issue: No ]
    Change from baseline in following pharmacodynamic parameters were planned to be calculated: expression and/or phosphorylation of Phosphoinositide-3-kinase (PI3K) pathway proteins in biopsied tumor tissue and markers of cell cycle and survival.

  • Number of Participants With Genetic Alterations: Phase 2 [ Time Frame: Phase 2: Baseline, Week 2, 6 ] [ Designated as safety issue: No ]
    Following genetic alterations were planned to be analyzed: mutations in Phosphoinositide 3-kinase, catalytic, alpha (PIK3CA), amplification of PIK3CA, Phosphate and tensin homolog (PTEN) deficiency, and changes in other genes or proteins in, or impacting V-Ki-ras2 Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS), Insulin-like Growth Factor 1 Receptor (IGF-1R), phosphatidylinositol 3-kinase (PI3K)/ mammalian target of rapamycin (mTOR) pathway.


Enrollment: 14
Study Start Date: March 2012
Study Completion Date: December 2012
Primary Completion Date: December 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: A Drug: PF-04691502
PF-04691502 administered as single agent for 2 weeks. After this period, patients in this arm will take PF-04691502 in combination with Letrozole until Week 6. Beyond Week 6, if considered appropriate, patients can be treated with the combination for up to 10 additional weeks until breast surgery.
Experimental: B Drug: PF-04691502 in combination with Letrozole
PF-04691502 in combination with Letrozole will be administered for 6 weeks. Beyond Week 6, if considered appropriate, patients can be treated for up to 10 additional weeks until breast surgery.
Active Comparator: C Drug: Letrozole
Letrozole will be administered for 6 weeks. Beyond Week 6, if considered appropriate, patients can be treated for up to 10 additional weeks until breast surgery.

Detailed Description:

The study was prematurely discontinued on 09Oct2012 due to the tolerability findings in 2 clinical studies testing PF-04691502 that have prompted the Sponsor to re-evaluate the strategic goals of the program. In the study B1271003 an unexpected frequency of severe skin toxicity was observed and in the study B1271004 5 cases of drug induced pneumonitis were reported.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Phase 1 - Postmenopausal women with diagnosis of breast cancer, metastatic disease or locally advanced disease / Estrogen Receptor positive and HER-2 negative / candidate to receive Letrozole
  • Phase 2 - Postmenopausal women with newly diagnosed primary breast cancer / Estrogen Receptor positive and HER-2 negative / Ki-67 levels >10% positive cells
  • Phase 1 & 2 - Glucose control, adequate bone marrow, liver, renal, and cardiac function

Exclusion Criteria:

  • Inflammatory carcinoma / Prior therapy with an agent active on PI3K and/or mTOR / Significant gastrointestinal abnormalities, which may impair intake, transit or absorption of the study drugs / Current or anticipated need for food or drugs that are known inhibitors or inducers of CYP3A4
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01430585

Locations
Belgium
Pfizer Investigational Site
Charleroi, Belgium, 6000
Italy
Pfizer Investigational Site
Milano, Italy, 20132
Spain
Pfizer Investigational Site
Barcelona, Spain, 08035
Sweden
Pfizer Investigational Site
Goteborg, Sweden, 413 45
Pfizer Investigational Site
Stockholm, Sweden, 171 76
Sponsors and Collaborators
Pfizer
Investigators
Study Director: Pfizer CT.gov Call Center Pfizer
  More Information

Additional Information:
No publications provided

Responsible Party: Pfizer
ClinicalTrials.gov Identifier: NCT01430585     History of Changes
Other Study ID Numbers: B1271003
Study First Received: August 18, 2011
Results First Received: July 18, 2014
Last Updated: July 18, 2014
Health Authority: United Kingdon: Medicines and Healthcare Products Regulatory Agency

Keywords provided by Pfizer:
Ki-67
postmenopausal early breast cancer
ER positive/HER2 negative early breast cancer

Additional relevant MeSH terms:
Breast Neoplasms
Breast Diseases
Neoplasms
Neoplasms by Site
Skin Diseases
Letrozole
Antineoplastic Agents
Aromatase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Therapeutic Uses

ClinicalTrials.gov processed this record on October 23, 2014