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A Study Of Inotuzumab Ozogamicin Plus Rituximab For Relapsed/Refractory Aggressive Non-Hodgkin Lymphoma Patients Who Are Not Candidates For Intensive High-Dose Chemotherapy

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: NCT01232556
Recruitment Status : Terminated (The study was terminated prematurely on May 16, 2013, for futility. No new or unexpected safety issues were identified.)
First Posted : November 2, 2010
Results First Posted : August 21, 2018
Last Update Posted : January 8, 2019
Sponsor:
Collaborator:
UCB Pharma
Information provided by (Responsible Party):
Pfizer

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Lymphoma, Non-Hodgkin
Interventions Drug: Inotuzumab ozogamicin
Drug: Rituximab
Drug: rituximab + gemcitabine
Drug: rituximab +bendamustine
Enrollment 338
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Inotuzumab Ozogamicin Plus (+) Rituximab Rituximab+Gemcitabine or Rituximab+Bendamustine
Hide Arm/Group Description Participants received rituximab 375 milligrams per square meter (mg/m^2) via intravenous (IV) infusion on Day 1 and inotuzumab ozogamicin 1.8 mg/m^2 via IV infusion on Day 2 of each 28-day cycle for a maximum of 6 cycles. Participants received either R-bendamustine (rituximab 375 mg/m^2 via IV infusion on Day 1 and bendamustine 120 mg/m^2 via IV infusion on Days 1 and 2 in 28-day cycles for a maximum of 6 cycles) or R-gemcitabine (rituximab 375 mg/m^2 via IV infusion on Days 1, 8, 15 and 22 of Cycle 1 and on Day 1 for all other cycles, and gemcitabine 1000 mg/m^2 via IV infusion on Days 1, 8 and 15 of each 28-day cycle for a maximum of 6 cycles). Choice of therapy was at the discretion of the investigator.
Period Title: Overall Study
Started 166 172
Treated 165 [1] 167
Completed 7 1
Not Completed 159 171
Reason Not Completed
Withdrawal by Subject             21             17
Death             97             97
Lost to Follow-up             0             2
Terminated by Sponsor             35             51
Other             6             4
[1]
One subject in this arm received rituximab only and was excluded from the safety population.
Arm/Group Title Inotuzumab Ozogamicin+Rituximab Rituximab+Gemcitabine or Rituximab+Bendamustine Total
Hide Arm/Group Description Participants received rituximab 375 mg/m^2 via IV infusion on Day 1 and inotuzumab ozogamicin 1.8 mg/m^2 via IV infusion on Day 2 of each 28-day cycle for a maximum of 6 cycles. Participants received either R-bendamustine (rituximab 375 mg/m^2 via IV infusion on Day 1 and bendamustine 120 mg/m^2 via IV infusion on Days 1 and 2 in 28-day cycles for a maximum of 6 cycles) or R-gemcitabine (rituximab 375 mg/m^2 via IV infusion on Days 1, 8, 15 and 22 of Cycle 1 and on Day 1 for all other cycles, and gemcitabine 1000 mg/m^2 via IV infusion on Days 1, 8 and 15 of each 28-day cycle for a maximum of 6 cycles). Choice of therapy was at the discretion of the investigator. Total of all reporting groups
Overall Number of Baseline Participants 166 172 338
Hide Baseline Analysis Population Description
Intent-to-treat (ITT) Population - included all participants who are randomized into the study.
Age, Continuous   [1] 
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 166 participants 172 participants 338 participants
68.6  (12.29) 66.9  (11.40) 67.7  (11.86)
[1]
Measure Description: Age measure using mean with Standard deviation
Sex: Female, Male   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 166 participants 172 participants 338 participants
Female
75
  45.2%
75
  43.6%
150
  44.4%
Male
91
  54.8%
97
  56.4%
188
  55.6%
[1]
Measure Description: Gender
1.Primary Outcome
Title Overall Survival
Hide Description Overall Survival (OS) was defined as the time from randomization to death due to any cause, censoring at the date of last contact or the end of the study. The Kaplan-Meier method was used to determine OS. The hazard ratio and corresponding 95% 2-sided confidence interval were calculated using stratified Cox proportional hazard regression.
Time Frame From randomization up to 5 years after last dose or up to final study visit, whichever occurs first.
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Population.
Arm/Group Title Inotuzumab Ozogamicin+Rituximab Rituximab+Gemcitabine or Rituximab+Bendamustine
Hide Arm/Group Description:
Participants received rituximab 375 mg/m^2 via IV infusion on Day 1 and inotuzumab ozogamicin 1.8 mg/m^2 via IV infusion on Day 2 of each 28-day cycle for a maximum of 6 cycles.
Participants received either R-bendamustine (rituximab 375 mg/m^2 via IV infusion on Day 1 and bendamustine 120 mg/m^2 via IV infusion on Days 1 and 2 in 28-day cycles for a maximum of 6 cycles) or R-gemcitabine (rituximab 375 mg/m^2 via IV infusion on Days 1, 8, 15 and 22 of Cycle 1 and on Day 1 for all other cycles, and gemcitabine 1000 mg/m^2 via IV infusion on Days 1, 8 and 15 of each 28-day cycle for a maximum of 6 cycles). Choice of therapy was at the discretion of the investigator.
Overall Number of Participants Analyzed 166 172
Median (95% Confidence Interval)
Unit of Measure: Months
9.5
(7.0 to 14.5)
9.5
(7.7 to 14.1)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Inotuzumab Ozogamicin+Rituximab, Rituximab+Gemcitabine or Rituximab+Bendamustine
Comments Primary null hypothesis: Equality of survival distributions. Sample size sufficient to have power 0.96 for an experimental/control hazard ratio of 0.6.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.708
Comments A one sided 0.025 level testing plan was specified with two interim analyses and final testing level at one-sided 0.023.
Method Log Rank
Comments From one sided stratified log-rank test.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.083
Confidence Interval (2-Sided) 95%
0.82 to 1.44
Estimation Comments From stratified Cox proportional hazards model. The stratification factors are are pre-randomization investigator choice, baseline Secondary International Prognostic Index (sIPI), and best response to most recent chemo therapy.
2.Primary Outcome
Title Percentage of Participants With a Treatment Emergent Adverse Event (TEAE) (Safety Population)
Hide Description Includes all TEAEs: Any event that occurred after the first dose of study drug and was not present prior to study drug administration or worsened in severity after study drug administration..
Time Frame Up to 20 weeks after the first dose of study drug
Hide Outcome Measure Data
Hide Analysis Population Description
Safety Population - included all participants who received at least 1 dose of test article (either inotuzumab ozogamicin administrated in combination with rituximab or investigator's choice). This population only excluded participants who never received any test article.
Arm/Group Title Inotuzumab Ozogamicin+Rituximab Rituximab+Gemcitabine or Rituximab+Bendamustine
Hide Arm/Group Description:
Participants received rituximab 375 mg/m^2 via IV infusion on Day 1 and inotuzumab ozogamicin 1.8 mg/m^2 via IV infusion on Day 2 of each 28-day cycle for a maximum of 6 cycles.
Participants received either R-bendamustine (rituximab 375 mg/m^2 via IV infusion on Day 1 and bendamustine 120 mg/m^2 via IV infusion on Days 1 and 2 in 28-day cycles for a maximum of 6 cycles) or R-gemcitabine (rituximab 375 mg/m^2 via IV infusion on Days 1, 8, 15 and 22 of Cycle 1 and on Day 1 for all other cycles, and gemcitabine 1000 mg/m^2 via IV infusion on Days 1, 8 and 15 of each 28-day cycle for a maximum of 6 cycles). Choice of therapy was at the discretion of the investigator.
Overall Number of Participants Analyzed 164 167
Measure Type: Number
Unit of Measure: Percentage of Participants
% participants with a TEAE 98.8 100.0
% participants with serious TEAE 37.2 37.7
% participants with Grade 3 or 4 TEAE 79.9 79.6
% participants with Grade 5 TEAE 14.6 13.8
% participants for study drug discontinuation 25.0 18.0
% participants with dose reductions due to TEAEs 27.4 29.3
% participants for study drug stopped temporarily 31.1 46.1
3.Secondary Outcome
Title Progression-Free Survival (PFS)
Hide Description

PFS is defined as time from date of randomization to date of progressive disease (PD, including investigator's claim of clinical progression), date of death from any cause, or initiation of a new treatment for the lymphoma due to persistent/refractory disease. The Kaplan-Meier method was used to determine PFS. The hazard ratio and corresponding 95% 2-sided confidence interval were calculated using stratified Cox proportional hazard regression.

PD requires the following:

  1. Appearance of any new lesion more than 1.5 cm in any axis during or at the end of treatment, even if other lesions are decreasing in size.
  2. At least a 50% increase from nadir in the sum of the product diameters of any previously involved nodes, or in a single involved node, or the size of other lesions.
  3. At least a 50% increase in the longest diameter of any single previously identified node more than 1 cm in its short axis.
Time Frame From randomization up to 2 years or final study visit, whichever occurs first, including but not limited to planned assessments scheduled approximately every 12 weeks.
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Population
Arm/Group Title Inotuzumab Ozogamicin+Rituximab Rituximab+Gemcitabine or Rituximab+Bendamustine
Hide Arm/Group Description:
Participants received rituximab 375 mg/m^2 via IV infusion on Day 1 and inotuzumab ozogamicin 1.8 mg/m^2 via IV infusion on Day 2 of each 28-day cycle for a maximum of 6 cycles.
Participants received either R-bendamustine (rituximab 375 mg/m^2 via IV infusion on Day 1 and bendamustine 120 mg/m^2 via IV infusion on Days 1 and 2 in 28-day cycles for a maximum of 6 cycles) or R-gemcitabine (rituximab 375 mg/m^2 via IV infusion on Days 1, 8, 15 and 22 of Cycle 1 and on Day 1 for all other cycles, and gemcitabine 1000 mg/m^2 via IV infusion on Days 1, 8 and 15 of each 28-day cycle for a maximum of 6 cycles). Choice of therapy was at the discretion of the investigator.
Overall Number of Participants Analyzed 166 172
Median (95% Confidence Interval)
Unit of Measure: Months
3.7
(2.9 to 5.0)
3.5
(2.8 to 4.9)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Inotuzumab Ozogamicin+Rituximab, Rituximab+Gemcitabine or Rituximab+Bendamustine
Comments Second comparison in hierarchical testing strategy was used for power calculation.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.271
Comments An hierarchical testing strategy was specified for OS, PFS and response. PFS could be tested at the 0.023 level if the OS test result were positive. Response could be tested if both the OS and PFS test results were positive.
Method Log Rank
Comments From one sided stratified log-rank test.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.924
Confidence Interval (2-Sided) 95%
0.72 to 1.19
Estimation Comments From stratified Cox proportional hazards model. The stratification factors are are pre-randomization investigator choice, baseline sIPI, and best response to most recent chemo therapy.
4.Secondary Outcome
Title Percentage of Participants With A Best Overall Response of CR or Partial Response (PR) Per NCI International Response Criteria for NHL
Hide Description

CR is defined as disappearance of all detectable clinical evidence of disease (including cleared infiltrate on repeat bone marrow aspirate/biopsy if lymphoma involvement of bone marrow before treatment).

Partial Response (PR) requires the following:

  1. ≥50 % decrease in SPD of the six largest dominant nodes or nodal masses.
  2. No increase in the size of other nodes, liver, or spleen.
  3. Splenic and hepatic nodules must regress by ≥50% in the SPD, or for single nodules, in the greatest transverse diameter.
  4. With the exception of splenic and hepatic nodules, involvement of other organs is usually assessable and no measurable disease should be present.
  5. No new sites of disease. The 95% CI was determined using the exact method based on binomial distribution.
Time Frame Up to 2 years from first study drug dose or up to final study visit, whichever occurs first, including but not limited to planned assessments scheduled approximately every 12 weeks.
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Population
Arm/Group Title Inotuzumab Ozogamicin+Rituximab Rituximab+Gemcitabine or Rituximab+Bendamustine
Hide Arm/Group Description:
Participants received rituximab 375 mg/m^2 via IV infusion on Day 1 and inotuzumab ozogamicin 1.8 mg/m^2 via IV infusion on Day 2 of each 28-day cycle for a maximum of 6 cycles.
Participants received either R-bendamustine (rituximab 375 mg/m^2 via IV infusion on Day 1 and bendamustine 120 mg/m^2 via IV infusion on Days 1 and 2 in 28-day cycles for a maximum of 6 cycles) or R-gemcitabine (rituximab 375 mg/m^2 via IV infusion on Days 1, 8, 15 and 22 of Cycle 1 and on Day 1 for all other cycles, and gemcitabine 1000 mg/m^2 via IV infusion on Days 1, 8 and 15 of each 28-day cycle for a maximum of 6 cycles). Choice of therapy was at the discretion of the investigator.
Overall Number of Participants Analyzed 166 172
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of Participants
29.5
(22.70 to 37.08)
29.7
(22.94 to 37.08)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Inotuzumab Ozogamicin+Rituximab, Rituximab+Gemcitabine or Rituximab+Bendamustine
Comments Third comparison in hierarchical testing strategy was used for power calculation.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.843
Comments An hierarchical testing strategy was specified for OS, PFS and response. PFS could be tested at the 0.023 level if the OS test result were positive. Response could be tested if both the OS and PFS test results were positive.
Method Cochran-Mantel-Haenszel
Comments The stratification factors are pre-randomization investigator choice, baseline sIPI, and best response to most recent chemo therapy.
5.Secondary Outcome
Title Percentage of Participants With A Best Overall Response of CR, Unconfirmed CR (unCR), PR, or Unconfirmed PR (unPR) Per NCI International Response Criteria for NHL
Hide Description

CR is defined as disappearance of all detectable clinical evidence of disease (including cleared infiltrate on repeat bone marrow aspirate/biopsy if lymphoma involvement of bone marrow before treatment).

Partial Response (PR) requires the following:

  1. ≥50 % decrease in SPD of the six largest dominant nodes or nodal masses.
  2. No increase in the size of other nodes, liver, or spleen.
  3. Splenic and hepatic nodules must regress by ≥50% in the SPD, or for single nodules, in the greatest transverse diameter.
  4. With the exception of splenic and hepatic nodules, involvement of other organs is usually assessable and no measurable disease should be present.
  5. No new sites of disease. unCR and unPR means didn't have confirmatory assessment (including bone marrow assessment for CR).

The 95% CI was determined using the exact method based on binomial distribution.

Time Frame Up to 2 years from first study drug dose or up to final study visit, whichever occurs first, including but not limited to planned assessments scheduled approximately every 12 weeks.
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Population
Arm/Group Title Inotuzumab Ozogamicin+Rituximab Rituximab+Gemcitabine or Rituximab+Bendamustine
Hide Arm/Group Description:
Participants received rituximab 375 mg/m^2 via IV infusion on Day 1 and inotuzumab ozogamicin 1.8 mg/m^2 via IV infusion on Day 2 of each 28-day cycle for a maximum of 6 cycles.
Participants received either R-bendamustine (rituximab 375 mg/m^2 via IV infusion on Day 1 and bendamustine 120 mg/m^2 via IV infusion on Days 1 and 2 in 28-day cycles for a maximum of 6 cycles) or R-gemcitabine (rituximab 375 mg/m^2 via IV infusion on Days 1, 8, 15 and 22 of Cycle 1 and on Day 1 for all other cycles, and gemcitabine 1000 mg/m^2 via IV infusion on Days 1, 8 and 15 of each 28-day cycle for a maximum of 6 cycles). Choice of therapy was at the discretion of the investigator.
Overall Number of Participants Analyzed 166 172
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of Participants
41.0
(33.40 to 48.85)
43.6
(36.07 to 51.36)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Inotuzumab Ozogamicin+Rituximab, Rituximab+Gemcitabine or Rituximab+Bendamustine
Comments Third comparison in hierarchical testing strategy was used for power calculation.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.714
Comments An hierarchical testing strategy was specified for OS, PFS and response. PFS could be tested at the 0.023 level if the OS test result were positive. Response could be tested if both the OS and PFS test results were positive.
Method Cochran-Mantel-Haenszel
Comments The stratification factors are pre-randomization investigator choice, baseline sIPI, and best response to most recent chemo therapy.
6.Secondary Outcome
Title Duration of Response
Hide Description The duration of overall response is measured from the first date of response until the first date that the progressive disease (PD) or death is objectively documented. The hazard ratio and corresponding 95% 2-sided confidence interval were calculated using stratified Cox proportional hazard regression.
Time Frame Up to 2 years from first study drug dose or up to final study visit, whichever occurs first, including but not limited to planned assessments scheduled approximately every 12 weeks.
Hide Outcome Measure Data
Hide Analysis Population Description
ITT population; only participants with a CR, unCR, PR, or unPR were included in the analysis
Arm/Group Title Inotuzumab Ozogamicin+Rituximab Rituximab+Gemcitabine or Rituximab+Bendamustine
Hide Arm/Group Description:
Participants received rituximab 375 mg/m^2 via IV infusion on Day 1 and inotuzumab ozogamicin 1.8 mg/m^2 via IV infusion on Day 2 of each 28-day cycle for a maximum of 6 cycles.
Participants received either R-bendamustine (rituximab 375 mg/m^2 via IV infusion on Day 1 and bendamustine 120 mg/m^2 via IV infusion on Days 1 and 2 in 28-day cycles for a maximum of 6 cycles) or R-gemcitabine (rituximab 375 mg/m^2 via IV infusion on Days 1, 8, 15 and 22 of Cycle 1 and on Day 1 for all other cycles, and gemcitabine 1000 mg/m^2 via IV infusion on Days 1, 8 and 15 of each 28-day cycle for a maximum of 6 cycles). Choice of therapy was at the discretion of the investigator.
Overall Number of Participants Analyzed 166 172
Median (95% Confidence Interval)
Unit of Measure: Months
11.56 [1] 
(7.8 to NA)
6.93
(5.5 to 10.8)
[1]
The upper limit of the 95 percent (%) confidence interval could not be determined due to the large number of censored events.
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Inotuzumab Ozogamicin+Rituximab, Rituximab+Gemcitabine or Rituximab+Bendamustine
Comments DOR was not part of the formal hypothesis testing strategy.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.142
Comments [Not Specified]
Method Log Rank
Comments From one sided stratified log-rank test.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.76
Confidence Interval (2-Sided) 95%
0.47 to 1.25
Estimation Comments From stratified Cox proportional hazards model. The stratification factors are pre-randomization investigator choice, baseline sIPI, and best response to most recent chemo therapy.
7.Secondary Outcome
Title Health Status as Assessed by the European Quality of Life 5 Dimension (EQ-5D) Questionnaire
Hide Description EQ-5D consists of a descriptive system and an EQ visual analogue scale. The descriptive system comprises the following 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 3 levels: no problems, some problems, extreme problems. The scale, the best state is marked 100 and the worst state is marked 0, is to help the participant to say how good or bad a health state is. EQ-5D index, which was reported, was derived based on US weight. The range of EQ-5D index is -0.109 to 1.00. Higher scores mean better outcomes. The average post-baseline scores for EQ-5D index were computed at approximately Week 12. The overall treatment comparisons were estimated at approximately Week 12.
Time Frame Assessed at Day 1 of each cycle and 6-9 weeks after the last dose, Cycle 3 (Week 12) reported
Hide Outcome Measure Data
Hide Analysis Population Description
ITT population
Arm/Group Title Inotuzumab Ozogamicin+Rituximab Rituximab+Gemcitabine or Rituximab+Bendamustine
Hide Arm/Group Description:
Participants received rituximab 375 mg/m^2 via IV infusion on Day 1 and inotuzumab ozogamicin 1.8 mg/m^2 via IV infusion on Day 2 of each 28-day cycle for a maximum of 6 cycles.
Participants received either R-bendamustine (rituximab 375 mg/m^2 via IV infusion on Day 1 and bendamustine 120 mg/m^2 via IV infusion on Days 1 and 2 in 28-day cycles for a maximum of 6 cycles) or R-gemcitabine (rituximab 375 mg/m^2 via IV infusion on Days 1, 8, 15 and 22 of Cycle 1 and on Day 1 for all other cycles, and gemcitabine 1000 mg/m^2 via IV infusion on Days 1, 8 and 15 of each 28-day cycle for a maximum of 6 cycles). Choice of therapy was at the discretion of the investigator.
Overall Number of Participants Analyzed 166 172
Mean (95% Confidence Interval)
Unit of Measure: Unit on a scale
0.79
(0.76 to 0.82)
0.77
(0.74 to 0.79)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Inotuzumab Ozogamicin+Rituximab, Rituximab+Gemcitabine or Rituximab+Bendamustine
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2892
Comments [Not Specified]
Method Mixed Models Analysis
Comments Repeated measures mixed effects model with treatment, time, treatment-by-time interaction, and baseline as covariate.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.02
Confidence Interval (2-Sided) 95%
-0.02 to 0.06
Estimation Comments [Not Specified]
8.Secondary Outcome
Title Health Related Quality of Life as Assessed by the Functional Assessment of Cancer Therapy for Lymphoma (FACT-Lym) Questionnaire
Hide Description FACT-Lym is a questionnaire that begins with 27 items covering four core Health-Related Quality of Life subscales: Physical Well-being (7 items), Social/Family Well-being (7), Emotional Well-being (6), and Functional Well-being (7). The FACT-Lym also includes an additional concerns subscale (15 items). It also asks participants about their concerns about lumps and swelling, fevers, infections, weight, appetite, emotional stability and treatment. The participants were requested to circle one number on a 0 to 4 points scale per line to indicate how true each statement has been for him/her during the past 7 days. FACT-Lym total score, which was reported, was derived based on FACT-Lym scoring guideline (Version 4). The range of FACT-Lym total score is 0 to 168. Higher scores mean better outcomes. The average post-baseline FACT-Lym total scores were computed at approximately Week 12. The overall treatment comparisons were estimated at approximately Week 12.
Time Frame Assessed at Day 1 of each cycle and 6-9 weeks after the last dose, Cycle 3 (Week 12) reported
Hide Outcome Measure Data
Hide Analysis Population Description
ITT population
Arm/Group Title Inotuzumab Ozogamicin+Rituximab Rituximab+Gemcitabine or Rituximab+Bendamustine
Hide Arm/Group Description:
Participants received rituximab 375 mg/m^2 via IV infusion on Day 1 and inotuzumab ozogamicin 1.8 mg/m^2 via IV infusion on Day 2 of each 28-day cycle for a maximum of 6 cycles.
Participants received either R-bendamustine (rituximab 375 mg/m^2 via IV infusion on Day 1 and bendamustine 120 mg/m^2 via IV infusion on Days 1 and 2 in 28-day cycles for a maximum of 6 cycles) or R-gemcitabine (rituximab 375 mg/m^2 via IV infusion on Days 1, 8, 15 and 22 of Cycle 1 and on Day 1 for all other cycles, and gemcitabine 1000 mg/m^2 via IV infusion on Days 1, 8 and 15 of each 28-day cycle for a maximum of 6 cycles). Choice of therapy was at the discretion of the investigator.
Overall Number of Participants Analyzed 166 172
Mean (95% Confidence Interval)
Unit of Measure: Unit on a scale
120.07
(116.74 to 123.41)
116.96
(113.74 to 120.19)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Inotuzumab Ozogamicin+Rituximab, Rituximab+Gemcitabine or Rituximab+Bendamustine
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1879
Comments [Not Specified]
Method Mixed Models Analysis
Comments Repeated measures mixed effects model with treatment, time, treatment-by-time interaction, and baseline as covariate.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 3.11
Confidence Interval (2-Sided) 95%
-1.52 to 7.74
Estimation Comments [Not Specified]
Time Frame Up to 22 weeks after the informed consent
Adverse Event Reporting Description Adverse Events calculated using safety population. One subject in the rituximab+ inotuzumab ozogamicin arm received rituximab only, and was excluded from the safety population analysis. AE summaries below are inclusive of AEs from first dose date up to 56 days after last dose of study drug.
 
Arm/Group Title Inotuzumab Ozogamicin+Rituximab Rituximab+Gemcitabine or Rituximab+Bendamustine
Hide Arm/Group Description Participants received rituximab 375 mg/m^2 via IV infusion on Day 1 and inotuzumab ozogamicin 1.8 mg/m^2 via IV infusion on Day 2 of each 28-day cycle for a maximum of 6 cycles. Participants received either R-bendamustine (rituximab 375 mg/m^2 via IV infusion on Day 1 and bendamustine 120 mg/m^2 via IV infusion on Days 1 and 2 in 28-day cycles for a maximum of 6 cycles) or R-gemcitabine (rituximab 375 mg/m^2 via IV infusion on Days 1, 8, 15 and 22 of Cycle 1 and on Day 1 for all other cycles, and gemcitabine 1000 mg/m^2 via IV infusion on Days 1, 8 and 15 of each 28-day cycle for a maximum of 6 cycles). Choice of therapy was at the discretion of the investigator.
All-Cause Mortality
Inotuzumab Ozogamicin+Rituximab Rituximab+Gemcitabine or Rituximab+Bendamustine
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/-- 
Hide Serious Adverse Events
Inotuzumab Ozogamicin+Rituximab Rituximab+Gemcitabine or Rituximab+Bendamustine
Affected / at Risk (%) Affected / at Risk (%)
Total   61/164 (37.20%)   63/167 (37.72%) 
Blood and lymphatic system disorders     
Anaemia * 1  0/164 (0.00%)  1/167 (0.60%) 
Febrile bone marrow aplasia * 1  0/164 (0.00%)  1/167 (0.60%) 
Febrile neutropenia * 1  5/164 (3.05%)  7/167 (4.19%) 
Neutropenia * 1  0/164 (0.00%)  1/167 (0.60%) 
Pancytopenia * 1  1/164 (0.61%)  1/167 (0.60%) 
Splenic infarction * 1  0/164 (0.00%)  1/167 (0.60%) 
Thrombocytopenia * 1  2/164 (1.22%)  2/167 (1.20%) 
Cardiac disorders     
Angina unstable * 1  0/164 (0.00%)  1/167 (0.60%) 
Atrial fibrillation * 1  2/164 (1.22%)  0/167 (0.00%) 
Atrial flutter * 1  0/164 (0.00%)  1/167 (0.60%) 
Atrial tachycardia * 1  0/164 (0.00%)  1/167 (0.60%) 
Myocardial infarction * 1  0/164 (0.00%)  1/167 (0.60%) 
Sinus tachycardia * 1  0/164 (0.00%)  1/167 (0.60%) 
Gastrointestinal disorders     
Abdominal pain * 1  1/164 (0.61%)  1/167 (0.60%) 
Abdominal wall haematoma * 1  0/164 (0.00%)  1/167 (0.60%) 
Colitis ulcerative * 1  1/164 (0.61%)  0/167 (0.00%) 
Diarrhoea * 1  0/164 (0.00%)  2/167 (1.20%) 
Dysphagia * 1  1/164 (0.61%)  1/167 (0.60%) 
Enteritis * 1  0/164 (0.00%)  1/167 (0.60%) 
Gastrointestinal haemorrhage * 1  2/164 (1.22%)  0/167 (0.00%) 
Ileus * 1  1/164 (0.61%)  1/167 (0.60%) 
Intestinal obstruction * 1  0/164 (0.00%)  1/167 (0.60%) 
Nausea * 1  0/164 (0.00%)  1/167 (0.60%) 
Pancreatitis acute * 1  1/164 (0.61%)  0/167 (0.00%) 
Small intestinal obstruction * 1  1/164 (0.61%)  0/167 (0.00%) 
Vomiting * 1  0/164 (0.00%)  1/167 (0.60%) 
General disorders     
Asthenia * 1  3/164 (1.83%)  2/167 (1.20%) 
Disease progression * 1  15/164 (9.15%)  20/167 (11.98%) 
Fatigue * 1  1/164 (0.61%)  1/167 (0.60%) 
General physical health deterioration * 1  1/164 (0.61%)  0/167 (0.00%) 
Oedema due to hepatic disease * 1  1/164 (0.61%)  0/167 (0.00%) 
Pain * 1  1/164 (0.61%)  0/167 (0.00%) 
Pyrexia * 1  5/164 (3.05%)  4/167 (2.40%) 
Sudden death * 1  0/164 (0.00%)  1/167 (0.60%) 
Hepatobiliary disorders     
Hepatitis * 1  1/164 (0.61%)  0/167 (0.00%) 
Hepatitis acute * 1  1/164 (0.61%)  0/167 (0.00%) 
Hyperbilirubinaemia * 1  1/164 (0.61%)  0/167 (0.00%) 
Venoocclusive liver disease * 1  2/164 (1.22%)  0/167 (0.00%) 
Infections and infestations     
Bacteraemia * 1  0/164 (0.00%)  1/167 (0.60%) 
Bronchitis * 1  1/164 (0.61%)  0/167 (0.00%) 
Cellulitis * 1  0/164 (0.00%)  2/167 (1.20%) 
Clostridium difficile colitis * 1  1/164 (0.61%)  0/167 (0.00%) 
Clostridium difficile infection * 1  1/164 (0.61%)  0/167 (0.00%) 
Cytomegalovirus infection * 1  0/164 (0.00%)  1/167 (0.60%) 
Cytomegalovirus viraemia * 1  0/164 (0.00%)  1/167 (0.60%) 
Device related infection * 1  1/164 (0.61%)  1/167 (0.60%) 
Gastroenteritis viral * 1  0/164 (0.00%)  1/167 (0.60%) 
Infection * 1  1/164 (0.61%)  1/167 (0.60%) 
Infectious pleural effusion * 1  1/164 (0.61%)  0/167 (0.00%) 
Influenza * 1  2/164 (1.22%)  0/167 (0.00%) 
Lung infection * 1  0/164 (0.00%)  1/167 (0.60%) 
Meningitis * 1  0/164 (0.00%)  1/167 (0.60%) 
Oesophageal candidiasis * 1  0/164 (0.00%)  1/167 (0.60%) 
Oral candidiasis * 1  0/164 (0.00%)  1/167 (0.60%) 
Pneumocystis jirovecii pneumonia * 1  0/164 (0.00%)  1/167 (0.60%) 
Pneumonia * 1  8/164 (4.88%)  1/167 (0.60%) 
Pneumonia fungal * 1  0/164 (0.00%)  1/167 (0.60%) 
Pyelonephritis * 1  1/164 (0.61%)  0/167 (0.00%) 
Respiratory tract infection * 1  1/164 (0.61%)  0/167 (0.00%) 
Salmonella sepsis * 1  0/164 (0.00%)  1/167 (0.60%) 
Sepsis * 1  1/164 (0.61%)  2/167 (1.20%) 
Sinusitis * 1  1/164 (0.61%)  0/167 (0.00%) 
Staphylococcal infection * 1  1/164 (0.61%)  1/167 (0.60%) 
Staphylococcal sepsis * 1  0/164 (0.00%)  1/167 (0.60%) 
Staphylococcal skin infection * 1  1/164 (0.61%)  0/167 (0.00%) 
Streptococcal bacteraemia * 1  1/164 (0.61%)  0/167 (0.00%) 
Upper respiratory tract infection * 1  0/164 (0.00%)  1/167 (0.60%) 
Urinary tract infection * 1  2/164 (1.22%)  2/167 (1.20%) 
Viral infection * 1  0/164 (0.00%)  1/167 (0.60%) 
Viral upper respiratory tract infection * 1  1/164 (0.61%)  0/167 (0.00%) 
Injury, poisoning and procedural complications     
Fall * 1  1/164 (0.61%)  0/167 (0.00%) 
Femoral neck fracture * 1  0/164 (0.00%)  1/167 (0.60%) 
Infusion related reaction * 1  1/164 (0.61%)  0/167 (0.00%) 
Overdose * 1  0/164 (0.00%)  1/167 (0.60%) 
Spinal fracture * 1  0/164 (0.00%)  2/167 (1.20%) 
Transfusion reaction * 1  1/164 (0.61%)  0/167 (0.00%) 
Investigations     
Alanine aminotransferase increased * 1  2/164 (1.22%)  0/167 (0.00%) 
Aspartate aminotransferase increased * 1  2/164 (1.22%)  0/167 (0.00%) 
Blood bilirubin increased * 1  1/164 (0.61%)  0/167 (0.00%) 
Metabolism and nutrition disorders     
Decreased appetite * 1  2/164 (1.22%)  2/167 (1.20%) 
Dehydration * 1  3/164 (1.83%)  0/167 (0.00%) 
Hypercalcaemia * 1  3/164 (1.83%)  1/167 (0.60%) 
Hyperkalaemia * 1  0/164 (0.00%)  1/167 (0.60%) 
Hyperuricaemia * 1  0/164 (0.00%)  1/167 (0.60%) 
Musculoskeletal and connective tissue disorders     
Arthralgia * 1  1/164 (0.61%)  0/167 (0.00%) 
Back pain * 1  0/164 (0.00%)  1/167 (0.60%) 
Groin pain * 1  1/164 (0.61%)  0/167 (0.00%) 
Muscular weakness * 1  1/164 (0.61%)  0/167 (0.00%) 
Pain in extremity * 1  0/164 (0.00%)  1/167 (0.60%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Lymphoma * 1  1/164 (0.61%)  0/167 (0.00%) 
Myelodysplastic syndrome transformation * 1  1/164 (0.61%)  0/167 (0.00%) 
Prostate cancer * 1  0/164 (0.00%)  1/167 (0.60%) 
Nervous system disorders     
Carotid artery stenosis * 1  0/164 (0.00%)  1/167 (0.60%) 
Cognitive disorder * 1  1/164 (0.61%)  0/167 (0.00%) 
Depressed level of consciousness * 1  0/164 (0.00%)  1/167 (0.60%) 
Dizziness * 1  1/164 (0.61%)  0/167 (0.00%) 
Dysarthria * 1  0/164 (0.00%)  1/167 (0.60%) 
IIIrd nerve paralysis * 1  0/164 (0.00%)  1/167 (0.60%) 
Paraplegia * 1  1/164 (0.61%)  0/167 (0.00%) 
Presyncope * 1  1/164 (0.61%)  1/167 (0.60%) 
Syncope * 1  0/164 (0.00%)  1/167 (0.60%) 
Tremor * 1  0/164 (0.00%)  1/167 (0.60%) 
VIIth nerve paralysis * 1  0/164 (0.00%)  1/167 (0.60%) 
Psychiatric disorders     
Confusional state * 1  0/164 (0.00%)  1/167 (0.60%) 
Delirium febrile * 1  1/164 (0.61%)  0/167 (0.00%) 
Mental status changes * 1  0/164 (0.00%)  1/167 (0.60%) 
Suicide attempt * 1  0/164 (0.00%)  1/167 (0.60%) 
Renal and urinary disorders     
Haematuria * 1  0/164 (0.00%)  1/167 (0.60%) 
Renal failure * 1  2/164 (1.22%)  2/167 (1.20%) 
Renal failure acute * 1  0/164 (0.00%)  1/167 (0.60%) 
Renal impairment * 1  0/164 (0.00%)  1/167 (0.60%) 
Urinary retention * 1  1/164 (0.61%)  0/167 (0.00%) 
Urinary tract obstruction * 1  0/164 (0.00%)  1/167 (0.60%) 
Respiratory, thoracic and mediastinal disorders     
Acute respiratory distress syndrome * 1  1/164 (0.61%)  0/167 (0.00%) 
Cough * 1  1/164 (0.61%)  0/167 (0.00%) 
Dyspnoea * 1  1/164 (0.61%)  3/167 (1.80%) 
Pneumonitis * 1  0/164 (0.00%)  1/167 (0.60%) 
Pulmonary embolism * 1  0/164 (0.00%)  1/167 (0.60%) 
Vascular disorders     
Haematoma * 1  1/164 (0.61%)  0/167 (0.00%) 
Hypotension * 1  0/164 (0.00%)  3/167 (1.80%) 
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, MedDRA v17.0
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Inotuzumab Ozogamicin+Rituximab Rituximab+Gemcitabine or Rituximab+Bendamustine
Affected / at Risk (%) Affected / at Risk (%)
Total   155/164 (94.51%)   158/167 (94.61%) 
Blood and lymphatic system disorders     
Anaemia * 1  24/164 (14.63%)  43/167 (25.75%) 
Leukopenia * 1  37/164 (22.56%)  54/167 (32.34%) 
Lymphopenia * 1  28/164 (17.07%)  39/167 (23.35%) 
Neutropenia * 1  57/164 (34.76%)  81/167 (48.50%) 
Thrombocytopenia * 1  101/164 (61.59%)  64/167 (38.32%) 
Gastrointestinal disorders     
Abdominal pain * 1  14/164 (8.54%)  13/167 (7.78%) 
Constipation * 1  38/164 (23.17%)  33/167 (19.76%) 
Diarrhoea * 1  22/164 (13.41%)  31/167 (18.56%) 
Nausea * 1  50/164 (30.49%)  54/167 (32.34%) 
Vomiting * 1  23/164 (14.02%)  32/167 (19.16%) 
General disorders     
Asthenia * 1  13/164 (7.93%)  14/167 (8.38%) 
Chills * 1  5/164 (3.05%)  9/167 (5.39%) 
Fatigue * 1  55/164 (33.54%)  42/167 (25.15%) 
Oedema peripheral * 1  17/164 (10.37%)  15/167 (8.98%) 
Pyrexia * 1  37/164 (22.56%)  35/167 (20.96%) 
Hepatobiliary disorders     
Hyperbilirubinaemia * 1  12/164 (7.32%)  3/167 (1.80%) 
Infections and infestations     
Nasopharyngitis * 1  9/164 (5.49%)  6/167 (3.59%) 
Urinary tract infection * 1  9/164 (5.49%)  12/167 (7.19%) 
Investigations     
Alanine aminotransferase increased * 1  28/164 (17.07%)  17/167 (10.18%) 
Aspartate aminotransferase increased * 1  44/164 (26.83%)  18/167 (10.78%) 
Blood alkaline phosphatase increased * 1  24/164 (14.63%)  16/167 (9.58%) 
Blood bilirubin increased * 1  10/164 (6.10%)  4/167 (2.40%) 
Blood creatinine increased * 1  5/164 (3.05%)  13/167 (7.78%) 
Blood lactate dehydrogenase increased * 1  9/164 (5.49%)  4/167 (2.40%) 
Gamma-glutamyltransferase increased * 1  38/164 (23.17%)  16/167 (9.58%) 
Haemoglobin decreased * 1  4/164 (2.44%)  10/167 (5.99%) 
Platelet count decreased * 1  9/164 (5.49%)  7/167 (4.19%) 
Weight decreased * 1  4/164 (2.44%)  11/167 (6.59%) 
White blood cell count decreased * 1  4/164 (2.44%)  12/167 (7.19%) 
Metabolism and nutrition disorders     
Decreased appetite * 1  28/164 (17.07%)  31/167 (18.56%) 
Hypercalcaemia * 1  9/164 (5.49%)  6/167 (3.59%) 
Hypokalaemia * 1  11/164 (6.71%)  14/167 (8.38%) 
Hypophosphataemia * 1  12/164 (7.32%)  12/167 (7.19%) 
Musculoskeletal and connective tissue disorders     
Arthralgia * 1  9/164 (5.49%)  4/167 (2.40%) 
Back pain * 1  10/164 (6.10%)  17/167 (10.18%) 
Pain in extremity * 1  6/164 (3.66%)  10/167 (5.99%) 
Nervous system disorders     
Dizziness * 1  8/164 (4.88%)  13/167 (7.78%) 
Dysgeusia * 1  10/164 (6.10%)  8/167 (4.79%) 
Headache * 1  8/164 (4.88%)  11/167 (6.59%) 
Psychiatric disorders     
Insomnia * 1  7/164 (4.27%)  9/167 (5.39%) 
Respiratory, thoracic and mediastinal disorders     
Cough * 1  24/164 (14.63%)  13/167 (7.78%) 
Dyspnoea * 1  9/164 (5.49%)  14/167 (8.38%) 
Skin and subcutaneous tissue disorders     
Pruritus * 1  6/164 (3.66%)  10/167 (5.99%) 
Rash * 1  8/164 (4.88%)  13/167 (7.78%) 
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, MedDRA v17.0

Interpretation of the results is limited by the small number of subjects analyzed and follow-up period was shortened due to the early termination of the study.

Adverse Events were calculated using the safety populations.

Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Pfizer ClinicalTrials.gov Call Center
Organization: Pfizer, Inc.
Phone: 1-800-718-1021
EMail: ClinicalTrials.gov_Inquiries@pfizer.com
Layout table for additonal information
Responsible Party: Pfizer
ClinicalTrials.gov Identifier: NCT01232556    
Other Study ID Numbers: B1931008
3129K5-3303 ( Other Identifier: Alias Study Number )
2010-020147-12 ( EudraCT Number )
First Submitted: October 27, 2010
First Posted: November 2, 2010
Results First Submitted: July 17, 2017
Results First Posted: August 21, 2018
Last Update Posted: January 8, 2019