B1931008

Pfizer Inc.

235 E 42nd Street, New York, United States, NY 10017

Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., 001 800-718-1021, ClinicalTrials.gov_Inquiries@pfizer.com

Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., 001 800-718-1021, ClinicalTrials.gov_Inquiries@pfizer.com

No

No

No

Final

01 Jun 2015

No

Yes

28 Mar 2014

Yes

To evaluate efficacy as measured by overall survival (OS), with a goal of demonstrating the superiority of inotuzumab ozogamicin when administered in combination with rituximab, compared with an active comparator arm.

The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed.

04 Apr 2011

Yes

Yes

Spain: 22

Sweden: 12

United Kingdom: 15

Belgium: 12

Bulgaria: 4

Czech Republic: 5

France: 30

Germany: 18

Hungary: 8

Ireland: 2

Lithuania: 2

Canada: 22

Croatia: 4

India: 1

Japan: 73

Mexico: 1

Russian Federation: 7

Singapore: 3

Taiwan: 7

Thailand: 2

Ukraine: 17

United States: 71

338

134

0

0

0

0

0

0

109

222

7

Overall Study (overall period)

Randomised - controlled

Yes

Inotuzumab ozogamicin

PF-05208773

Powder for injection

Intravenous use

Inotuzumab ozogamicin 1.8 milligram per square meter (mg/m^2) via IV infusion on Day 2 of each 28-day cycle for a maximum of 6 cycles.

Rituximab

Concentrate for solution for infusion

Intravenous use

Rituximab 375 mg/m^2 via IV infusion on Day 1 of each 28-day cycle for a maximum of 6 cycles.

Rituximab

Powder for solution for injection

Intravenous use

Rituximab 375 mg/m^2 via IV infusion on Day 1 in 28-day cycles for a maximum of 6 cycles when given in combination with bendamustine and 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 when given in combination with gemcitabine.

Bendamustine

Powder for solution for infusion

Intravenous use

Bendamustine 120 mg/m^2 via IV infusion on Days 1 and 2 in 28-day cycles for a maximum of 6 cycles.

Gemcitabine

Powder for solution for infusion

Intravenous use

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.

Inotuzumab ozogamicin plus (+) rituximab

Rituximab+gemcitabine or rituximab+bendamustine

Inotuzumab ozogamicin plus (+) rituximab

Rituximab+gemcitabine or rituximab+bendamustine

Inotuzumab ozogamicin+rituximab

Subjects 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.

Rituximab+gemcitabine or rituximab+bendamustine

Subjects 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.

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 per cent (%) 2-sided confidence interval were calculated using stratified Cox proportional hazard regression. Intent-to-treat (ITT) Population.

Primary

From randomization up to 5 years after last dose or up to final study visit, whichever occurs first

Primary null hypothesis: Equality of survival distributions. Sample size sufficient to have power 0.96 for an experimental/control hazard ratio of 0.6. Hazard's Ratio 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. One sided stratified log-rank test was used.

Inotuzumab ozogamicin+rituximab v Rituximab+gemcitabine or rituximab+bendamustine

338

Pre-specified

1.083

2-sided

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: a. Appearance of any new lesion more than 1.5 centimeters (cm) in any axis during or at the end of treatment, even if other lesions are decreasing in size. b. 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. c. At least a 50% increase in the longest diameter of any single previously identified node more than 1 cm in its short axis. ITT Population.

Secondary

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

Second comparison in hierarchical testing strategy was used for power calculation. HR 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. From one sided stratified log-rank test.

Rituximab+gemcitabine or rituximab+bendamustine v Inotuzumab ozogamicin+rituximab

338

Pre-specified

0.924

2-sided

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: a. Greater than or equal to (≥)50 % decrease in SPD of the six largest dominant nodes or nodal masses. b. No increase in the size of other nodes, liver, or spleen. c. Splenic and hepatic nodules must regress by ≥50% in the SPD, or for single nodules, in the greatest transverse diameter. d. With the exception of splenic and hepatic nodules, involvement of other organs is usually assessable and no measurable disease should be present. e. No new sites of disease. The 95% CI was determined using the exact method based on binomial distribution. ITT Population.

Secondary

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

Third comparison in hierarchical testing strategy was used for power calculation. Third comparison in hierarchical testing strategy was used for power calculation. The stratification factors are pre-randomization investigator choice, baseline sIPI, and best response to most recent chemo therapy.

Inotuzumab ozogamicin+rituximab v Rituximab+gemcitabine or rituximab+bendamustine

338

Pre-specified

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: a. ≥50 % decrease in SPD of the six largest dominant nodes or nodal masses. b. No increase in the size of other nodes, liver, or spleen. c. Splenic and hepatic nodules must regress by ≥50% in the SPD, or for single nodules, in the greatest transverse diameter. d. With the exception of splenic and hepatic nodules, involvement of other organs is usually assessable and no measurable disease should be present. e. 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. ITT Population.

Secondary

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

Third comparison in hierarchical testing strategy was used for power calculation. The stratification factors are pre-randomization investigator choice, baseline sIPI, and best response to most recent chemo therapy.

Inotuzumab ozogamicin+rituximab v Rituximab+gemcitabine or rituximab+bendamustine

338

Pre-specified

The duration of overall response is measured from the time measurement criteria are met for CR or PR (whichever status is recorded first) until the first date that recurrence or progressive disease is objectively documented, taking as reference for progressive disease the smallest measurements recorded since the treatment started. ITT population; only subjects with a CR, unCR, PR, or unPR were included in the analysis. Here, "99999" in confidence interval signifies "not estimable". The upper limit of the 95 percent (%) confidence interval could not be determined due to the large number of censored events.

Secondary

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

DOR was not part of the formal hypothesis testing strategy. HR from stratified Cox proportional hazards model. The stratification factors are pre-randomization investigator choice, baseline sIPI, and best response to most recent chemo therapy. One sided stratified log-rank test was used.

Inotuzumab ozogamicin+rituximab v Rituximab+gemcitabine or rituximab+bendamustine

338

Pre-specified

0.76

2-sided

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 subject to say how good or bad a health state is.

Secondary

Day 1 of each cycle and 6-9 weeks after the last dose

FACT-Lym is a questionnaire to record the physical well-being, social/family well-being, emotional well-being, and functional well-being. It contains 42 items (questions) covering HRQOL and common lymphoma symptoms and treatment side-effects. The questionnaire begins with 27 items covering four core HRQOL 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 subjects about their concerns about lumps and swelling, fevers, infections, weight, appetite, emotional stability and treatment. The subjects 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.

Secondary

Day 1 of each cycle and 6-9 weeks after the last dose

An AE was any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. 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. Treatment-Emergent Adverse Events (TEAEs) were defined as those starting on the first study drug dose date and within 56 days after the last study drug dose date. Summaries are based on safety population (subjects who received study drug). One subject in the rituximab+ inotuzumab ozogamicin arm received rituximab only, and was excluded from the safety population analysis.

Other pre-specified

First dose date up to 56 days after last dose of study drug

SAEs: from informed consent through and including end of treatment (EOT) visit. NonSAEs: from first dose through and including EOT visit. EOT visit = at least 42 days post last dose. Summaries include SAE/AEs from first dose up to 56 days post last dose

AEs use safety population.1 subject in rituximab+inotuzumab arm received rituximab only(excluded from safety population).Source for SAEs, deaths is project database(PDB), safety database (SDB),respectively.Death(all causes)=fatal SAEs within 56 days post last dose;deaths resulting from AEs=fatal treatment related SAEs within 56 days post last dose.

17.0

Inotuzumab ozogamicin+rituximab

Rituximab+gemcitabine or rituximab+bendamustine