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

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the efficacy of inotuzumab ozogamicin plus rituximab in relapsed/refractory aggressive Non-Hodgkin lymphoma patients who are not candidates for intensive high-dose chemotherapy. Specifically, the goal is to demonstrate the superiority of this combination compared with an active comparator arm (investigator's choice of rituximab+bendamustine or rituximab+gemcitabine) using the primary endpoint of overall survival.

Official Title
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AN OPEN-LABEL, RANDOMIZED, PHASE 3 STUDY OF INOTUZUMAB OZOGAMICIN ADMINISTERED IN COMBINATION WITH RITUXIMAB COMPARED TO DEFINED INVESTIGATOR'S CHOICE THERAPY IN SUBJECTS WITH RELAPSED OR REFRACTORY CD22-POSITIVE AGGRESSIVE NON-HODGKIN LYMPHOMA WHO ARE NOT CANDIDATES FOR INTENSIVE HIGH-DOSE CHEMOTHERAPY

Conditions
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Lymphoma, Non-Hodgkin

Intervention / Treatment
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* Drug: Inotuzumab ozogamicin
* Drug: Rituximab
* Drug: rituximab + gemcitabine
* Drug: rituximab +bendamustine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: - Exclusion Criteria: -

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br>Inotuzumab ozogamicin+rituximab | Drug: Inotuzumab ozogamicin<br>* 1.8 mg/m2 on day 2 every 28 days by IV infusion, 3 to 6 cycles<br>* Other names: CMC-544;Drug: Rituximab<br>* 375 mg/m2 on day 1 every 28 days by IV infusion, 3 to 6 cycles<br>|
| Active Comparator: 2<br>Investigator's choice of (1) rituximab+gemcitabine, or (2) rituximab+bendamustine | Drug: rituximab + gemcitabine<br>* rituximab 375 mg/m2 on days 1, 8, 15, and 22 of cycle 1, and day 1 of cycles 2 to 6, every 28 days by IV infusion, 3 to 6 cycles; gemcitabine 1000 mg/m2 on days 1, 8, and 15 every 28 days, 3 to 6 cycles<br>Drug: rituximab +bendamustine<br>* rituximab 375 mg/m2 on day 1 every 28 days by IV infusion, 3 to 6 cycles; bendamustine 120 mg/m2 on days 1 and 2 by IV infusion every 28 days, 3 to 6 cycles<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | 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. | From randomization up to 5 years after last dose or up to final study visit, whichever occurs first. | 
| Percentage of Participants With a Treatment Emergent Adverse Event (TEAE) (Safety Population) | 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.. | Up to 20 weeks after the first dose of study drug | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) | 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: 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. 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. At least a 50% increase in the longest diameter of any single previously identified node more than 1 cm in its short axis. | 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. | 
| Percentage of Participants With A Best Overall Response of CR or Partial Response (PR) Per NCI International Response Criteria for NHL | 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: ≥50 % decrease in SPD of the six largest dominant nodes or nodal masses. No increase in the size of other nodes, liver, or spleen. Splenic and hepatic nodules must regress by ≥50% in the SPD, or for single nodules, in the greatest transverse diameter. With the exception of splenic and hepatic nodules, involvement of other organs is usually assessable and no measurable disease should be present. No new sites of disease. The 95% CI was determined using the exact method based on binomial distribution. | 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. | 
| 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 | 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: ≥50 % decrease in SPD of the six largest dominant nodes or nodal masses. No increase in the size of other nodes, liver, or spleen. Splenic and hepatic nodules must regress by ≥50% in the SPD, or for single nodules, in the greatest transverse diameter. With the exception of splenic and hepatic nodules, involvement of other organs is usually assessable and no measurable disease should be present. 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. | 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. | 
| Duration of Response | 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. | 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. | 
| Health Status as Assessed by the European Quality of Life 5 Dimension (EQ-5D) Questionnaire | 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. | Assessed at Day 1 of each cycle and 6-9 weeks after the last dose, Cycle 3 (Week 12) reported | 
| Health Related Quality of Life as Assessed by the Functional Assessment of Cancer Therapy for Lymphoma (FACT-Lym) Questionnaire | 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. | Assessed at Day 1 of each cycle and 6-9 weeks after the last dose, Cycle 3 (Week 12) reported | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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inotuzumab ozogamicin, aggressive Non-Hodgkin lymphoma, diffuse large b-cell lymphoma, relapsed/refractory lymphoma