A Study to Evaluate the Safety and Efficacy of Polatuzumab Vedotin in Combination With Rituximab, Gemcitabine and Oxaliplatin Compared to Rituximab, Gemcitabine and Oxaliplatin Alone in Participants With Relapsed or Refractory Diffuse Large B-Cell Lymphoma

Study Overview
=================
Brief Summary
-----------------
This study is a multicenter, open-label study of polatuzumab vedotin administered by intravenous (IV) infusion in combination with rituximab, gemcitabine and oxaliplatin (R-GemOx) in participants with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). The study comprises of two stages: a safety run-in stage and a randomized controlled trial (RCT).

Detailed Description
-----------------
The safety run-in stage (Stage 1) will assess the safety of polatuzumab vedotin plus rituximab, gemcitabine and oxaliplatin (Pola-R-GemOx) in 10 participants. The randomized controlled trial (RCT) (Stage 2) will compare Pola-R-GemOx versus R-GemOx alone using overall survival (OS). This is an event-driven trial.

Official Title
-----------------
A Phase III, Open-Label, Multicenter, Randomized, Study Evaluating the Safety and Efficacy of Polatuzumab Vedotin in Combination With Rituximab Plus Gemcitabine Plus Oxaliplatin (R-GEMOX) Versus R-GEMOX Alone in Patients With Relapsed/Refractory Diffuse Large B-Cell Lymphoma

Conditions
-----------------
Diffuse Large B-Cell Lymphoma

Intervention / Treatment
-----------------
* Drug: Polatuzumab Vedotin
* Drug: Rituximab
* Drug: Gemcitabine
* Drug: Oxaliplatin


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histologically-confirmed diffuse large B-cell lymphoma, not otherwise specified (NOS) or history of transformation of indolent disease to DLBCL Relapsed disease (disease that has recurred following a response that lasted ≥ 6 months from completion of the last line of therapy) or refractory disease (disease that did not respond to or that progressed during therapy or progressed within 6 months (< 6 months) of prior therapy) At least one (≥ 1) line of prior systemic therapy: Patients may have undergone autologous hematopoietic stem cell transplantation (HSCT) prior to recruitment; In such cases, salvage chemotherapy (e.g., rituximab, dexamethasone, cytarabine, and cisplatin [R-DHAP] and rituximab, ifosfamide, carboplatin, and etoposide phosphate [R-ICE]) will be counted as one line of therapy and conditioning chemotherapy (e.g., BEAM) followed by consolidative autologous HSCT will be counted as one line of therapy Patients may have undergone allogeneic HSCT prior to recruitment, so long as they are off all immunosuppressive therapy and have no active GVHD; In such cases, salvage chemotherapy (e.g., R-DHAP and R-ICE) will be counted as one line of therapy and conditioning chemotherapy (e.g., carmustine, etoposide, cytarabine, and melphalan [BEAM]) followed by allogeneic HSCT will be counted as a separate line of therapy Participants may have undergone CAR T-cell therapy prior to recruitment. In such cases, cell collection, conditioning chemotherapy, and infusion will be counted as one line of therapy. Local therapies (e.g., radiotherapy) will not be considered as lines of treatment For participants with a history of the transformation of indolent disease to DLBCL, it is preferred that participants have received at least one treatment for the transformed lymphoma. However, if there are cases where the participants have received an anthracycline-containing chemotherapy regimen (such as R-CHOP) for the indolent lymphoma only, then these participants can be considered as eligible. At least one bi-dimensionally measurable lesion, defined as > 1.5 cm in its longest dimension as measured by CT or MRI Eastern Cooperative Oncology Group (ECOG) performance status of 0,1 or 2 Adequate hematological function For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraception, and agreement to refrain from donating eggs For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm, Exclusion Criteria: History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies (or recombinant antibody-related fusion proteins) or known sensitivity or allergy to murine products Contraindication to rituximab, gemcitabine or oxaliplatin Peripheral neuropathy assessed to be > Grade 1 according to NCI CTCAE v5.0 Prior use of polatuzumab vedotin or a gemcitabine plus platinum-based agent combination, recent participation in a clinical trial, and/or treatment with radiotherapy, chemotherapy, immunotherapy, immunosuppressive therapy within 2 weeks Planned autologous or allogenic stem cell transplantation or CAR T-cell therapy at time of recruitment Primary or secondary central nervous system (CNS) lymphoma Richter's transformation or prior CLL Abnormal laboratory values or health conditions, as assessed by the investigator, any known conditions preventing adherence to protocol or active bacterial, viral, fungal, mycobacterial, parasitic, or other infection Vaccination with a live vaccine within 4 weeks prior to treatment Recent major surgery (within 6 weeks before the start of Cycle 1 Day 1) other than for diagnosis Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the patient at high risk from treatment complications Pregnant or breastfeeding, or intending to become pregnant during the study or within 12 months after the last dose of study drug Women of childbearing potential must have a negative serum pregnancy test result within 7 days prior to initiation of study drug

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: In stage 1 participants are all assigned to one group. In stage 2 participants are assigned to two groups in parallel for the duration of the study.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pola-R-GemOx (Stage 1)<br>Participants will receive polatuzumab vedotin 1.8 milligrams per kilogram (mg/kg) for a maximum dose of 240 mg per cycle (mg/cycle) administered intravenously (IV) and rituximab 375 milligrams per square meter (mg/m^2) administered IV on Day 1. Participants will receive gemcitabine 1000 mg/m^2 administered IV and oxaliplatin 100 mg/m^2 administered IV on Day 2. Each cycle will consist of 21 days with up to 8 cycles of treatment administration. | Drug: Polatuzumab Vedotin<br>* Polatuzumab vedotin 1.8 mg/kg for a maximum dose of 240 mg/cycle IV on Day 1 of each 21-day cycle for up to 8 cycles.<br>Drug: Rituximab<br>* Rituximab 375 mg/m2 IV on Day 1 of each 21-day cycle for up to 8 cycles.<br>* Other names: Mabthera; Rituxan;Drug: Gemcitabine<br>* Gemcitabine 1000 mg/m2 IV on Day 2 of each 21-day cycle for up to 8 cycles.<br>Drug: Oxaliplatin<br>* Oxaliplatin 100 mg/m2 IV on Day 2 of each 21-day cycle for up to 8 cycle.<br>|
| Experimental: Pola-R-GemOx (Stage 2)<br>Participants will receive polatuzumab vedotin 1.8 mg/kg for a maximum dose of 240 mg/cycle administered IV and rituximab 375 mg/m^2 administered IV on Day 1. Participants will receive gemcitabine 1000 mg/m^2 administered IV and oxaliplatin 100 mg/m^2 administered IV on Day 2. Each cycle will consist of 21 days with up to 8 cycles of treatment administration. | Drug: Polatuzumab Vedotin<br>* Polatuzumab vedotin 1.8 mg/kg for a maximum dose of 240 mg/cycle IV on Day 1 of each 21-day cycle for up to 8 cycles.<br>Drug: Rituximab<br>* Rituximab 375 mg/m2 IV on Day 1 of each 21-day cycle for up to 8 cycles.<br>* Other names: Mabthera; Rituxan;Drug: Gemcitabine<br>* Gemcitabine 1000 mg/m2 IV on Day 2 of each 21-day cycle for up to 8 cycles.<br>Drug: Oxaliplatin<br>* Oxaliplatin 100 mg/m2 IV on Day 2 of each 21-day cycle for up to 8 cycle.<br>|
| Active Comparator: R-GemOx (Stage 2)<br>Participants will receive rituximab 375 mg/m^2 administered IV on Day 1. Participants will receive gemcitabine 1000 mg/m^2 administered IV and oxaliplatin 100 mg/m^2 administered IV on Day 2. Each cycle will consist of 21 days with up to 8 cycles of treatment administration. | Drug: Rituximab<br>* Rituximab 375 mg/m2 IV on Day 1 of each 21-day cycle for up to 8 cycles.<br>* Other names: Mabthera; Rituxan;Drug: Gemcitabine<br>* Gemcitabine 1000 mg/m2 IV on Day 2 of each 21-day cycle for up to 8 cycles.<br>Drug: Oxaliplatin<br>* Oxaliplatin 100 mg/m2 IV on Day 2 of each 21-day cycle for up to 8 cycle.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Stage 1: Percentage of Participants with Adverse Events (AEs) |  | From baseline until 90 days after last dose (up to approximately 55 months) | 
| Stage 2: Overall Survival (OS) | Overall survival was defined as the time from the date of randomization to the date of death from any cause. | From randomization in RCT up to approximately 34 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Stage 1: Percentage of Participants with Peripheral Neuropathy | Peripheral neuropathy will be measured by the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity 12-Item Scale (FACT-GOG/Ntx12). FACT-GOG/Ntx12 is a 12-item self-reported questionnaire designed to measure chemotherapy-induced peripheral neuropathy and contains 12 items, covering sensory neuropathy, motor neuropathy, hearing neuropathy, and dysfunction associated with neuropathy. | From baseline up to approximately 71 months | 
| Stage 1: Percentage of Participants with Polatuzumab Vedotin Dose Interruptions and Dose Reductions |  | From baseline up to approx. 55 months | 
| Stage 1: Polatuzumab Vedotin Dose Intensity | Dose intensity is defined as the ratio of actual dose administered versus intended dose. | From baseline up to approx. 55 months | 
| Stage 1: Percentage of Participants with Anti-drug Antibodies (ADAs) to Polatuzumab Vedotin at Baseline |  | Baseline (Day 1 of Stage 1) | 
| Stage 1: Percentage of Participants with Anti-drug Antibodies (ADAs) to Polatuzumab Vedotin Post-Baseline |  | Baseline up until Month 2 of the Post-Treatment Follow-up period (up to approx. 55 months) | 
| Stage 1: Percentage of Participants with Complete Response (CR) | CR was defined as complete metabolic response assessed by the investigator through PET-CT Scan according to Lugano 2014 response criteria. | From baseline up to approximately 55 months | 
| Stage 1: Percentage of Participants with Objective Response (OR) | OR is defined as complete metabolic response (CR) or partial metabolic response (PR) and will be assessed by the investigator through PET-CT scan according to Lugano 2014 response criteria. | From baseline up to approximately 55 months | 
| Stage 1: Best Overall Response (BOR) | BOR is defined as the best response recorded from the start of treatment until end of treatment (based on PET-CT or CT data) according to Lugano 2014 response criteria, determined by the investigator | From baseline up to approximately 71 months | 
| Stage 1: Progression Free Survival (PFS) | PFS is defined as the time from enrollment to the first occurrence of disease progression (as determined by the investigator according to Lugano 2014 response criteria) or death. | From baseline up to approximately 71 months | 
| Stage 1: Overall Survival (OS) | OS is defined as the time from enrollment to death from any cause. | From baseline up to approximately 71 months | 
| Stage 1: Event Free Survival (EFS) | EFS is defined as the time from enrollment to the first occurrence of disease progression or relapse, death due to any cause or initiation of any non-protocol-specified antilymphoma treatment (NALT). | From baseline up to approximately 71 months | 
| Stage 2: Percentage of Participants with Objective Response (OR) | OR is defined as CR or PR and will be assessed by an Independent review committee through PET-CT scan according to Lugano 2014 response criteria. OR will also be assessed by the investigator using Response alone (not including PET data) and will consider complete response instead of complete metabolic response. | From randomization in RCT until up to 34 months | 
| Stage 2: Percentage of Participants with Complete Response (CR) | CR will be assessed by an Independent review committee through PET-CT scan according to Lugano 2014 response criteria. CR will also be assessed by the Investigator using Response (not including PET data) and will consider complete response instead of complete metabolic response. | From randomization in RCT until up to 34 months | 
| Stage 2: Best Overall Response (BOR) | BOR is defined as the best response recorded from the start of treatment until end of treatment (based on PET-CT or CT data) according to Lugano 2014 response criteria, determined by the investigator | From randomization in RCT until up to 49 months | 
| Stage 2: Progression Free Survival (PFS) | PFS is defined as the time from the time of randomization to the first occurrence of disease progression (as determined by the investigator according to Lugano 2014 response criteria) or death. | From randomization in RCT until up to 49 months | 
| Stage 2: Duration of Response (DOR) | DOR will be assessed in patients who had an OR, as determined by the investigator, using Lugano 2014 response criteria. DOR is defined as the time interval from the date of the first occurrence of a CR or PR (whichever status is recorded first) until the first date that progressive disease or death is documented, whichever occurs first. | From randomization in RCT until up to 49 months | 
| Stage 2: Event Free Survival (EFS) | EFS is defined as the time from enrollment to the first occurrence of disease progression or relapse, death due to any cause or initiation of NALT. | From randomization in RCT until up to 49 months | 
| Stage 2: Change From Baseline in European Organisation for Research and Treatment of Cancer (EORTC) Quality-of-Life Questionnaire Core 30 (QLQ-C30) Score | The EORTC QLQ-C30 includes five functional scales (physical, role, cognitive, emotional, social); a global health status (GHS)/quality of life (QoL) scale; and items measuring fatigue, pain, nausea and vomiting, dyspnea, appetite loss, sleep disturbance, constipation, diarrhea, and financial difficulties. The score range for each scale and single-item measure is 0 to 100, where higher scores indicate a higher response level (i.e., better functioning, better QoL, worse symptoms). Key scales included physical functioning, and fatigue, and GHS. | Baseline (Cycle 1 [each cycle is 21 days]), Cycles 2, 3, 5, and 7; 28 days after last dose; and every 2 months during follow up (up to 49 months) | 
| Stage 2: Time to Deterioration in Physical Functioning and Fatigue | Time to deterioration in physical functioning and fatigue is defined as the time from randomization to the first documentation of a 10-point decrease in EORTC QLQ-C30 physical functioning and fatigue scales from baseline. The EORTC QLQ-C30 includes five functional scales (physical, role, cognitive, emotional, social); a global health status (GHS)/quality of life (QoL) scale; and items measuring fatigue, pain, nausea and vomiting, dyspnea, appetite loss, sleep disturbance, constipation, diarrhea, and financial difficulties. The score range for each scale and single-item measure is 0 to 100, where higher scores indicate a higher response level (i.e., better functioning, better QoL, worse symptoms). Key scales included physical functioning, and fatigue, and GHS. | Baseline (Cycle 1 [each cycle is 21 days]), Cycles 2, 3, 5, and 7; 28 days after last dose; and every 2 months during follow up (up to 49 months) | 
| Stage 2: Change From Baseline in Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) Total Score | The FACT-Lym is a validated health-related quality of life (HRQoL) instrument used specifically in patients with lymphoma. It is composed of the 27-item FACT-general questionnaire (FACT-G), which measures health-related quality of life in patients undergoing any type of cancer therapy, plus the 15-item Lymphoma-Specific Subscale (FACT-Lym LYMS), which assesses the HRQoL impacts of more lymphoma-specific symptoms. Each item of the FACT-Lym is answered using a 5-point scale ranging from 0 = not at all to 4 = very much. 0 = Not at all, 1 = a little bit, 2 = somewhat, 3 = quite a bit, and 4 = Very much. FACT-LYM total score can be calculated and higher scores are reflective of better HRQoL. | Baseline (Cycle 1 [each cycle is 21 days]), Cycles 2, 3, 5, and 7; 28 days after last dose; and every 2 months during follow up (up to 49 months) | 
| Stage 2: Time to Progression in Lymphoma Symptoms According to FACT-Lym Subscale | Time to progression is defined as the time from randomization to the first documentation of a 3-point decrease (clinically meaningful change) from baseline. | Baseline (Cycle 1 [each cycle is 21 days]), Cycles 2, 3, 5, and 7; 28 days after last dose; and every 2 months during follow up (up to 49 months) | 
| Stage 2: Change from Baseline in Peripheral Neuropathy According to FACT/GOG-NTX-12 Subscale Score | FACT/GOG-Ntx12 is a 12-item self-reported questionnaire designed to measure chemotherapy-induced peripheral neuropathy and contains 12 items, covering sensory neuropathy, motor neuropathy, hearing neuropathy, and dysfunction associated with neuropathy. It is answered using a 5-point scale ranging from 0 = not at all to 4 = very much. 0 = Not at all, 1 = a little bit, 2 = somewhat, 3 = quite a bit, and 4 = Very much. FACT/GOG-Ntx12 subscale scores can be calculated with higher scores reflective of a better outcome. | Baseline (Cycle 1 [each cycle is 21 days]), Cycles 2, 3, 5, and 7; 28 days after last dose; and every 2 months during follow up (up to 49 months) | 
| Stage 2: Percentage of Participants with Adverse Events (AEs) |  | From randomization in RCT until up to 34 months | 
| Stage 2: Percentage of Participants with Polatuzumab Vedotin Dose Interruptions and Dose Reductions |  | From baseline in RCT up to approx. 34 months | 
| Stage 2: Polatuzumab Vedotin Dose Intensity | Dose intensity is defined as the ratio of actual dose administered versus intended dose. | From baseline in RCT up to approx. 34 months | 
| Stage 2: Percentage of Participants with Peripheral Neuropathy | Peripheral neuropathy will be measured by the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity 12-Item Scale (FACT-GOG/Ntx12). FACT-GOG/Ntx12 is a 12-item self-reported questionnaire designed to measure chemotherapy-induced peripheral neuropathy and contains 12 items, covering sensory neuropathy, motor neuropathy, hearing neuropathy, and dysfunction associated with neuropathy. | From randomization in RCT until up to 49 months | 
| Stage 2: Percentage of Participants with Anti-drug Antibodies (ADAs) to Polatuzumab Vedotin at Baseline |  | Baseline (Day 1 of Stage 2) | 
| Stage 2: Percentage of Participants with Anti-drug Antibodies (ADAs) to Polatuzumab Vedotin Post-Baseline |  | Baseline (Day 1 of Stage 2) up until Month 2 of the Post-Treatment Follow-up period (up to approx. 34 months) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Lymphoma, Large B-Cell, Diffuse