A Study of Pinatuzumab Vedotin (DCDT2980S) Combined With Rituximab or Polatuzumab Vedotin (DCDS4501A) Combined With Rituximab or Obinutuzumab in Participants With Relapsed or Refractory B-Cell Non-Hodgkin's Lymphoma (NHL)

Genentech, Inc.231 enrolled

Overview

This multicenter, open-label study will evaluate the safety and efficacy of pinatuzumab vedotin (DCDT2980S) or polatuzumab vedotin (DCDS4501A) in combination with rituximab (RTX), as well as of polatuzumab vedotin in combination with obinutuzumab in participants with relapsed or refractory (r/r) follicular lymphoma (FL) and r/r diffuse large B-cell lymphoma (DLBCL).

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

231

Conditions

Follicular Lymphoma Diffuse Large B-Cell Lymphoma

Interventions

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1, or 2 * Life expectancy of at least 12 weeks * History of histologically documented r/r Grades 1 to 3a FL, or r/r DLBCL * Availability of an archival or freshly biopsied tumor tissue sample must be confirmed for study enrollment * Have a clinical indication for treatment as determined by the investigator * Must have at least one bi-dimensionally measurable lesion (greater than \[\>\] 1.5 centimeters \[cm\] in its largest dimension by CT scan or Magnetic Resonance Imaging \[MRI\]) Exclusion Criteria: * Prior use of any monoclonal antibody, radio-immuno-conjugate or antibody drug conjugate within 4 weeks before study start * Treatment with radiotherapy, chemotherapy, immunotherapy, immunosuppressive therapy, or any investigational anti-cancer agent within 2 weeks prior study start * Adverse events except for sensory neuropathy from any previous treatments must be resolved or stabilized to Grade less than equal to (\</=) 2 prior study start * Completion of autologous stem cell transplant (SCT) within 100 days prior study start * Prior allogeneic SCT * Eligibility for autologous SCT (participants with r/r DLBCL) * History of severe allergic or anaphylactic reactions to monoclonal antibody therapy (or recombinant antibody-related fusion proteins) * History of other malignancy that could affect compliance with the protocol or interpretation of results * Current or past history of central nervous system lymphoma * Current Grade \>1 peripheral neuropathy * Vaccination with a live vaccine within 28 days prior to treatment

Locations (41)

Cedars-Sinai Medical Center

Los Angeles, California, United States

Stanford Cancer Center

Stanford, California, United States

Colorado Blood Cancer Institute (CBCI) at Presbyterian/ St. Luke's Medical Center

Denver, Colorado, United States

Georgetown University Medical Center Lombardi Cancer Center

Washington D.C., District of Columbia, United States

Florida Cancer Specialists - Fort Myers (Colonial Center Dr)

Fort Myers, Florida, United States

Outcomes

Primary Outcomes

Percentage of Participants With a Best Overall Response (OR) of Complete Response (CR) or Partial Response (PR) as Determined by Modified Response and Progression Criteria for NHL: Rituximab Containing Regimens (Arms A and B, Cohort C)

Tumor response was evaluated according to modified response and progression criteria for NHL published by Cheson et al (2007 and 2014) and confirmed by repeat assessments greater than or equal to (\>/=) 4 weeks after initial documentation. CR was defined as disappearance of all clinical/radiographic evidence of disease, regression of lymph nodes to normal size, absence of splenomegaly, and absence of bone marrow involvement. PR was defined as \>/=50 percent (%) decrease in sum of the products of greatest diameters (SPD) of up to six of the largest dominant lymph nodes, no increase in size of other nodes, liver, or spleen volume, a \>/=50% decrease in SPD of hepatic and splenic nodules, absence of other organ involvement, and no new sites of disease. Participants with insufficient data to determine response were classified as non-responders.

Time frame: Baseline up to 12 months after the last dose of study treatment (up to approximately 3.5 years)

Duration of Objective Response (DOR) as Determined by Modified Response and Progression Criteria for NHL: Rituximab Containing Regimens (Arms A and B, Cohort C)

Tumor response was evaluated according to modified response and progression criteria for NHL published by Cheson et al (2007 and 2014). DOR was defined as the time from the initial documentation of a CR or PR to the time of PD or death. CR was defined as disappearance of all clinical/radiographic evidence of disease, regression of lymph nodes to normal size, absence of splenomegaly, and absence of bone marrow involvement. PR was defined as \>/=50% decrease in SPD of up to six of the largest dominant lymph nodes, no increase in size of other nodes, liver, or spleen volume, a \>/=50% decrease in SPD of hepatic and splenic nodules, absence of other organ involvement, and no new sites of disease. PD was defined as appearance of any new lesion more than 1.5 centimeters (cm) in any axis, at least a 50% increase from nadir in the SPD or longest diameter of any previous lesion or node.

Time frame: First occurrence of objective response up to PD/relapse or death due to any cause, whichever occurred first (up to approximately 3.5 years)

Percentage of Participants With CR at End of Treatment (EOT) Based on Positron Emission Tomographic/Computed Tomography (PET/CT) Assessment Determined by Independent Review Committee (IRC) Per Lugano 2014 Response Criteria: Cohorts E, G, and H

Tumor response assessment was performed by an IRC according to modified Lugano classification using PET/CT scan. CR was defined as a score of 1 (no uptake above background), 2 (uptake less than or equal to \[\</=\] mediastinum), or 3 (uptake less than \[\<\] mediastinum but \</=liver) with or without a residual mass on PET 5-point scale (5-PS), for lymph nodes and extralymphatic sites; no new lesions; no evidence of fluorodeoxyglucose (FDG)-avid disease in bone marrow; and normal/immunohistochemistry (IHC)-negative bone marrow morphology. 90% confidence interval (CI) for percentage of responders was calculated using Clopper-Pearson method.

Time frame: 6-8 weeks after Cycle 8 Day 1 (cycle length = 21 Days) or last study treatment (maximum up to 27-29 weeks)

Secondary Outcomes

Number of Participants With Anti-Drug Antibodies (ADA) to Pinatuzumab Vedotin

Participants provided blood samples for evaluation of ADA. The number of participants with positive results for ADA against pinatuzumab vedotin at Baseline and at any of the post-baseline assessment time-points (overall 1.5 years) was reported. Participants positive at any post-baseline time points were post-baseline evaluable participants determined to have "Treatment-induced ADAs" or "Treatment-enhanced ADA" during the study period. Treatment-induced ADA = a participant with negative or missing Baseline ADA result(s) and at least one positive post-Baseline ADA result. Treatment-enhanced ADA = a participant with positive ADA result at Baseline who has one or more post Baseline titer results that are at least 0.60 titer unit greater than the Baseline titer result.

Time frame: Baseline, post-baseline (up to approximately 5.5 years)

Number of Participants With ADA to Polatuzumab Vedotin

Participants provided blood samples for evaluation of ADA. The number of participants with positive results for ADA against polatuzumab vedotin at Baseline and at any of the post-baseline assessment time-points (overall 1.5 years) was reported. Participants positive at any post-baseline time points were post-baseline evaluable participants determined to have "Treatment-induced ADAs" or "Treatment-enhanced ADA" during the study period. Treatment-induced ADA = a participant with negative or missing Baseline ADA result(s) and at least one positive post-Baseline ADA result. Treatment-enhanced ADA = a participant with positive ADA result at Baseline who has one or more post Baseline titer results that are at least 0.60 titer unit greater than the Baseline titer result.

Time frame: Baseline, post-baseline (up to approximately 5.5 years)

Number of Participants With ADA to Obinutuzumab

Participants provided blood samples for evaluation of ADA. The number of participants with positive results for ADA against obinutuzumab at Baseline and at any of the post-baseline assessment time-points (overall 1.5 years) was reported. Participants positive at any post-baseline time points were post-baseline evaluable participants determined to have "Treatment-induced ADAs" or "Treatment-enhanced ADA" during the study period. Treatment-induced ADA = a participant with negative or missing Baseline ADA result(s) and at least one positive post-Baseline ADA result. Treatment-enhanced ADA = a participant with positive ADA result at Baseline who has one or more post Baseline titer results that are at least 0.60 titer unit greater than the Baseline titer result.

Percentage of Participants With PD as Determined by Modified Response and Progression Criteria for NHL or Death Due to Any Cause: Rituximab Containing Regimens (Arms A and B, Cohort C)

Time frame: Baseline up to PD or death due to any cause, whichever occurred first (up to approximately 5.5 years)

Progression-free Survival (PFS) as Determined by Modified Response and Progression Criteria for NHL: Rituximab Containing Regimens (Arms A and B, Cohort C)

Tumor response was evaluated according to modified response and progression criteria for NHL published by Cheson et al (2007 and 2014) and confirmed by repeat assessments \>/=4 weeks after initial documentation. PD was defined as appearance of any new lesion more than 1.5 cm in any axis, at least a 50% increase from nadir in the SPD or longest diameter of any previous lesion or node. PFS was defined as the time from the date of randomization to the date of PD or death from any cause, whichever occurred first. In absence of PD or death, PFS was censored at the date of the last tumor assessment. Participants with no post-baseline tumor assessment were censored on the date of randomization or date of enrollment. The median PFS was estimated using Kaplan-Meier estimates and the 95% CI for median was computed using the method of Brookmeyer and Crowley.

Time frame: Baseline up to PD or death due to any cause, whichever occurred first (up to approximately 5.5 years)

Percentage of Participants Who Died Due to Any Cause: Rituximab Containing Regimens (Arms A and B, Cohort C)

Percentage of participants who died due to any cause was reported.

Time frame: Baseline up to death due to any cause (from baseline up to study completion date, up to approximately 5.5 years)

Overall Survival (OS): Rituximab Containing Regimens (Arms A and B, Cohort C)

OS was defined as the time from the date of randomization or enrollment to the date of death from any cause. The median OS was estimated using Kaplan-Meier estimates and the 95% CI for median was computed using the method of Brookmeyer and Crowley.

Time frame: Baseline up to death due to any cause (from baseline up to study completion date, up to approximately 5.5 years)

Percentage of Participants With CR at EOT Based on PET/CT Assessment as Determined by Investigator Per Lugano 2014 Response Criteria: Obinutuzumab-Containing Cohorts (Cohorts E, G, and H)

Tumor response assessment was performed by the investigator according to modified Lugano classification using PET/CT scan. CR was defined as a score of 1 (no uptake above background), 2 (uptake \</=mediastinum), or 3 (uptake \<mediastinum but \</=liver) with or without a residual mass on PET 5-PS, for lymph nodes and extralymphatic sites; no new lesions; no evidence of FDG-avid disease in bone marrow; and normal/IHC-negative bone marrow morphology. 90% CI for percentage of responders was calculated using Clopper-Pearson method.

Time frame: 6-8 weeks after Cycle 8 Day 1 (cycle length = 21 Days) or last study treatment (maximum up to 27-29 weeks)

Percentage of Participants With OR at EOT Based on PET/CT Assessment as Determined by IRC Per Lugano 2014 Response Criteria: Obinutuzumab-Containing Cohorts (Cohorts E, G, and H)

Tumor response assessment was performed by an IRC according to modified Lugano classification using PET/CT scan. OR was defined as a response of CR or PR. CR was defined as a score of 1 (no uptake above background), 2 (uptake \</=mediastinum), or 3 (uptake \<mediastinum but \</=liver) with or without a residual mass on PET 5-PS, for lymph nodes and extralymphatic sites; no new lesions; no evidence of FDG-avid disease in bone marrow; and normal/IHC-negative bone marrow morphology. PR was defined as a score 4 (uptake moderately greater than \[\>\] liver) or 5 (uptake markedly \>liver and/or new lesions) with reduced uptake compared with baseline and residual mass(es) of any size on PET 5-PS for lymph nodes and extralymphatic sites; no new lesions; and reduced residual uptake in bone marrow compared with baseline. 90% CI for percentage of responders was calculated using Clopper-Pearson method.

Time frame: 6-8 weeks after Cycle 8 Day 1 (cycle length = 21 Days) or last study treatment (maximum up to 27-29 weeks)

Percentage of Participants With OR at EOT Based on PET/CT Assessment as Determined by the Investigator Per Lugano 2014 Response Criteria: Obinutuzumab-Containing Cohorts (Cohorts E, G, and H)

Tumor response assessment was performed by investigator according to modified Lugano classification using PET/CT scan. OR was defined as a response of CR or PR. CR was defined as a score of 1 (no uptake above background), 2 (uptake \</=mediastinum), or 3 (uptake \<mediastinum but \</=liver) with or without a residual mass on PET 5-PS, for lymph nodes and extralymphatic sites; no new lesions; no evidence of FDG-avid disease in bone marrow; and normal/IHC-negative bone marrow morphology. PR was defined as a score 4 (uptake moderately \>liver) or 5 (uptake markedly \>liver and/or new lesions) with reduced uptake compared with baseline and residual mass(es) of any size on PET 5-PS for lymph nodes and extralymphatic sites; no new lesions; and reduced residual uptake in bone marrow compared with baseline. 90% CI for percentage of responders was calculated using Clopper-Pearson method.

Time frame: 6-8 weeks after Cycle 8 Day 1 (cycle length = 21 Days) or last study treatment (maximum up to 27-29 weeks)

Percentage of Participants With CR at EOT Based on CT Assessment Alone as Determined by IRC Per Lugano 2014 Response Criteria: Obinutuzumab-Containing Cohorts (Cohorts E + H and E + G)

Tumor response assessment was performed by an IRC according to modified Lugano classification using CT scan. CR was defined as reduction of longest transverse diameter (LDi) of target nodes/nodal masses to less than or equal to (\</=) 1.5 cm, no extralymphatic sites of disease, absence of non-measured lesions and new lesions, reduction of enlarged organs to normal, and normal/IHC-negative bone marrow morphology. 90% CI for percentage of responders was calculated using Clopper-Pearson method.

Time frame: 6-8 weeks after Cycle 8 Day 1 (cycle length = 21 Days) or last study treatment (maximum up to 27-29 weeks)

Percentage of Participants With CR at EOT Based on CT Assessment Alone as Determined by Investigator Per Lugano 2014 Response Criteria: Obinutuzumab-Containing Cohorts (Cohorts E + H and E + G)

Tumor response assessment was performed by investigator according to modified Lugano classification using CT scan. CR was defined as reduction of LDi of target nodes/nodal masses to \</=1.5 cm, no extralymphatic sites of disease, absence of non-measured lesions and new lesions, reduction of enlarged organs to normal, and normal/IHC-negative bone marrow morphology. 90% CI for percentage of responders was calculated using Clopper-Pearson method.

Time frame: 6-8 weeks after Cycle 8 Day 1 (cycle length = 21 Days) or last study treatment (maximum up to 27-29 weeks)

Percentage of Participants With OR at EOT Based on CT Assessment Alone as Determined by IRC Per Lugano 2014 Response Criteria: Obinutuzumab-Containing Cohorts (Cohorts E + H and E + G)

Tumor response assessment was performed by an IRC according to modified Lugano classification using CT scan. OR was defined as a response of CR or PR. CR was defined as reduction of LDi of target nodes/nodal masses to \</=1.5 cm, no extralymphatic sites of disease, absence of non-measured lesions and new lesions, reduction of enlarged organs to normal, and normal/IHC-negative bone marrow morphology. PR was defined as \>/=50% decrease in SPD of up to 6 target measurable nodes and extra-nodal sites; absence/reduction/no increase in size of non-measured lesions; reduction in length of spleen by at least \>50% beyond normal; and no new lesions. 90% CI for percentage of responders was calculated using Clopper-Pearson method.

Time frame: 6-8 weeks after Cycle 8 Day 1 (cycle length = 21 Days) or last study treatment (maximum up to 27-29 weeks)

Percentage of Participants With OR at EOT Based on CT Assessment Alone as Determined by Investigator Per Lugano 2014 Response Criteria: Obinutuzumab-Containing Cohorts (Cohorts E + H and E + G)

Tumor response assessment was performed by investigator according to modified Lugano classification using CT scan. OR was defined as a response of CR or PR. CR was defined as reduction of LDi of target nodes/nodal masses to \</=1.5 cm, no extralymphatic sites of disease, absence of non-measured lesions and new lesions, reduction of enlarged organs to normal, and normal/IHC-negative bone marrow morphology. PR was defined as \>/=50% decrease in SPD of up to 6 target measurable nodes and extra-nodal sites; absence/reduction/no increase in size of non-measured lesions; reduction in length of spleen by at least \>50% beyond normal; and no new lesions. 90% CI for percentage of responders was calculated using Clopper-Pearson method.

Time frame: 6-8 weeks after Cycle 8 Day 1 (cycle length = 21 Days) or last study treatment (maximum up to 27-29 weeks)

Percentage of Participants With Best OR Based on PET/CT or CT Assessment as Determined by Investigator Per Lugano 2014 Response Criteria: Obinutuzumab-Containing Cohorts (Cohorts E, G, and H)

Tumor response assessment was performed by investigator according to modified Lugano classification using PET/CT or CT scan. Best OR was defined as a response of CR or PR. CR was defined as a score of 1 (no uptake above background), 2 (uptake \</=mediastinum), or 3 (uptake \<mediastinum but \</=liver) with or without a residual mass on PET 5-PS, for lymph nodes and extralymphatic sites; no new lesions; no evidence of FDG-avid disease in bone marrow; and normal/IHC-negative bone marrow morphology. PR was defined as a score 4 (uptake moderately \>liver) or 5 (uptake markedly \>liver and/or new lesions) with reduced uptake compared with baseline and residual mass(es) of any size on PET 5-PS for lymph nodes and extralymphatic sites; no new lesions; and reduced residual uptake in bone marrow compared with baseline. 90% CI for percentage of responders was calculated using Clopper-Pearson method.

Time frame: Baseline up to disease progression or death, whichever occurred first (up to approximately 5.5 years)

Area Under the Concentration-Time Curve From Time Zero to Infinity (AUCinf) of Rituximab: Rituximab Containing Regimens (Arms A and B, Cohort C)

AUCinf for rituximab was estimated from serum concentration data using non-compartmental analysis.

Time frame: Pre-infusion (Hour 0) & 30 minutes post-infusion (infusion length= 2-6 hours) on Day 1 of Cycle 1; Day 8, Day 15 of Cycle 1 (Cycle length= 21 days)

Maximum Observed Concentration (Cmax) of Rituximab: Rituximab Containing Regimens (Arms A and B, Cohort C)

Cmax for rituximab was estimated from serum concentration data using non-compartmental analysis.

Time frame: Pre-infusion (Hour 0) & 30 minutes post-infusion (infusion length= 2-6 hours) on Day 1 of Cycle 1; Day 8, Day 15 of Cycle 1 (Cycle length= 21 days)

Systemic Clearance (CL) of Rituximab: Rituximab Containing Regimens (Arms A and B, Cohort C)

CL for rituximab was estimated from serum concentration data using non-compartmental analysis.

Time frame: Pre-infusion (Hour 0) & 30 minutes post-infusion (infusion length= 2-6 hours) on Day 1 of Cycle 1; Day 8, Day 15 of Cycle 1 (Cycle length= 21 days)

Half-Life (t1/2) of Rituximab: Rituximab Containing Regimens (Arms A and B, Cohort C)

t1/2 for rituximab was estimated from serum concentration data using non-compartmental analysis. Time Frame: Pre-infusion (Hour 0) \& 30 minutes post-infusion (infusion length= 2-6 hours) on Day 1 of Cycle 1-4 and every 4th Cycle thereafter (approximately up to 1.5 years); Day 8, Day 15 of Cycle 1 and 3; 30 Days after last infusion; 2, 4, \& 6 months after treatment completion visit (approximately up to 1.5 years, Cycle length= 21 days).

Time frame: Day 1 up to 1.5 years (detailed timeframe is provided in the Outcome Measure Description)

Volume of Distribution at Steady State (Vss) of Rituximab: Rituximab Containing Regimens (Arms A and B, Cohort C)

Vss for rituximab was estimated from serum concentration data using non-compartmental analysis. Time Frame: Pre-infusion (Hour 0) \& 30 minutes post-infusion (infusion length= 2-6 hours) on Day 1 of Cycle 1-4 and every 4th Cycle thereafter (approximately up to 1.5 years); Day 8, Day 15 of Cycle 1 and 3; 30 Days after last infusion; 2, 4, \& 6 months after treatment completion visit (approximately up to 1.5 years, Cycle length= 21 days)

Time frame: Day 1 up to 1.5 years (detailed timeframe is provided in the Outcome Measure Description)

AUCinf of Total Antibody for Pinatuzumab Vedotin at Dose Level 2.4 mg/kg Given in Combination With Rituximab

AUCinf of total antibody for pinatuzumab vedotin was estimated from serum concentration data using non-compartmental analysis. Total antibody is defined as antibody with Monomethyl Auristatin E (MMAE)-to-antibody ratio equal or greater than zero, including fully conjugated, partially unconjugated, and fully unconjugated antibody.