A Study of Obinutuzumab, Rituximab, Polatuzumab Vedotin, and Venetoclax in Relapsed or Refractory Follicular Lymphoma (FL) or Diffuse Large B-Cell Lymphoma (DLBCL)

Sponsor

Hoffmann-La Roche (Industry)

Overall Status

Completed

CT.gov ID

NCT02611323

Collaborator

(none)

133

Enrollment

Locations

Arms

76.8

Actual Duration (Months)

5.8

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This study will evaluate the safety, efficacy, and pharmacokinetics of induction treatment with obinutuzumab, polatuzumab vedotin, and venetoclax in participants with relapsed or refractory FL, and with rituximab, polatuzumab vedotin, and venetoclax in participants with DLBCL. Participants with FL who achieve complete response (CR), partial response (PR), or stable disease (SD) at the end of induction therapy will receive post-induction treatment with obinutuzumab and venetoclax, and participants with DLBCL who achieve CR or PR at the end of induction (EOI) will receive post-induction treatment with rituximab and venetoclax.

Condition or Disease	Intervention/Treatment	Phase
Non-Hodgkin's Lymphoma	Drug: Obinutuzumab Drug: Rituximab Drug: Polatuzumab Vedotin Drug: Venetoclax	Phase 1

Study Design

Study Type:

Interventional

Actual Enrollment :

133 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase Ib/II Study Evaluating the Safety and Efficacy of Obinutuzumab in Combination With Polatuzumab Vedotin and Venetoclax in Patients With Relapsed or Refractory Follicular Lymphoma and Rituximab in Combination With Polatuzumab Vedotin and Venetoclax in Patients With Relapsed or Refractory Diffuse Large B-Cell Lymphoma

Actual Study Start Date :

Mar 9, 2016

Actual Primary Completion Date :

Aug 4, 2022

Actual Study Completion Date :

Aug 4, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Dose-Escalation Cohort: FL Participants with relapsed or refractory FL will receive 18 weeks of induction treatment with polatuzumab vedotin and venetoclax at escalating doses to identify the recommended Phase 2 dose (RP2D) for polatuzumab vedotin and venetoclax when combined with a fixed dose of obinutuzumab. Those who achieve CR, PR, or SD at the EOI will be eligible to receive a 24-month maintenance regimen consisting of 8 months of venetoclax and 24 months of obinutuzumab.	Drug: Obinutuzumab Participants will receive a fixed dose of obinutuzumab, 1000 mg via intravenous (IV) infusion to be given on Days 1, 8 and 15 of Cycle 1 and on Day 1 of Cycles 2 to 6. Cycle length will be 21 days. For eligible participants, post-induction treatment may be given at a dose of 1000 mg via IV infusion on Day 1 of every other month (starting from Month 2) for up to 24 months, until disease progression or unacceptable toxicity. Drug: Polatuzumab Vedotin Participants will receive polatuzumab vedotin via IV infusion at doses of 1.4 or 1.8 milligrams per kilogram (mg/kg) (for FL), and 1.8 mg/kg (for DLBCL) on Day 1 of each 21-day cycle for up to 18 weeks during induction treatment. Polatuzumab vedotin will not be given during the post-induction period. Drug: Venetoclax Participants will receive venetoclax film-coated tablets at doses of 200, 400, 600, or 800 mg (for FL), and 400, 600, or 800 mg (for DLBCL) on Days 1 to 21 of each 21-day cycle. Post-induction venetoclax may continue for up to 8 months, until disease progression or unacceptable toxicity.
Experimental: Dose-Escalation Cohort: DLBCL Participants with relapsed or refractory DLBCL will receive 18 weeks of induction treatment. Venetoclax will be administered at escalating doses to identify the RP2D of venetoclax when combined with fixed doses of polatuzumab vedotin and rituximab. Those who achieve CR or PR at the EOI will be eligible to receive an 8-month consolidation regimen consisting of venetoclax and rituximab.	Drug: Rituximab Participants will receive a fixed dose of rituximab, 375 milligrams per square meter (mg/m^2) via IV infusion to be given on Day 1 of Cycles 1 to 6. Cycle length will be 21 days. For eligible participants, post-induction treatment may be given at a dose of 375 mg/m^2 via IV infusion on Day 1 of every other month (starting from Month 2) for up to 8 months, until disease progression or unacceptable toxicity. Drug: Polatuzumab Vedotin Participants will receive polatuzumab vedotin via IV infusion at doses of 1.4 or 1.8 milligrams per kilogram (mg/kg) (for FL), and 1.8 mg/kg (for DLBCL) on Day 1 of each 21-day cycle for up to 18 weeks during induction treatment. Polatuzumab vedotin will not be given during the post-induction period. Drug: Venetoclax Participants will receive venetoclax film-coated tablets at doses of 200, 400, 600, or 800 mg (for FL), and 400, 600, or 800 mg (for DLBCL) on Days 1 to 21 of each 21-day cycle. Post-induction venetoclax may continue for up to 8 months, until disease progression or unacceptable toxicity.
Experimental: Expansion Cohort: FL Participants with relapsed or refractory FL will receive 18 weeks of induction treatment with polatuzumab vedotin and venetoclax at the RP2D identified during the dose-escalation phase, in addition to obinutuzumab. Those who achieve CR, PR, or SD at the EOI will be eligible to receive a 24-month maintenance regimen consisting of 8 months of venetoclax and 24 months of obinutuzumab.	Drug: Obinutuzumab Participants will receive a fixed dose of obinutuzumab, 1000 mg via intravenous (IV) infusion to be given on Days 1, 8 and 15 of Cycle 1 and on Day 1 of Cycles 2 to 6. Cycle length will be 21 days. For eligible participants, post-induction treatment may be given at a dose of 1000 mg via IV infusion on Day 1 of every other month (starting from Month 2) for up to 24 months, until disease progression or unacceptable toxicity. Drug: Polatuzumab Vedotin Participants will receive polatuzumab vedotin via IV infusion at doses of 1.4 or 1.8 milligrams per kilogram (mg/kg) (for FL), and 1.8 mg/kg (for DLBCL) on Day 1 of each 21-day cycle for up to 18 weeks during induction treatment. Polatuzumab vedotin will not be given during the post-induction period. Drug: Venetoclax Participants will receive venetoclax film-coated tablets at doses of 200, 400, 600, or 800 mg (for FL), and 400, 600, or 800 mg (for DLBCL) on Days 1 to 21 of each 21-day cycle. Post-induction venetoclax may continue for up to 8 months, until disease progression or unacceptable toxicity.
Experimental: Expansion Cohort: DLBCL Participants with relapsed or refractory DLBCL will receive 18 weeks of induction treatment. Venetoclax will be administered at the RP2D identified during the dose-escalation phase, in addition to polatuzumab vedotin and rituximab. Those who achieve CR or PR at the EOI will be eligible to receive an 8-month consolidation regimen consisting of venetoclax and rituximab.	Drug: Rituximab Participants will receive a fixed dose of rituximab, 375 milligrams per square meter (mg/m^2) via IV infusion to be given on Day 1 of Cycles 1 to 6. Cycle length will be 21 days. For eligible participants, post-induction treatment may be given at a dose of 375 mg/m^2 via IV infusion on Day 1 of every other month (starting from Month 2) for up to 8 months, until disease progression or unacceptable toxicity. Drug: Polatuzumab Vedotin Participants will receive polatuzumab vedotin via IV infusion at doses of 1.4 or 1.8 milligrams per kilogram (mg/kg) (for FL), and 1.8 mg/kg (for DLBCL) on Day 1 of each 21-day cycle for up to 18 weeks during induction treatment. Polatuzumab vedotin will not be given during the post-induction period. Drug: Venetoclax Participants will receive venetoclax film-coated tablets at doses of 200, 400, 600, or 800 mg (for FL), and 400, 600, or 800 mg (for DLBCL) on Days 1 to 21 of each 21-day cycle. Post-induction venetoclax may continue for up to 8 months, until disease progression or unacceptable toxicity.

Outcome Measures

Primary Outcome Measures

Percentage of Participants with CR, Determined by an Independent Review Committee (IRC) on the Basis of Positron Emission Tomography (PET) and Computed Tomography (CT) Scans [Within 6 to 8 weeks after Day 1 of Cycle 6 (up to approximately 23 weeks) (1 cycle:21days)]
Percentage of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) [Baseline up to 5 years]
Percentage of Participants with Dose-Limiting Toxicities (DLTs) [Baseline up to 21 days]
Recommended Phase 2 Dose (RP2D) of Polatuzumab Vedotin [Baseline up to 21 days]
Recommended Phase 2 Dose (RP2D) of Venetoclax [Baseline up to 21 days]

Secondary Outcome Measures

Percentage of Participants with CR, Determined by the Investigator on the basis of PET and CT Scans [Within 6 to 8 weeks after Day 1 of Cycle 6 (up to approximately 23 weeks) (1 cycle:21days)]
Percentage of Participants with CR, Determined by the Investigator on the Basis of CT Scans Alone [Within 6 to 8 weeks after Day 1 of Cycle 6 (up to approximately 23 weeks) (1 cycle:21days)]
Percentage of Participants with CR, Determined by the IRC on the Basis of CT Scans Alone [Within 6 to 8 weeks after Day 1 of Cycle 6 (up to approximately 23 weeks) (1 cycle:21days)]
Percentage of Participants with Objective Response, Determined by an IRC on the Basis of PET and CT Scans [Within 6 to 8 weeks after Day 1 of Cycle 6 (up to approximately 23 weeks) (1 cycle:21days)]
Percentage of Participants with Objective Response, Determined by the Investigator on the Basis of PET and CT Scans [Within 6 to 8 weeks after Day 1 of Cycle 6 (up to approximately 23 weeks) (1 cycle:21days)]
Percentage of Participants with Objective Response, Determined by an IRC on the Basis of CT Scans Alone [Within 6 to 8 weeks after Day 1 of Cycle 6 (up to approximately 23 weeks) (1 cycle:21days)]
Percentage of Participants with Objective Response, Determined by the Investigator on the Basis of CT Scans Alone [Within 6 to 8 weeks after Day 1 of Cycle 6 (up to approximately 23 weeks) (1 cycle:21days)]
Percentage of Participants with Best Response of CR or PR, Determined by the Investigator on the Basis of CT Scans Alone [Baseline up to 5 years]
Observed Serum Obinutuzumab Concentration [Pre-infusion (0 hour [hr]) on Day 1 of Cycle 1 up to maximum 5 years. Detailed timeframe is given in outcome measure description.]
Induction: pre-infusion (0 hr), 0.5 hr post-infusion on Day 1 of Cycle 1; pre-infusion (within 5 hr prior to dose), 0.5 hr post-infusion on Day 1 on Cycles 2, 4, 6; Post-induction: pre-infusion (within 5 hr before dose) on Day 1 of Months 2, 8, 14, 20; at treatment discontinuation (up to Month 24), 120 days and 1-2 years post-last dose (maximum up to 5 years) (infusion duration: 1-2 days) (1 cycle: 21 days)
Observed Serum Rituximab Concentration [Pre-infusion (0 hr) on Day 1 of Cycle 1 up to 0.5 hr post-infusion on Day 1 of Cycle 6. Detailed timeframe is given in outcome measure description.]
Induction: pre-infusion (0 hr), 0.5 hr post-infusion on Day1 of Cycle 1; pre-infusion (within 5 hr prior to dose) on Day 1 of Cycles 2, 4; pre-infusion (-5 hr), 0.5 hr post-infusion on Day 1 of Cycle 6 (infusion duration: 60-90 minutes) (1 cycle: 21 days)
Observed Serum Polatuzumab Vedotin Concentration [Pre-infusion (0 hr) on Day 1 of Cycle 1 up to maximum 5 years. Detailed timeframe is given in outcome measure description.]
Induction: pre-infusion (0 hr) on Day 1 of Cycle 1; pre-infusion (within 5 hr prior to dose) on Day 1 on Cycles 2, 4; Post-induction: at treatment discontinuation (up to Month 24); 120 days and 1-2 years post-last dose (maximum up to 5 years) (infusion duration: 90 minutes) (1 cycle: 21 days)
Observed Plasma Polatuzumab Vedotin Concentration [Pre-infusion (0 hr) on Day 1 of Cycle 1 up to pre-infusion (within 5 hr prior to dose) on Day 1 of Cycle 6. Detailed timeframe is given in outcome measure description.]
Induction: pre-infusion (0 hr), 0.5 hr post-infusion on Day 1 of Cycle 1; Cycle 1 Days 8, 15; pre-infusion (within 5 hr prior to dose), 0.5 hr post-infusion on Day 1 on Cycles 2, 4; pre-infusion (within 5 hr prior to dose) on Day 1 of Cycle 6 (infusion duration: 90 minutes) (1 cycle: 21 days)
Observed Serum Concentration of Total Antibody to Polatuzumab Vedotin [Pre-infusion (0 hr) on Day 1 of Cycle 1 up to maximum 5 years. Detailed timeframe is given in outcome measure description.]
Induction: pre-infusion (0 hr) on Day 1 of Cycle 1; pre-infusion (within 5 hr prior to dose) on Day 1 on Cycles 2, 4; Post-induction: at treatment discontinuation (up to Month 24); 120 days and 1-2 years post-last dose (maximum up to 5 years) (infusion duration: 90 minutes) (1 cycle: 21 days)
Observed Plasma Concentration of Polatuzumab Vedotin Antibody-Conjugated Mono-Methyl Auristatin E (MMAE) (acMMAE) [Pre-infusion (0 hr) on Day 1 of Cycle 1 up to pre-infusion (within 5 hr prior to dose) on Day 1 of Cycle 6. Detailed timeframe is given in outcome measure description.]
Induction: pre-infusion (0 hr), 0.5 hr post-infusion on Day 1 of Cycle 1; Cycle 1 Days 8, 15; pre-infusion (within 5 hr prior to dose), 0.5 hr post-infusion on Day 1 on Cycles 2, 4; pre-infusion (within 5 hr prior to dose) on Day 1 of Cycle 6 (infusion duration: 90 minutes) (1 cycle: 21 days)
Observed Plasma Concentration of Polatuzumab Vedotin Unconjugated MMAE [Pre-infusion (0 hr) on Day 1 of Cycle 1 up to pre-infusion (within 5 hr prior to dose) on Day 1 of Cycle 6. Detailed timeframe is given in outcome measure description.]
Induction: pre-infusion (0 hr), 0.5 hr post-infusion on Day 1 of Cycle 1; Cycle 1 Days 8, 15; pre-infusion (within 5 hr prior to dose), 0.5 hr post-infusion on Day 1 on Cycles 2, 4; pre-infusion (within 5 hr prior to dose) on Day 1 of Cycle 6 (infusion duration: 90 minutes) (1 cycle: 21 days)
Observed Plasma Venetoclax Concentration [4 hr post-dose on Day 1 of Cycle 1 up to pre-dose (within 1 hr prior to dose) on Day 1 of Cycle 6. Detailed timeframe is given in outcome measure description.]
Induction: 4 hr post-dose on Day 1 of Cycle 1, pre-dose (within 1 hr prior to dose) and 2, 4, 6, and 8 hr post-dose on Day 1 of Cycle 2, pre-dose (within 1 hr prior to dose) on Day 1 of Cycles 4, and 6 (1 cycle: 21 days)
Percentage of Participants with Human Anti-Human Antibodies (HAHAs) to Obinutuzumab [Pre-infusion (0 hr) on Day 1 of Cycle 1 up to maximum 5 years. Detailed timeframe is given in outcome measure description.]
Induction: pre-infusion (0 hr) on Day 1 of Cycle 1; pre-infusion (within 5 hr prior to dose) on Day 1 on Cycle 6; Post-induction: at treatment discontinuation (up to Month 24), 120 days and 1-2 years post-last dose (maximum up to 5 years) (infusion duration: 1-2 days) (1 cycle: 21 days)
Percentage of Participants with Anti-Therapeutic Antibodies (ATAs) to Polatuzumab Vedotin [Pre-infusion (0 hr) on Day 1 of Cycle 1 up to maximum 5 years. Detailed timeframe is given in outcome measure description.]
Induction: pre-infusion (0 hr) on Day 1 of Cycle 1; pre-infusion (within 5 hr prior to dose) on Day 1 on Cycles 2, 4; Post-induction: at treatment discontinuation (up to Month 24), 120 days and 1-2 years post-last dose (maximum up to 5 years) (infusion duration: 1-2 days) (1 cycle: 21 days)

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
For obinutuzumab + polatuzumab vedotin + venetoclax treatment group, relapsed or refractory FL after treatment with at least one prior chemoimmunotherapy regimen that included an anti-cluster of differentiation 20 (CD20) (anti-CD20) monoclonal antibody (mAb) and for which no other more appropriate treatment option exists, as determined by the investigator
For rituximab + polatuzumab vedotin + venetoclax treatment group, relapsed or refractory DLBCL after treatment with at least one prior chemoimmunotherapy regimen that included an anti-CD20 mAb and for which no curative option exists as determined by the investigator
At least one bidimensionally measurable lesion

Exclusion Criteria:

Known CD20-negative status at relapse or progression
Prior allogeneic stem cell transplantation (SCT), or autologous SCT within 100 days prior to Day 1 of Cycle 1
Grade 3b FL
History of transformation of indolent disease to DLBCL
Current use of systemic corticosteroids greater than (>) 20 milligrams (mg) prednisone per day (or equivalent); or prior anti-cancer therapy to include: radioimmunoconjugate within 12 weeks; mAb or antibody-drug conjugate within 4 weeks; or radiotherapy/chemotherapy/hormone therapy/targeted small-molecule therapy within 2 weeks prior to Day 1 of Cycle 1
Central nervous system (CNS) disease
Active infection
Actual or potential cytochrome P450 (CYP) 3A interactions including: requirement for warfarin; use of strong and moderate CYP3A inhibitors or inducers within 7 days prior to first dose of venetoclax; or consumption of grapefruit, Seville oranges, or star fruit within 3 days prior to first dose of venetoclax
Positive for human immunodeficiency virus (HIV) or hepatitis B or C
Receipt of a live virus vaccine within 28 days prior to Day 1 of Cycle 1
Poor hematologic, renal, or hepatic function
Pregnant or lactating women
Life expectancy <3 months

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Arizona Cancer Center	Tucson	Arizona	United States	85719
2	Yale Cancer Center	New Haven	Connecticut	United States	06520
3	Memorial Healthcare System	Pembroke	Florida	United States	33028
4	Emory Univ Winship Cancer Inst	Atlanta	Georgia	United States	30322
5	University of Louisville Hospital; The James Graham Brown Cancer Center	Louisville	Kentucky	United States	40202
6	University of Michigan	Ann Arbor	Michigan	United States	48109-0934
7	Rutgers Cancer Institute of New Jersey	New Brunswick	New Jersey	United States	08901
8	Roswell Park Cancer Inst.	Buffalo	New York	United States	14263
9	Fox Chase Cancer Center	Philadelphia	Pennsylvania	United States	19111
10	Scott and White	Temple	Texas	United States	76508
11	Royal North Shore Hospital; Haematology Department	St. Leonards	New South Wales	Australia	2065
12	Calvary Mater Newcastle	Waratah	New South Wales	Australia	2298
13	Princess Alexandra Hospital	Woolloongabba	Queensland	Australia	4102
14	The Queen Elizabeth Hospital	Adelaide	South Australia	Australia	5011
15	Royal Hobart Hospital	Hobart	Tasmania	Australia	7000
16	Peter MacCallum Cancer Center	North Melbourne	Victoria	Australia	3051
17	Papa Giovanni Hospital XXIII	Bergamo	Emilia-Romagna	Italy	24127
18	Istituto Scientifico Romagnolo Per Lo Studio e La Cura Dei Tumori	Meldola	Emilia-Romagna	Italy	47014
19	UO Ematologia, Ospedale S.Maria delle Croci	Ravenna	Emilia-Romagna	Italy	48121
20	Ospedale Infermi U.O. Ematologia	Rimini	Emilia-Romagna	Italy	47923
21	Fondazione IRCCS Istituto Nazionale dei Tumori	Milano	Lombardia	Italy	20133
22	SCDU Ematologia	Novara	Piemonte	Italy	28100
23	A.O.U. Citta' Della Salute E Della Scienza-P.O. Molinette;S.C. Ematologia	Torino	Piemonte	Italy	10126