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

• ClinicalTrials.gov Identifier: NCT02611323
• Recruitment Status: Completed
• First Posted: November 20, 2015
• Last Update Posted: August 8, 2022
• Sponsor: Hoffmann-La Roche
• Information provided by (Responsible Party): Hoffmann-La Roche

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 (Clinical Trial)
• 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: March 9, 2016
• Actual Primary Completion Date: August 4, 2022
• Actual Study Completion Date: August 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 :

1. 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 [ Time Frame: Within 6 to 8 weeks after Day 1 of Cycle 6 (up to approximately 23 weeks) (1 cycle:21days) ]
2. Percentage of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Baseline up to 5 years ]
3. Percentage of Participants with Dose-Limiting Toxicities (DLTs) [ Time Frame: Baseline up to 21 days ]
4. Recommended Phase 2 Dose (RP2D) of Polatuzumab Vedotin [ Time Frame: Baseline up to 21 days ]
5. Recommended Phase 2 Dose (RP2D) of Venetoclax [ Time Frame: Baseline up to 21 days ]

Secondary Outcome Measures :

1. Percentage of Participants with CR, Determined by the Investigator on the basis of PET and CT Scans [ Time Frame: Within 6 to 8 weeks after Day 1 of Cycle 6 (up to approximately 23 weeks) (1 cycle:21days) ]
2. Percentage of Participants with CR, Determined by the Investigator on the Basis of CT Scans Alone [ Time Frame: Within 6 to 8 weeks after Day 1 of Cycle 6 (up to approximately 23 weeks) (1 cycle:21days) ]
3. Percentage of Participants with CR, Determined by the IRC on the Basis of CT Scans Alone [ Time Frame: Within 6 to 8 weeks after Day 1 of Cycle 6 (up to approximately 23 weeks) (1 cycle:21days) ]
4. Percentage of Participants with Objective Response, Determined by an IRC on the Basis of PET and CT Scans [ Time Frame: Within 6 to 8 weeks after Day 1 of Cycle 6 (up to approximately 23 weeks) (1 cycle:21days) ]
5. Percentage of Participants with Objective Response, Determined by the Investigator on the Basis of PET and CT Scans [ Time Frame: Within 6 to 8 weeks after Day 1 of Cycle 6 (up to approximately 23 weeks) (1 cycle:21days) ]
6. Percentage of Participants with Objective Response, Determined by an IRC on the Basis of CT Scans Alone [ Time Frame: Within 6 to 8 weeks after Day 1 of Cycle 6 (up to approximately 23 weeks) (1 cycle:21days) ]
7. Percentage of Participants with Objective Response, Determined by the Investigator on the Basis of CT Scans Alone [ Time Frame: Within 6 to 8 weeks after Day 1 of Cycle 6 (up to approximately 23 weeks) (1 cycle:21days) ]
8. Percentage of Participants with Best Response of CR or PR, Determined by the Investigator on the Basis of CT Scans Alone [ Time Frame: Baseline up to 5 years ]
9. Observed Serum Obinutuzumab Concentration [ Time Frame: 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)
10. Observed Serum Rituximab Concentration [ Time Frame: 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)
11. Observed Serum Polatuzumab Vedotin Concentration [ Time Frame: 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)
12. Observed Plasma Polatuzumab Vedotin Concentration [ Time Frame: 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)
13. Observed Serum Concentration of Total Antibody to Polatuzumab Vedotin [ Time Frame: 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)
14. Observed Plasma Concentration of Polatuzumab Vedotin Antibody-Conjugated Mono-Methyl Auristatin E (MMAE) (acMMAE) [ Time Frame: 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)
15. Observed Plasma Concentration of Polatuzumab Vedotin Unconjugated MMAE [ Time Frame: 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)
16. Observed Plasma Venetoclax Concentration [ Time Frame: 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)
17. Percentage of Participants with Human Anti-Human Antibodies (HAHAs) to Obinutuzumab [ Time Frame: 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)
18. Percentage of Participants with Anti-Therapeutic Antibodies (ATAs) to Polatuzumab Vedotin [ Time Frame: 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

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

United States, Arizona

University of Arizona Cancer Center

Tucson, Arizona, United States, 85719

United States, Connecticut

Yale Cancer Center

New Haven, Connecticut, United States, 06520

United States, Florida

Memorial Healthcare System

Pembroke, Florida, United States, 33028

United States, Georgia

Emory Univ Winship Cancer Inst

Atlanta, Georgia, United States, 30322

United States, Kentucky

University of Louisville Hospital; The James Graham Brown Cancer Center

Louisville, Kentucky, United States, 40202

United States, Michigan

University of Michigan

Ann Arbor, Michigan, United States, 48109-0934

United States, New Jersey

Rutgers Cancer Institute of New Jersey

New Brunswick, New Jersey, United States, 08901

United States, New York

Roswell Park Cancer Inst.

Buffalo, New York, United States, 14263

United States, Pennsylvania

Fox Chase Cancer Center

Philadelphia, Pennsylvania, United States, 19111

United States, Texas

Scott and White

Temple, Texas, United States, 76508

Australia, New South Wales

Royal North Shore Hospital; Haematology Department

St. Leonards, New South Wales, Australia, 2065

Calvary Mater Newcastle

Waratah, New South Wales, Australia, 2298

Australia, Queensland

Princess Alexandra Hospital

Woolloongabba, Queensland, Australia, 4102

Australia, South Australia

The Queen Elizabeth Hospital

Adelaide, South Australia, Australia, 5011

Australia, Tasmania

Royal Hobart Hospital

Hobart, Tasmania, Australia, 7000

Australia, Victoria

Peter MacCallum Cancer Center

North Melbourne, Victoria, Australia, 3051

Italy

Papa Giovanni Hospital XXIII

Bergamo, Emilia-Romagna, Italy, 24127

Istituto Scientifico Romagnolo Per Lo Studio e La Cura Dei Tumori

Meldola, Emilia-Romagna, Italy, 47014

UO Ematologia, Ospedale S.Maria delle Croci

Ravenna, Emilia-Romagna, Italy, 48121

Ospedale Infermi U.O. Ematologia

Rimini, Emilia-Romagna, Italy, 47923

Fondazione IRCCS Istituto Nazionale dei Tumori

Milano, Lombardia, Italy, 20133

SCDU Ematologia

Novara, Piemonte, Italy, 28100

A.O.U. Citta' Della Salute E Della Scienza-P.O. Molinette;S.C. Ematologia

Torino, Piemonte, Italy, 10126

Sponsors and Collaborators

Hoffmann-La Roche

Investigators

• Study Director: Clinical Trials; Hoffmann-La Roche

More Information

• Responsible Party: Hoffmann-La Roche
• ClinicalTrials.gov Identifier: NCT02611323
• Other Study ID Numbers: GO29833; 2015-001998-40 ( EudraCT Number )
• First Posted: November 20, 2015
• Last Update Posted: August 8, 2022
• Last Verified: August 2022

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Lymphoma; Lymphoma, Follicular; Lymphoma, Large B-Cell, Diffuse; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Lymphoma, Non-Hodgkin; Lymphoma, B-Cell; Rituximab; Obinutuzumab; Venetoclax; Antineoplastic Agents, Immunological; Antineoplastic Agents; Immunologic Factors; Physiological Effects of Drugs; Antirheumatic Agents