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

NCT02611323 | Completed Phase 1 Results FDA Drug

• 2 other identifiers: GO298332015-001998-40
• Study Type: interventional
• Target: 133
• Locations: 3 countries
• Sites: 23

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.

Conditions

Non-Hodgkin's Lymphoma

Outcome Measures

Primary Outcomes (6)

• Percentage of Participants With CR at EOI Determined by an Independent Review Committee (IRC) on the Basis of Positron Emission Tomography (PET) and Computed Tomography (CT) Scans

  CR at EOI was assessed by the IRC according to modified Lugano Response Criteria (MLRC) for Malignant Lymphoma 2014 using PET-CT scan. Per MLRC, CR was defined as complete metabolic response (MR) in lymph nodes and extra lymphatic sites (ELS) with a score of 1, 2, or 3, with or without a residual mass on PET 5-point scale (5-PS), where 1=no uptake above background; 2= uptake ≤mediastinum; 3= uptake \> mediastinum but ≤ liver; 4=uptake moderately \> liver; 5=uptake markedly higher than liver and/or new lesions. No new lesions; no evidence of fluorodeoxyglucose (FDG)-avid disease in bone marrow. 90% confidence interval (CI) for percentage of responders was calculated using Clopper-Pearson method. Percentages have been rounded off to the first decimal point.

  6 to 8 weeks after Day 1 of Cycle 6 (up to approximately 23 weeks) (1 cycle=21 days)

• FL Cohorts: Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)

  An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An AE could therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Any new disease or worsening of an existing disease were also considered as AEs. An SAE was defined as any AE that was fatal, life threatening, requires prolonged inpatient hospitalization, resulted in significant disability or resulted in a congenital anomaly to a mother exposed to study treatment. AEs and SAEs were reported based on the National Cancer Institute Common Terminology Criteria for AEs, version 4.0 (NCI-CTCAE, v4.0). Percentages have been rounded off to the first decimal point.

  From study start to 24 months after last dose of study drug (approximately 56 months)

• DLBCL Cohorts: Percentage of Participants With AEs and SAEs

  An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An AE could therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Any new disease or worsening of an existing disease were also considered as AEs. An SAE was defined as any AE that was fatal, life threatening, requires prolonged inpatient hospitalization, resulted in significant disability or resulted in a congenital anomaly to a mother exposed to study treatment. AEs and SAEs were reported based on the NCI-CTCAE, v4.0. Percentages have been rounded off to the first decimal point.

  From study start to 3 months after last dose of study drug (approximately 21 months)

• Number of Participants With Dose-Limiting Toxicities (DLTs)

  DLT=any one of the events that occurred in first treatment cycle \& per the investigator was related to study treatment. Any AE that lead to a delay of \> 14 days in start of next treatment cycle; Any Grade 3/4 non-hematologic AE with few exceptions; Any increase in hepatic transaminase \>3×baseline(BL) \& increase in direct bilirubin \>2×upper limit of normal (ULN), without any findings of cholestasis/jaundice/signs of hepatic dysfunction \& in absence of other contributory factors; Grade1 alanine transaminase (ALT)/aspartate transaminase (AST) elevation at BL as result of liver metastases, only a Grade ≥3 elevation, also ≥3×BL lasting \>7 days; Hematologic AE meeting protocol specified criteria. Events were graded per NCI CTCAE v4.0. Grade 1:Mild; asymptomatic/mild symptoms; Grade 2:Moderate;minimal,local/non-invasive intervention indicated; Grade 3:Severe/medically significant, but not immediately life-threatening; Grade 4:Life-threatening consequences/urgent intervention indicated.

  Day 1 of Cycle 1 to Day 1 of Cycle 2 (1 cycle=21 days) in dose-escalation phase

• RP2D of Polatuzumab Vedotin

  RP2D was defined as the highest dose with acceptable toxicity as determined from dose-escalation phase. The RP2D of polatuzumab vedotin when given in combination with fixed dose of obinutuzumab in participants with FL was determined.

  Day 1 of Cycle 1 to Day 1 of Cycle 2 (1 cycle=21 days) in dose-escalation phase

• RP2D of Venetoclax

  RP2D was defined as the highest dose with acceptable toxicity as determined from dose-escalation phase. The RP2D of venetoclax when given in combination with fixed dose of polatuzumab vedotin in participants with FL and DLBCL was determined.

  Day 1 of Cycle 1 to Day 1 of Cycle 2 (1 cycle=21 days) in dose-escalation phase

Secondary Outcomes (16)

• Percentage of Participants With CR at EOI, Determined by the Investigator on the Basis of PET-CT Scans

  6 to 8 weeks after Day 1 of Cycle 6 (up to approximately 23 weeks) (1 cycle=21days)

• Percentage of Participants With CR at EOI, Determined by the IRC on the Basis of CT Scans Alone

  6 to 8 weeks after Day 1 of Cycle 6 (up to approximately 23 weeks) (1 cycle=21days)

• Percentage of Participants With CR at EOI, Determined by the Investigator on the Basis of CT Scans Alone

  6 to 8 weeks after Day 1 of Cycle 6 (up to approximately 23 weeks) (1 cycle=21days)

• Percentage of Participants With Objective Response (OR) at EOI, Determined by an IRC on the Basis of PET and CT Scans

  6 to 8 weeks after Day 1 of Cycle 6 (up to approximately 23 weeks) (1 cycle=21days)

• Percentage of Participants With OR at EOI, Determined by the Investigator on the Basis of PET and CT Scans

  6 to 8 weeks after Day 1 of Cycle 6 (up to approximately 23 weeks) (1 cycle=21days)

Study Arms (4)

Dose-Escalation Cohort: FL

EXPERIMENTAL

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; Drug: Polatuzumab Vedotin; Drug: Venetoclax

Dose-Escalation Cohort: DLBCL

EXPERIMENTAL

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; Drug: Polatuzumab Vedotin; Drug: Venetoclax

Expansion Cohort: FL

EXPERIMENTAL

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; Drug: Polatuzumab Vedotin; Drug: Venetoclax

Expansion Cohort: DLBCL

EXPERIMENTAL

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; Drug: Polatuzumab Vedotin; Drug: Venetoclax

Interventions

Obinutuzumab DRUG

Participants will receive a fixed dose of obinutuzumab, 1000 milligrams (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.

Dose-Escalation Cohort: FL; Expansion Cohort: FL

Rituximab DRUG

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.

Dose-Escalation Cohort: DLBCL; Expansion Cohort: DLBCL

Polatuzumab Vedotin DRUG

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.

Dose-Escalation Cohort: DLBCL; Dose-Escalation Cohort: FL; Expansion Cohort: DLBCL; Expansion Cohort: FL

Venetoclax DRUG

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.

Dose-Escalation Cohort: DLBCL; Dose-Escalation Cohort: FL; Expansion Cohort: DLBCL; Expansion Cohort: FL

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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 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

Sponsors & Collaborators

• Hoffmann-La Roche: lead

Study Sites (23)

University of Arizona Cancer Center

Tucson, Arizona, 85719, United States

Location

Yale Cancer Center

New Haven, Connecticut, 06520, United States

Location

Memorial Healthcare System

Pembroke, Florida, 33028, United States

Location

Emory Univ Winship Cancer Inst

Atlanta, Georgia, 30322, United States

Location

University of Louisville Hospital; The James Graham Brown Cancer Center

Louisville, Kentucky, 40202, United States

Location

University of Michigan

Ann Arbor, Michigan, 48109-0934, United States

Location

Rutgers Cancer Institute of New Jersey

New Brunswick, New Jersey, 08901, United States

Location

Roswell Park Cancer Inst.

Buffalo, New York, 14263, United States

Location

Fox Chase Cancer Center

Philadelphia, Pennsylvania, 19111, United States

Location

Scott and White

Temple, Texas, 76508, United States

Location

Royal North Shore Hospital; Haematology Department

St Leonards, New South Wales, 2065, Australia

Location

Calvary Mater Newcastle

Waratah, New South Wales, 2298, Australia

Location

Princess Alexandra Hospital

Woolloongabba, Queensland, 4102, Australia

Location

The Queen Elizabeth Hospital

Adelaide, South Australia, 5011, Australia

Location

Royal Hobart Hospital

Hobart, Tasmania, 7000, Australia

Location

Peter MacCallum Cancer Center

North Melbourne, Victoria, 3051, Australia

Location

Papa Giovanni Hospital XXIII

Bergamo, Emilia-Romagna, 24127, Italy

Location

Istituto Scientifico Romagnolo Per Lo Studio e La Cura Dei Tumori

Meldola, Emilia-Romagna, 47014, Italy

Location

UO Ematologia, Ospedale S.Maria delle Croci

Ravenna, Emilia-Romagna, 48121, Italy

Location

Ospedale Infermi U.O. Ematologia

Rimini, Emilia-Romagna, 47923, Italy

Location

Fondazione IRCCS Istituto Nazionale dei Tumori

Milan, Lombardy, 20133, Italy

Location

SCDU Ematologia

Novara, Piedmont, 28100, Italy

Location

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

Turin, Piedmont, 10126, Italy

Location

MeSH Terms

Conditions

Lymphoma, Non-Hodgkin

Interventions

obinutuzumab; Rituximab; polatuzumab vedotin; venetoclax

Condition Hierarchy (Ancestors)

Lymphoma; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Results Point of Contact

• Title: Medical Communications
• Organization: Hoffmann-La Roche

genentech@druginfo.com

800 821-8590

Study Officials

• Clinical Trials

  Hoffmann-La Roche

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 19, 2015
• First Posted: November 20, 2015
• Study Start: March 9, 2016
• Primary Completion: August 4, 2022
• Study Completion: August 4, 2022
• Last Updated: October 10, 2023
• Results First Posted: October 10, 2023

Record last verified: 2023-09

Locations

AU (6); IT (7); US (10)