A Study Evaluating the Safety, Efficacy and Pharmacokinetics of Venetoclax in Combination With Polatuzumab Vedotin Plus Rituximab (R) and Cyclophosphamide, Doxorubicin, Prednisone (CHP) in Participants With Untreated BCL-2 Immunohistochemistry (IHC)-Positive Diffuse Large B-Cell Lymphoma (DLBCL)

A Phase Ib Study Evaluating the Safety, Efficacy, and Pharmacokinetics of Venetoclax in Combination With Polatuzumab Vedotin Plus Rituximab (R) and Cyclophosphamide, Doxorubicin, Prednisone (CHP) in Patients With Untreated BCL-2 Immunohistochemistry (IHC)-Positive Diffuse Large B-Cell Lymphoma

This Phase Ib, open-label, multicenter study evaluates the safety, efficacy, and pharmacokinetics of venetoclax in combination with Pola + R-CHP in previously untreated participants with BCL-2 IHC-positive DLBCL. Approximately 50 participants will be enrolled in this study in five consecutive cohorts each consisting of approximately 10 participants.

Study Overview

• Status: Active, not recruiting
• Conditions: Lymphoma, Large B-Cell, Diffuse
• Intervention / Treatment: Drug: Venetoclax; Drug: Polatuzumab Vedotin; Drug: Rituximab; Drug: Cyclophosphamide; Drug: Doxorubicin; Drug: Prednisone

• Study Type: Interventional
• Enrollment (Estimated): 50
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Reference Study ID Number: BO42203 https://forpatients.roche.com/; Phone Number: 888-662-6728 (U.S. and Canada); Email: global-roche-genentech-trials@gene.com

Study Locations

• France
  • Lille, France, 59037
    • Centre Hospitalier Régional Universitaire de Lille (CHRU) - Hôpital Claude Huriez
  • Montpellier, France, 34295
    • CHU Montpellier - Saint ELOI
  • Nantes, France, 44093
    • CHU de Nantes; Cancéro-dermatologie
  • Paris, France, 75475
    • Hôpital Saint-Louis
  • Pierre Benite, France, 69310
    • Centre Hospitalier Lyon Sud; Service d'Oncologie Médicale
  • Rennes cedex 09, France, 35033
    • CHU Rennes - Hôpital Pontchaillou
  • Rouen, France, 76038
    • Centre Henri Becquerel
• Italy
  • Campania
    • Napoli, Campania, Italy, 80131
      • Istituto Nazionale Tumori Irccs Fondazione g. Pascale;s.c. Ematologia Oncologica
  • Emilia-Romagna
    • Bologna, Emilia-Romagna, Italy, 40138
      • Azienda Ospedaliero-Universitaria Policlinico S. Orsola Malpighi; Dip. Scienze Mediche e Chirurgiche
    • Meldola, Emilia-Romagna, Italy, 47014
      • Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori - IRST; Farmacia Oncologica
    • Ravenna, Emilia-Romagna, Italy, 48100
      • Ospedale Santa Maria Delle Croci
  • Piemonte
    • Pisa, Piemonte, Italy, 56126
      • Azienda Ospedaliero Universitaria Pisana-Ospedale Santa Chia
• Spain
  • Barcelona, Spain, 08035
    • Hospital Universitari Vall d'Hebron
  • Barcelona, Spain, 08025
    • Hospital de la Santa Creu i Sant Pau; Servicio de Dermatologia
  • Madrid, Spain, 28007
    • Hospital General Univ. Gregorio Marañón
  • Valencia, Spain, 46026
    • Hospital Universitario La Fe; Servicio de Farmacia
  • Navarra
    • Pamplona, Navarra, Spain, 31008
      • Clinica Universidad de Navarra
• United States
  • New York
    • New York, New York, United States, 10065
      • Memorial Sloan-Kettering Cancer Center
    • New York, New York, United States, 10016
      • NYU Langone Hospitals, NYU Langone Rusk Ambulatory Surgical Pharmacy
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • SARAH CANNON RESEARCH INST.; Tennessee Oncology, PLLC

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Previously untreated participants with CD20-positive DLBCL.
• BCL-2 protein overexpression by IHC, as assessed by local testing.
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1, or 2.
• International Prognostic Index (IPI) 2-5.
• Life expectancy of more than 6 months.
• Left ventricular ejection fraction (LVEF) ≥ 50%, as determined on cardiac multiple-gated acquisition (MUGA) scan or cardiac echocardiogram (ECHO).
• Availability of archival or freshly collected tumor tissue prior to study enrollment.
• At least one bi-dimensionally fluorodeoxyglucose-avid measurable lymphoma lesion on PET/CT scan, defined as > 1.5 cm in its longest dimension on CT scan.
• Adequate hematopoietic 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 a condom, and agreement to refrain from donating sperm.

Exclusion Criteria:

• Current diagnosis of unclassifiable B-cell lymphoma.
• Prior treatment for indolent lymphoma.
• Current Grade > 1 peripheral neuropathy.
• Prior organ transplantation.
• Prior use of any monoclonal antibody within 3 months and any investigational therapy within 28 days prior to the start of Cycle 1.
• Vaccination with live vaccines within 28 days prior to the start of Cycle 1.
• Prior therapy for DLBCL and High-Grade B-cell Lymphoma (HGBCL) with the exception of palliative, short-term treatment with corticosteroids.
• Recent major surgery (within 6 weeks prior to the start of Day 1 of Cycle 1), other than for diagnosis.
• History of other cancers within 2 years prior to screening.
• Any active infection that, in the opinion of the investigator, would impact participant safety within 7 days prior to Day 1 of Cycle 1.
• Serious infection requiring oral or IV antibiotics within 4 weeks prior to Day 1 of Cycle 1.
• Any serious medical condition or abnormality in clinical laboratory tests that, in the investigator's judgment, precludes the participant's safe participation in and completion of the study.
• Positive test for Hepatitis B/C Viruses (HBV/HCV) and Human T-cell Leukemia Virus (HTLV)-1.
• Known infection with HIV.
• History of progressive multifocal leukoencephalopathy.
• Suspected active or latent tuberculosis.
• Clinically significant history of liver disease, including viral or other hepatitis or cirrhosis.
• Substance abuse, including non-prescription drug and alcohol dependence, within 12 months prior to screening.
• Pregnant or breastfeeding, or intending to become pregnant during the study within 6 months after the final dose of venetoclax, 9 months after the final dose of polatuzumab vedotin, or 12 months after the final dose of rituximab.
• History or presence of an abnormal ECG that is clinically significant in the investigator's opinion.
• Malabsorption syndrome or other condition that would interfere with enteral absorption.
• Blood transfusion within 14 days prior to screening.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Venetoclax (Schedule A); Participants enrolled in dosing Schedule A will receive a total of six 21-day cycles of venetoclax treatment for 5 days in combination with Polatuzumab Vedotin + R-CHP (Rituximab, Cyclophosphamide, Doxorubicin and Prednisone) as described below: Schedule A: Participants will self-administer Venetoclax orally (PO) once daily (QD) at a dose of 800 mg for 5 consecutive days as follows: Cycle 1: 5 consecutive days of dosing on Days 4-8. Cycles 2-6: 5 consecutive days of dosing on Days 1-5.	Drug: Venetoclax; Participants will self-administer Venetoclax, as described in the Arm Descriptions.; Drug: Polatuzumab Vedotin; Participants will receive Polatuzumab Vedotin at a dose of 1.8 mg/kg by intravenous (IV) infusion on Day 1 of Cycles 1-6.; Drug: Rituximab; Participants will receive Rituximab at a dose of 375 mg/m^2 by IV infusion on Day 1 of Cycles 1-6.; Drug: Cyclophosphamide; Participants will receive Cyclophosphamide at a dose of 750 mg/m^2 by IV infusion or bolus on Day 1 of Cycles 1-6.; Drug: Doxorubicin; Participants will receive Doxorubicin at a dose of 50 mg/m^2 by IV infusion or bolus on Day 1 of Cycles 1-6.; Drug: Prednisone; Participants will receive Prednisone orally (PO) at a dose of 100 mg/day on Days 1-5 of Cycles 1-6.
Experimental: Venetoclax (Schedule B); Participants enrolled in dosing Schedule B will receive a total of six 21-day cycles of venetoclax treatment for 10 days in combination with Polatuzumab Vedotin + R-CHP as described below: Schedule B: Participants will self-administer Venetoclax orally (PO) once daily (QD) at a dose of 800 mg for 10 consecutive days as follows: Cycle 1: 10 consecutive days of dosing on Days 4-10. Cycles 2-6: 10 consecutive days of dosing on Days 1-10.	Drug: Venetoclax; Participants will self-administer Venetoclax, as described in the Arm Descriptions.; Drug: Polatuzumab Vedotin; Participants will receive Polatuzumab Vedotin at a dose of 1.8 mg/kg by intravenous (IV) infusion on Day 1 of Cycles 1-6.; Drug: Rituximab; Participants will receive Rituximab at a dose of 375 mg/m^2 by IV infusion on Day 1 of Cycles 1-6.; Drug: Cyclophosphamide; Participants will receive Cyclophosphamide at a dose of 750 mg/m^2 by IV infusion or bolus on Day 1 of Cycles 1-6.; Drug: Doxorubicin; Participants will receive Doxorubicin at a dose of 50 mg/m^2 by IV infusion or bolus on Day 1 of Cycles 1-6.; Drug: Prednisone; Participants will receive Prednisone orally (PO) at a dose of 100 mg/day on Days 1-5 of Cycles 1-6.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Percentage of Participants with Dose-Limiting Toxicities (DLTs)	Cycle 1 Day 1 up to but not including Cycle 3 Day 1 (Cycle length = 21 days)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants with Adverse Events (AEs)		Up to 4 years
Complete Response (CR) rate at the end of treatment	Assessed by the investigator on PET and computed tomography (PET/CT) scans according to the Lugano Response Criteria for Malignant Lymphoma (Cheson et al. 2014)	Up to 4 years
Objective Response Rate (ORR) at the end of treatment	Defined as the proportion of patients with a CR or a partial response (PR), as determined by the investigator on PET/CT scans according to the Lugano 2014 Response Criteria	Up to 4 years
Duration of Response (DOR)	Defined as the time from the first occurrence of a documented objective response (a PR or a CR) to disease progression, relapse, or death from any cause (whichever occurs first), as determined by the investigator according to the Lugano 2014 Response Criteria	Up to 4 years
Progression-Free Survival (PFS)	Defined as the time from the date of first study treatment to the first occurrence of disease progression or relapse, as assessed by the investigator, according to the Lugano 2014 Response Criteria, or death from any cause, whichever occurs earlier	Up to 4 years
Plasma Concentrations of Venetoclax at specified timepoints		Up to 4 years
Plasma Concentrations of Polatuzumab Vedotin analytes at specified timepoints		Up to 4 years

Collaborators and Investigators

• Sponsor: Hoffmann-La Roche
• Investigators: Study Director: Clinical Trials, Hoffmann-La Roche

Study record dates

Study Major Dates

• Study Start (Actual): July 2, 2021
• Primary Completion (Estimated): June 19, 2024
• Study Completion (Estimated): February 12, 2025

Study Registration Dates

• First Submitted: March 8, 2021
• First Submitted That Met QC Criteria: March 8, 2021
• First Posted (Actual): March 10, 2021

Study Record Updates

• Last Update Posted (Estimated): February 28, 2024
• Last Update Submitted That Met QC Criteria: February 27, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma, Non-Hodgkin; Lymphoma, B-Cell; Lymphoma; Lymphoma, Large B-Cell, Diffuse; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Anti-Inflammatory Agents; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antineoplastic Agents, Immunological; Antibiotics, Antineoplastic; Immunoconjugates; Cyclophosphamide; Venetoclax; Rituximab; Prednisone; Doxorubicin; Polatuzumab vedotin
• Other Study ID Numbers: BO42203; 2020-002376-12 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Qualified researchers may request access to individual patient level data through the clinical study data request platform (www.vivli.org). Further details on Roche's criteria for eligible studies are available here (https://vivli.org/ourmember/roche/). For further details on Roche's Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents, see here (https://www.roche.com/research_and_development/who_we_are_how_we_work/clinical_trials/our_commitment_to_data_sharing.htm).

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No