A Study to Evaluate the Effect of Venetoclax on Participants Receiving a Covalent Bruton's Tyrosine Kinase Inhibitor (cBTKi) for First-line Chronic Lymphocytic Leukemia (1L CLL) to Achieve Deep Durable Remissions to Allow Off-treatment Period (BRAVE)

Phase II, Open-label, Prospective Single-arm, Multi-center Clinical Trial to Evaluate if Adding Venetoclax to Patients on Covalent BTKi For 1L CLL Can Achieve Deep Durable Remissions (by UMRD 10^-4) to Allow Off-treatment Period

The main purpose of the study is to evaluate if adding venetoclax to participants receiving cBTKi for the 1L CLL can achieve deep durable remissions of undetectable measurable residual disease [uMRD < or 10^-4 in peripheral blood (PB)] by end of combination treatment (EOCT) to allow off-treatment period.

The acronym BRAVE stands for Btki Responders to Achieve deep remission (or off-treatment periods) with VEnetoclax.

Study Overview

• Status: Active, not recruiting
• Conditions: Chronic Lymphocytic Leukemia
• Intervention / Treatment: Drug: Venetoclax; Drug: cBTKi Monotherapy

• Study Type: Interventional
• Enrollment (Actual): 118
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Arkansas
    • Springdale, Arkansas, United States, 72762
      • Highlands Oncology Group
  • Colorado
    • Aurora, Colorado, United States, 80012-5405
      • Rocky Mountain Cancer Centers (Aurora) - USOR
  • Florida
    • Jacksonville, Florida, United States, 32256-6932
      • Cancer Specialists of North Florida
  • Indiana
    • Fort Wayne, Indiana, United States, 46804
      • Fort Wayne Medical Oncology and Hematology, Inc
  • Iowa
    • Des Moines, Iowa, United States, 50314-3030
      • Mission Blood and Cancer - MercyOne Cancer Center
  • Maryland
    • Bethesda, Maryland, United States, 20817-1915
      • American Oncology Partners of Maryland, PA
  • Massachusetts
    • Boston, Massachusetts, United States, 02215-5418
      • Dana-Farber Cancer Institute - Hematologic Oncology Treatment Center
  • Nebraska
    • Grand Island, Nebraska, United States, 68803
      • Nebraska Cancer Specialists St Francis - Grand Island
    • Omaha, Nebraska, United States, 68130-2042
      • Nebraska Cancer Specialists
  • New Jersey
    • East Brunswick, New Jersey, United States, 08816-4096
      • Astera Cancer Care East Brunswick
  • New Mexico
    • Farmington, New Mexico, United States, 87401
      • San Juan Oncology Associates, PC
  • Ohio
    • Cincinnati, Ohio, United States, 45236-2725
      • Oncology Hematology Care Inc - Cincinnati - USOR
    • Columbus, Ohio, United States, 43210
      • Ohio State University
  • Oregon
    • Eugene, Oregon, United States, 97401-6043
      • Willamette Valley Cancer Institute and Research Center
    • Medford, Oregon, United States, 97504-8332
      • Asante Rogue Regional Medical Center
  • Tennessee
    • Chattanooga, Tennessee, United States, 37404
      • Tennessee Oncology, PLLC - Chattanooga
    • Nashville, Tennessee, United States, 37203
      • Tennessee Oncology - Midtown
  • Texas
    • Houston, Texas, United States, 77030
      • MD Anderson Cancer Center
    • Tyler, Texas, United States, 75702
      • Texas Oncology- Northeast Texas
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Medical College of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Diagnosed with CLL and currently receiving a stable dose of cBTKi (i.e., ibrutinib, acalabrutinib, or zanubrutinib) for at least 6 months for 1L treatment with a response of at least a PR per iwCLL criteria
2. Eastern Cooperative Oncology Group (ECOG) performance score of less than or equal to (</=) 2
3. Adequate renal and liver function

Exclusion Criteria:

1. Prior B-cell lymphoma (Bcl-2) inhibitor therapy
2. Anti-cluster of differentiation 20 (CD20) therapy within the month prior to screening
3. Progressive or stable disease on cBTKi
4. Transformation of CLL to aggressive non-Hodgkin lymphoma (NHL) (Richter's transformation or pro-lymphocytic leukemia)
5. History of cardiomyopathy
6. Hypersensitivity to venetoclax or to any of the excipients (e.g., trehalose)
7. Clinically significant cardiovascular disease
8. Active bleeding or history of bleeding diathesis
9. Pregnant women and nursing mothers
10. Uncontrolled autoimmune hemolytic anemia or immune thrombocytopenia

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Venetoclax Added to cBTKi (Commercially Prescribed); Participants will receive venetoclax, orally, once daily (QD) with a starting ramp-up dose of 20 milligrams (mg) on Day 1 of Cycle 1 (cycle length= 28 days). The dose will increase weekly; thereafter, treatment will continue with venetoclax at the target dose of 400 mg, QD from Week 5 up to Day 28 of Cycle 12. Participant will discontinue from venetoclax and/or cBTKi after 12 cycles. Participants with detectable measurable residual disease with the presence of less than 1 CLL cell in 10,000 leukocytes (< 10^-4) (MRD4) or uMRD4 with partial response (PR) may continue receiving cBTKi-monotherapy (i.e. ibrutinib or acalabrutinib, or zanubrutinib) as previously prescribed by the investigator according to the prescribing label.

Drug: Venetoclax; Venetoclax tablets will be administered as per the schedule specified in the arm.; Other Names: RO5537382; Drug: cBTKi Monotherapy; Commercially available cBTKi (ibrutinib or acalabrutinib, or zanubrutinib) will be administered in accordance with its prescribing label.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
uMRD4 Rate at EOCT	uMRD4 will be assessed using next generation sequencing (NGS) (sensitivity 10^-4) from PB.	Cycle 12 Day 28 (Cycle length= 28 Days)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
CR/CRi Rate at EOCT as Determined by the Investigator According to International Workshop on Chronic Lymphocytic Leukemia (iwCLL) Guidelines	Complete response (CR)/complete response with incomplete recovery of the bone marrow (CRi) rate is defined as the percentage of participants with a CR or CRi at EOCT, as determined by the investigator according to the iwCLL.	Up to approximately 12 months
PR Rate at EOCT as Determined by the Investigator According to iwCLL Guidelines	PR rate is defined as the percentage of participants with a PR at EOCT, as determined by the investigator according to the iwCLL.	Up to approximately 12 months
Overall Response Rate (ORR) at EOCT as Determined by the Investigator According to iwCLL Guidelines	ORR is defined as the percentage of participants with a CR/CRi or PR at EOCT, as determined by the investigator according to the iwCLL.	Up to approximately 12 months
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)	AE and SAEs will be collected as part of this study at baseline and every clinical visit, until 30 days after the final dose of study treatment.	Up to approximately 13 months
Number of Participants Who Withdrew Prematurely from the Study	Participants who discontinued treatment before Cycle 12 Day 28 (cycle length= 28 days).	Up to approximately 12 months
Overall Survival (OS)	OS is defined as the time from the first study treatment to death from any cause.	Up to approximately 48 months
Progression-free Survival (PFS) as Determined by the Investigator According to iwCLL Guidelines	PFS is defined as the time from the first study treatment to the first occurrence of disease progression (PD) or death from any cause during study, whichever occurs first, as determined by the investigator according to the iwCLL.	Up to approximately 48 months
Event-free Survival (EFS) as Determined by the Investigator According to iwCLL Guidelines	EFS is defined as the time from the first study treatment to the first occurrence of PD, anti-leukemic treatment subsequent to the study treatment, or death from any cause during study, whichever occurs first, as determined by the investigator according to the iwCLL.	Up to approximately 48 months
Duration of Response (DOR) in Participants With CR/CRi or PR as Determined by the Investigator According to iwCLL Guidelines	DOR is defined as the time from the first occurrence of a documented objective response (i.e., CR/CRi or PR) to PD or death from any cause, whichever occurs first, as determined by the investigator according to the iwCLL.	Up to approximately 12 months
DOR in Participants With CR or CRi as Determined by the Investigator According to iwCLL Guidelines	DOR is defined as the time from the first occurrence of a documented objective response (i.e., CR or CRi ) to PD or death from any cause, whichever occurs first, as determined by the investigator according to the iwCLL.	Up to approximately 12 months
Time to Next CLL Treatment (TTNT)	TTNT is defined as the time from the first study treatment to the start of anti-leukemic treatment subsequent to the study treatment or death, whichever occurs first.	Up to approximately 12 months

Collaborators and Investigators

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

Study record dates

Study Major Dates

• Study Start (Actual): August 9, 2024
• Primary Completion (Estimated): October 31, 2026
• Study Completion (Estimated): January 31, 2030

Study Registration Dates

• First Submitted: July 23, 2024
• First Submitted That Met QC Criteria: July 23, 2024
• First Posted (Actual): July 29, 2024

Study Record Updates

• Last Update Posted (Actual): February 25, 2026
• Last Update Submitted That Met QC Criteria: February 23, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Chronic Disease; Disease Attributes; Immune System Diseases; Neoplasms by Histologic Type; Hematologic Diseases; Lymphatic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Leukemia, B-Cell; Leukemia, Lymphoid; Leukemia; Pathological Conditions, Signs and Symptoms; Hemic and Lymphatic Diseases; Leukemia, Lymphocytic, Chronic, B-Cell; Antineoplastic Agents; venetoclax
• Other Study ID Numbers: ML45219

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: For eligible studies, qualified researchers may request access to individual patient level clinical data. See Roche's commitment to transparency of clinical study information here: https://go.roche.com/data_sharing

Drug and device information, study documents

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