Venetoclax + cBTKi for Chronic Lymphocytic Leukemia

(BRAVE Trial)

Recruiting at 26 trial locations

Overseen By Reference Study ID Number: ML45219 https://forpatients.roche.com/

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Genentech, Inc.

Must be taking: cBTKi

Must not be taking: Bcl-2 inhibitors

Disqualifiers: Cardiomyopathy, Cardiovascular disease, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 12 months

110 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if adding venetoclax to current treatment can help individuals with chronic lymphocytic leukemia (CLL) achieve long-lasting remission. It focuses on those already taking a stable dose of medications like ibrutinib, acalabrutinib, or zanubrutinib (cBTKi monotherapy) for at least six months and responding well. The goal is to discover if this combination allows patients to take breaks from treatment without the disease returning. Participants should not have received certain previous treatments or have specific health issues. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it does require that you are already on a stable dose of cBTKi (like ibrutinib, acalabrutinib, or zanubrutinib) for at least 6 months. It seems you will continue with this medication during the trial.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

A previous study found that venetoclax was generally well-tolerated by people with chronic lymphocytic leukemia (CLL). Neutropenia, a low count of a type of white blood cell, was the most common side effect, occurring in about 60% of patients. Other common side effects included diarrhea (28%) and fatigue (21%). Some patients discontinued treatment due to side effects, but this was uncommon.

Real-world studies indicate that treatments like ibrutinib, acalabrutinib, and zanubrutinib are generally safe as well. These medications are already approved for CLL, and their safety is well-documented. While they can cause side effects, these are often manageable. Long-term use may lead to additional effects.

Overall, these treatments have been shown to be safe for many patients in other studies. However, all medicines can have side effects, so discussing any concerns with a doctor is important. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Venetoclax is unique because it works differently from the typical treatments for chronic lymphocytic leukemia (CLL). While most treatments focus on inhibiting Bruton's tyrosine kinase (BTK) with drugs like ibrutinib, acalabrutinib, or zanubrutinib, venetoclax specifically targets and blocks the BCL-2 protein, which helps cancer cells survive. This means it can potentially work alongside BTK inhibitors to more effectively eliminate cancer cells. Researchers are excited because combining venetoclax with BTK inhibitors could lead to better outcomes and possibly a shorter duration of therapy for patients with CLL.

What evidence suggests that adding venetoclax to cBTKi could be effective for chronic lymphocytic leukemia?

Research has shown that venetoclax effectively treats chronic lymphocytic leukemia (CLL). In studies, 77% of patients with CLL that had returned or didn't respond to previous treatments showed improvement with venetoclax. Additionally, 27% of these patients had no detectable cancer cells in their blood. In this trial, participants will receive venetoclax added to their existing cBTKi monotherapy, which includes treatments like ibrutinib and zanubrutinib. These Bruton tyrosine kinase inhibitors (cBTKi) effectively control CLL in up to 94% of cases. Combining these treatments in this trial aims to provide long-lasting remissions, potentially allowing patients to take breaks from treatment. ^{4 5 6 7 8}

Who Is on the Research Team?

Clinical Trials

Principal Investigator

Hoffmann-La Roche

Are You a Good Fit for This Trial?

This trial is for individuals with first-line Chronic Lymphocytic Leukemia (1L CLL) who are already receiving a cBTKi treatment. The study aims to see if adding Venetoclax can lead to deep remissions, allowing patients periods off treatment.

Inclusion Criteria

I have CLL and have been on a stable dose of a cBTKi treatment for over 6 months with at least partial response.

I can perform daily activities with minimal assistance.

My kidney and liver are working well.

Exclusion Criteria

My condition has not improved on cBTKi treatment.

I do not have active bleeding or a history of bleeding disorders.

I am currently pregnant or breastfeeding.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive venetoclax in combination with cBTKi for up to 12 months to achieve deep durable remissions

12 months

Monthly visits for dose adjustments and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 months

Off-Treatment Period

Participants may enter an off-treatment period if deep durable remission is achieved

Variable

What Are the Treatments Tested in This Trial?

Interventions

• cBTKi Monotherapy
• Venetoclax

Trial Overview The BRAVE study tests whether combining Venetoclax with an ongoing cBTKi therapy in 1L CLL patients leads to undetectable levels of residual disease, potentially enabling breaks from treatment.

How Is the Trial Designed?

Group I: Venetoclax Added to cBTKi (Commercially Prescribed) Experimental Treatment 2 Interventions

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 Day 1 of Cycle 2 up to Day 28 of Cycle 12. Participants will continue receiving cBTKi-monotherapy (i.e. ibrutinib or acalabrutinib, or zanubrutinib) as previously prescribed by the investigator according to the prescribing label.

cBTKi Monotherapy is already approved in United States, European Union for the following indications:

Approved in United States as Imbruvica for:

• Chronic lymphocytic leukemia (CLL)
• Small lymphocytic lymphoma (SLL)
• Mantle cell lymphoma (MCL)
• Waldenström's macroglobulinemia (WM)
• Marginal zone lymphoma (MZL)

Approved in United States as Calquence for:

• Chronic lymphocytic leukemia (CLL)
• Small lymphocytic lymphoma (SLL)
• Mantle cell lymphoma (MCL)

Approved in United States as Brukinsa for:

• Mantle cell lymphoma (MCL)
• Waldenström's macroglobulinemia (WM)
• Chronic lymphocytic leukemia (CLL)
• Small lymphocytic lymphoma (SLL)

Approved in European Union as Imbruvica for:

• Chronic lymphocytic leukemia (CLL)
• Small lymphocytic lymphoma (SLL)
• Mantle cell lymphoma (MCL)
• Waldenström's macroglobulinemia (WM)

Approved in European Union as Calquence for:

• Chronic lymphocytic leukemia (CLL)
• Small lymphocytic lymphoma (SLL)
• Mantle cell lymphoma (MCL)

Approved in European Union as Brukinsa for:

• Mantle cell lymphoma (MCL)
• Waldenström's macroglobulinemia (WM)
• Chronic lymphocytic leukemia (CLL)
• Small lymphocytic lymphoma (SLL)

Who Is Running the Clinical Trial?

Genentech, Inc.

Lead Sponsor

Trials

1,578

Recruited

569,000+

Ashley Magargee

Genentech, Inc.

Chief Executive Officer since 2024

MBA from Harvard University, BA from Princeton University

Levi Garraway

Genentech, Inc.

Chief Medical Officer since 2021

MD, PhD

Published Research Related to This Trial

In a study of 205 patients with chronic lymphocytic leukemia (CLL) treated with ibrutinib, the overall survival rate at 12 months was 88.8%, and the progression-free survival rate was 86.3%, indicating that ibrutinib is effective in a real-world setting.

However, 97.6% of patients experienced at least one adverse event, with 48.8% having severe (grade ≥3) events, and 42% discontinued treatment, primarily due to these adverse effects, suggesting that while ibrutinib is effective, its safety profile may lead to higher discontinuation rates compared to clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-world outcomes for 205 patients with chronic lymphocytic leukemia treated with ibrutinib. Aarup, K., Rotbain, EC., Enggaard, L., et al.[2021]

Ibrutinib is a targeted therapy specifically designed for treating chronic lymphocytic leukemia (CLL), which is a type of cancer that affects the blood and bone marrow.

This novel treatment works by inhibiting Bruton's tyrosine kinase (BTK), a key enzyme that helps cancer cells survive and proliferate, leading to improved patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ibrutinib (imbruvica): a novel targeted therapy for chronic lymphocytic leukemia. Parmar, S., Patel, K., Pinilla-Ibarz, J.[2021]

In a phase 3 trial with 523 patients, the combination of ibrutinib and venetoclax significantly improved progression-free survival compared to the traditional FCR treatment, with only 12 patients experiencing disease progression or death in the ibrutinib-venetoclax group versus 75 in the FCR group.

The study also found that 65.9% of patients on ibrutinib-venetoclax achieved undetectable measurable residual disease (MRD) in bone marrow after 5 years, indicating effective disease control, although there was a higher incidence of serious cardiac adverse events in this group compared to FCR.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chronic Lymphocytic Leukemia Therapy Guided by Measurable Residual Disease. Munir, T., Cairns, DA., Bloor, A., et al.[2023]

In a study of 23 patients with relapsed/refractory chronic lymphocytic leukemia (CLL), BTK inhibitors (ibrutinib and zanubrutinib) were found to provide durable disease control after patients progressed on venetoclax, with a median progression-free survival of 34 months.

Patients who had a prior remission duration of 24 months or longer and those who achieved complete remission on venetoclax experienced significantly longer progression-free survival after starting BTK inhibitors, highlighting the importance of previous treatment response in predicting outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

BTK inhibitor therapy is effective in patients with CLL resistant to venetoclax. Lin, VS., Lew, TE., Handunnetti, SM., et al.[2021]

The treatment landscape for chronic lymphocytic leukemia (CLL) has significantly evolved with the introduction of targeted therapies like B cell receptor inhibitors (ibrutinib, idelalisib, duvelisib) and the BCL-2 inhibitor venetoclax, which have become essential in managing the disease.

New monoclonal antibodies targeting CD20 (obinutuzumab and ofatumumab) enhance the efficacy of existing treatments, while chemoimmunotherapy remains a viable option for certain patients, highlighting the need for personalized treatment strategies based on molecular and cytogenetic profiles.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

How to Choose the Best Treatment and Testing for Chronic Lymphocytic Leukemia in the Tsunami of New Treatment Options. Yeung, CCS., Shadman, M.[2020]

The management of chronic lymphocytic leukemia (CLL) has evolved significantly over the past 20 years, with new therapies like ibrutinib and venetoclax now being standard initial treatments for patients requiring therapy.

Current clinical trials are exploring the best ways to sequence or combine these targeted therapies to improve outcomes for patients with previously untreated CLL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment-naive CLL: lessons from phase 2 and phase 3 clinical trials. Woyach, JA.[2021]

In a phase 1b/2 trial involving 31 elderly patients (median age 71) with chronic lymphocytic leukaemia, ibrutinib demonstrated a favorable safety profile, with most adverse effects being mild to moderate, and only 10% of patients experiencing grade 3 infections.

The treatment showed promising efficacy, with 71% of patients achieving an objective response after a median follow-up of 22.1 months, indicating that ibrutinib could be a viable option for elderly patients who are often at risk for severe side effects from traditional therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ibrutinib as initial therapy for elderly patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma: an open-label, multicentre, phase 1b/2 trial. O'Brien, S., Furman, RR., Coutre, SE., et al.[2022]

Three new oral small molecule inhibitors—ibrutinib, idelalisib, and venetoclax—have been approved for chronic lymphocytic leukemia (CLL) treatment in the last four years, showing excellent efficacy.

These inhibitors have different toxicity profiles, which is important for tailoring treatment, especially in older patients, and raises questions about how to best sequence their use in clinical practice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Approaches to Chronic Lymphocytic Leukemia Therapy in the Era of New Agents: The Conundrum of Many Options. Jain, N., Thompson, P., Ferrajoli, A., et al.[2020]

Chronic lymphocytic leukemia (CLL) treatment has significantly improved with targeted therapies like BTK inhibitors (ibrutinib, acalabrutinib) and the BCL-2 inhibitor (venetoclax) combined with obinutuzumab, allowing for more personalized treatment plans based on individual prognostic factors.

Current treatment decisions are influenced by safety profiles, patient preferences, and the ability to sequence therapies, as there are no definitive head-to-head comparisons of efficacy among these options; ongoing clinical trials may further refine standard care approaches.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Current Perspectives on Therapy for Chronic Lymphocytic Leukemia. Awan, FT., Al-Sawaf, O., Fischer, K., et al.[2020]

The management of chronic lymphocytic leukemia (CLL) has evolved significantly over the past 20 years, with new therapies like ibrutinib and venetoclax now being standard initial treatments for patients requiring therapy.

Current clinical trials are exploring the best ways to sequence or combine these targeted therapies to improve treatment outcomes for newly diagnosed asymptomatic patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment-naive CLL: lessons from phase 2 and phase 3 clinical trials. Woyach, JA.[2021]

The combination of venetoclax with rituximab showed remarkable efficacy and a manageable safety profile in treating chronic lymphocytic leukemia (CLL), both in relapsed/refractory cases and as a first-line therapy for high-risk patients.

Similarly, the combination of ibrutinib with venetoclax also demonstrated striking efficacy, suggesting that these combinations could become new standard treatment options for CLL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chronic lymphocytic leukemia at ASH 2017. Wanner, D., Steurer, M.[2020]

The combination of venetoclax and rituximab has shown significant efficacy in treating relapsed or refractory chronic lymphocytic leukemia (CLL), allowing for time-limited treatment and prolonged remission without continuous therapy.

This treatment approach offers advantages over traditional chemo-immunotherapy, including reduced long-term toxicities and costs, while also minimizing the risk of developing drug-resistant cancer cell subclones.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The combination of venetoclax and rituximab for the treatment of patients with recurrent chronic lymphocytic leukemia. Vitale, C., Ferrajoli, A.[2021]

In a phase 3 trial involving 652 patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), zanubrutinib demonstrated superior progression-free survival compared to ibrutinib, with a hazard ratio of 0.65, indicating a significant reduction in the risk of disease progression or death.

Zanubrutinib also had a better safety profile than ibrutinib, resulting in fewer adverse events that led to treatment discontinuation, particularly fewer cardiac events, making it a safer option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Zanubrutinib or Ibrutinib in Relapsed or Refractory Chronic Lymphocytic Leukemia. Brown, JR., Eichhorst, B., Hillmen, P., et al.[2023]

Ibrutinib and idelalisib, two B-cell receptor signaling inhibitors, have shown significant clinical activity in treating chronic lymphocytic leukemia (CLL), particularly in relapsed or refractory cases, and have been FDA-approved for this use.

Both drugs are generally well tolerated, even by older patients, with mild and self-resolving side effects; however, clinicians should be aware of specific adverse events that could limit their use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

BCR Signaling Inhibitors: an Overview of Toxicities Associated with Ibrutinib and Idelalisib in Patients with Chronic Lymphocytic Leukemia. Falchi, L., Baron, JM., Orlikowski, CA., et al.[2020]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5026291/

The potential of venetoclax (ABT-199) in chronic lymphocytic ... Venetoclax (ABT-199): clinical data in chronic lymphocytic leukemia patients. The first in-human trial started with three patients with refractory CLL.

2. venclextahcp.com venclextahcp.com/cll/efficacy/ven-g/data.html

VENCLEXTA efficacy results: 6-year overall survival 1 In patients with CLL, Grade 3 or 4 neutropenia developed in 63% to 64% of patients and Grade 4 neutropenia developed in 31% to 33% of patients when treated with ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT01889186

NCT01889186 | A Study of the Efficacy of ABT-199 in ... This was an open-label, multicenter, global study to determine the efficacy of ABT-199 (Venetoclax) monotherapy in participants with relapsed/refractory (R/R) ...

4. sciencedirect.com sciencedirect.com/science/article/pii/S0006497118526343

Venetoclax (ABT-199/GDC-0199) Monotherapy Induces ... A phase 1 study of VEN showed high response rates in pts with relapsed/refractory (R/R) CLL, including del(17p) CLL (overall response rate, ORR = 77%). This ...

5. ashpublications.org ashpublications.org/blood/article/134/2/111/260687/Efficacy-of-venetoclax-in-relapsed-chronic

Efficacy of venetoclax in relapsed chronic lymphocytic ... Objective responses were documented in 75% of all patients, including 22% CR/CRi. Overall, 27% and 16% of the patients achieved U-MRD in blood ...

6. venclextahcp.com venclextahcp.com/cll/side-effects/ven-r-safety-profile.html

VEN+R Safety Data for CLL/SLL - venclexta The most common adverse reactions (≥20%) of any grade were neutropenia (60%), diarrhea (28%), and fatigue (21%). Fatal adverse reactions that occurred in the ...

7. venclextahcp.com venclextahcp.com/cll/side-effects/ven-g-safety-profile.html

VEN+G Safety Data for CLL/SLL - venclexta In the VEN+G arm, adverse reactions led to treatment discontinuation in 16% of patients, dose reduction in 21%, and dose interruption in 74% · Neutropenia led to ...

8. sciencedirect.com sciencedirect.com/science/article/pii/S0006497118474733

Safety and Efficacy of a Combination of Venetoclax (GDC ... These preliminary data suggest that VEN + G can be safely administered in pts with CLL with no difference in tolerability between R/R and TN subgroups. AEs ...