Venetoclax + cBTKi for Chronic Lymphocytic Leukemia

(BRAVE Trial)

Recruiting at 25 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

100 Participants Needed

Trial Summary

What is the purpose of this trial?

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.

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.

What data supports the effectiveness of the drug combination Venetoclax and cBTKi for Chronic Lymphocytic Leukemia?

Research shows that targeted therapies like Bruton's tyrosine kinase inhibitors (such as ibrutinib) and BCL-2 inhibitors (like venetoclax) have become key treatments for chronic lymphocytic leukemia, with studies indicating that these drugs are effective in managing the disease. Additionally, trials have shown that zanubrutinib, a similar drug, was superior to ibrutinib in terms of overall response, suggesting potential benefits of using these types of drugs. ^{1 2 3 4 5}

Is the combination of Venetoclax and BTK inhibitors like Ibrutinib safe for treating chronic lymphocytic leukemia?

Ibrutinib and other BTK inhibitors, when used alone or with other drugs, are generally well tolerated by most patients, including older individuals. However, they can cause some side effects, which are usually mild and go away on their own, but some can be serious enough to limit their use. Safety considerations are important when using these drugs, and ongoing research is looking into the best ways to manage any potential toxicities. ^{2 6 7 8 9}

What makes the drug combination of Venetoclax and cBTKi unique for treating chronic lymphocytic leukemia?

The combination of Venetoclax and cBTKi (such as Ibrutinib) is unique because it targets two different pathways in cancer cells, potentially improving outcomes for patients with chronic lymphocytic leukemia (CLL) compared to traditional chemoimmunotherapy. This combination has shown promising results in both relapsed and high-risk CLL cases, offering a new standard treatment option. ^{10 11 12 13 14}

Research Team

Clinical Trials

Principal Investigator

Hoffmann-La Roche

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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

Findings from Research

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]

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]

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]

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]

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]

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 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]

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]

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]

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]

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]

References

1. United States pubmed.ncbi.nlm.nih.gov

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

2. United States pubmed.ncbi.nlm.nih.gov

Current Perspectives on Therapy for Chronic Lymphocytic Leukemia. [2020]

3. United States pubmed.ncbi.nlm.nih.gov

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

4. United States pubmed.ncbi.nlm.nih.gov

Zanubrutinib or Ibrutinib in Relapsed or Refractory Chronic Lymphocytic Leukemia. [2023]

5. United States pubmed.ncbi.nlm.nih.gov

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

6. Italy pubmed.ncbi.nlm.nih.gov

BCR Signaling Inhibitors: an Overview of Toxicities Associated with Ibrutinib and Idelalisib in Patients with Chronic Lymphocytic Leukemia. [2020]

7. England pubmed.ncbi.nlm.nih.gov

Real-world outcomes for 205 patients with chronic lymphocytic leukemia treated with ibrutinib. [2021]

8. United States pubmed.ncbi.nlm.nih.gov

Ibrutinib (imbruvica): a novel targeted therapy for chronic lymphocytic leukemia. [2021]

9. England 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. [2022]

10. United States pubmed.ncbi.nlm.nih.gov

BTK inhibitor therapy is effective in patients with CLL resistant to venetoclax. [2021]

11. United States pubmed.ncbi.nlm.nih.gov

Chronic Lymphocytic Leukemia Therapy Guided by Measurable Residual Disease. [2023]

12. United States pubmed.ncbi.nlm.nih.gov

Approaches to Chronic Lymphocytic Leukemia Therapy in the Era of New Agents: The Conundrum of Many Options. [2020]

13. Austria pubmed.ncbi.nlm.nih.gov

Chronic lymphocytic leukemia at ASH 2017. [2020]

14. England pubmed.ncbi.nlm.nih.gov

The combination of venetoclax and rituximab for the treatment of patients with recurrent chronic lymphocytic leukemia. [2021]