Triple Therapy for Chronic Lymphocytic Leukemia

Overseen By Nitin Jain, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Warfarin, Strong CYP3A4 inhibitors

Disqualifiers: HIV, Hepatitis B, Hepatitis C, 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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: Unknown

Duration: 6-12 months

60 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of three drugs—pirtobrutinib, venetoclax, and obinutuzumab (Gazyva)—to determine their safety and effectiveness for individuals with chronic lymphocytic leukemia (CLL) or Richter transformation (RT). It targets those who have not received prior treatment for CLL or have developed RT following previous CLL treatment. The trial seeks participants diagnosed with either CLL or RT who can commit to regular visits and medication. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

The trial requires a washout period (time without taking certain medications) for strong CYP3A4 inhibitors or inducers and certain P-gp inhibitors before starting the study. If you are taking these medications, you will need to stop them for a specific period before joining the trial.

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

Research has shown that the combination of pirtobrutinib, venetoclax, and obinutuzumab may be promising for treating chronic lymphocytic leukemia (CLL). In one study, patients who took venetoclax and obinutuzumab experienced long-lasting remissions, with more than half remaining cancer-free after six years.

Another study found that adding pirtobrutinib to this mix led to deep remissions for most patients. These results suggest that this treatment combination can be effective and generally well-tolerated. Importantly, no known negative interactions exist between pirtobrutinib and venetoclax, indicating they are safe to use together.

While these findings are encouraging, the current trial seeks to gather more information about the safety of this combination for patients who have not been treated before. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Obinutuzumab, Pirtobrutinib, and Venetoclax for treating Chronic Lymphocytic Leukemia (CLL) because it targets the cancer in a novel way. Unlike traditional treatments that often focus on chemotherapy, this combination leverages a targeted approach. Obinutuzumab is an antibody that specifically binds to cancer cells, while Venetoclax disrupts the cancer cells' ability to survive by blocking a protein called BCL-2. Pirtobrutinib, a new addition, inhibits Bruton’s tyrosine kinase, which is crucial for CLL cell survival and proliferation. This triple therapy has the potential to be more precise and effective, offering hope for better outcomes with potentially fewer side effects.

What evidence suggests that this trial's treatments could be effective for chronic lymphocytic leukemia?

Research shows that the combination of pirtobrutinib, venetoclax, and obinutuzumab, which participants in this trial will receive, holds promise for treating chronic lymphocytic leukemia (CLL). Studies have found that this combination can lead to deep remissions, where the cancer becomes undetectable or greatly reduced. Each medicine works differently to combat cancer cells, creating a powerful team. Pirtobrutinib blocks signals that help cancer cells grow, venetoclax encourages cancer cells to self-destruct, and obinutuzumab is an antibody that helps the immune system find and attack cancer cells. Together, they form a strong defense against CLL. ^{1 6 7 8 9}

Who Is on the Research Team?

Nitin Jain, MD

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults with untreated chronic lymphocytic leukemia (CLL) or Richter transformation (RT). Participants must have certain levels of bilirubin, renal function, and blood counts. They should not have active hepatitis B/C, HIV, uncontrolled infections or autoimmune diseases requiring high-dose steroids. Pregnant women are excluded and participants must agree to use effective contraception.

Inclusion Criteria

My blood tests show enough platelets, hemoglobin, and neutrophils.

My kidneys work well, with a creatinine clearance rate of 50 ml/min or more.

I have untreated CLL/SLL needing treatment or treated/untreated RT from CLL.

Exclusion Criteria

I have a condition that affects how my body absorbs medication.

I have a serious heart condition that is not under control.

I have not had major surgery in the last 4 weeks.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive pirtobrutinib, venetoclax, and obinutuzumab in 28-day cycles

6-12 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 months

What Are the Treatments Tested in This Trial?

Interventions

• Obinutuzumab
• Pirtobrutinib
• Venetoclax

Trial Overview The study tests a combination of three drugs: Pirtobrutinib, Venetoclax, and Obinutuzumab in patients who haven't been treated before for CLL or RT. It aims to determine the safety and effectiveness of this drug regimen.

How Is the Trial Designed?

Group I: Pirtobrutinib plus Venetoclax plus Obinutuzumab (combination) Experimental Treatment 5 Interventions

Participants will receive the study drugs in cycles. Each cycle is 28 days.

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

Approved in United States as Gazyva for:

• Chronic Lymphocytic Leukemia (CLL)
• Follicular Lymphoma

Approved in European Union as Gazyva for:

• Chronic Lymphocytic Leukemia (CLL)
• Follicular Lymphoma

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

The Leukemia and Lymphoma Society

Collaborator

Trials

87

Recruited

26,200+

Loxo Oncology, Inc.

Industry Sponsor

Trials

72

Recruited

11,600+

Jacob Van Naarden

Loxo Oncology, Inc.

Chief Executive Officer since 2019

A.B. in Molecular Biology from Princeton University

Dr. Jennifer Low

Loxo Oncology, Inc.

Chief Medical Officer since 2014

MD and PhD from Georgetown University; Undergraduate degree from California Institute of Technology

Published Research Related to This Trial

In a phase 2 trial involving 70 patients with chronic lymphocytic leukaemia, both 12 cycles of venetoclax consolidation and minimal residual disease-guided consolidation showed similar effectiveness, with around 50% of patients achieving undetectable minimal residual disease in bone marrow after treatment.

While consolidation treatment did not lead to treatment-related deaths, it was associated with a higher incidence of adverse events, particularly infections, indicating that while it may extend treatment duration, it does not significantly improve disease response or reduce relapse risk.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax consolidation after fixed-duration venetoclax plus obinutuzumab for previously untreated chronic lymphocytic leukaemia (HOVON 139/GiVe): primary endpoint analysis of a multicentre, open-label, randomised, parallel-group, phase 2 trial. Kersting, S., Dubois, J., Nasserinejad, K., et al.[2022]

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 obinutuzumab has been approved as a superior first-line treatment for elderly, unfit patients with chronic lymphocytic leukaemia (CLL), showing better efficacy than chlorambucil/obinutuzumab based on a phase-III trial.

For patients with high-risk features like deletion 17p or TP53 mutations, targeted therapies such as ibrutinib or venetoclax/obinutuzumab are recommended due to their poor response to traditional chemotherapy, highlighting the importance of personalized treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Current diagnosis and treatment of chronic lymphocytic leukaemia]. Cramer, P., von Tresckow, J., Eichhorst, B., et al.[2021]

Pirtobrutinib, a non-covalent BTK inhibitor, showed a significantly higher objective response rate (80.2%) compared to venetoclax (64.8%) in patients with chronic lymphocytic leukemia (CLL) who had previously been treated with covalent BTK inhibitors, based on a comparison of 146 patients receiving pirtobrutinib and 91 patients receiving venetoclax.

While progression-free survival (PFS) and overall survival (OS) rates were comparable between pirtobrutinib and venetoclax, pirtobrutinib was associated with fewer grade ≥3 treatment-emergent adverse events, indicating it may be a safer option for patients with relapsed CLL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pirtobrutinib versus venetoclax in covalent Bruton tyrosine kinase inhibitor-pretreated chronic lymphocytic leukemia: a matching-adjusted indirect comparison. Al-Sawaf, O., Jen, MH., Hess, LM., et al.[2023]

In a phase 1/2 clinical trial involving 46 patients with relapsed/refractory chronic lymphocytic leukemia (CLL), the combination therapy of venetoclax, umbralisib, and ublituximab (U2-VeN) demonstrated a remarkable overall response rate of 98%, with 42% achieving complete responses.

The treatment was found to be safe, with manageable adverse effects, including diarrhea in 50% of patients and liver enzyme elevations in 33%, but no cases of tumor lysis syndrome, indicating that this time-limited therapy can effectively control CLL while minimizing prolonged treatment risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Response-Adapted, Time-Limited Venetoclax, Umbralisib and Ublituximab for Relapsed/Refractory Chronic Lymphocytic Leukemia. Hill, BT., Ma, S., Zent, CS., et al.[2023]

Venetoclax is a highly effective treatment for relapsed or refractory chronic lymphocytic leukemia (CLL), achieving response rates of about 80% in clinical trials involving 240 patients from 2011 to 2016.

While venetoclax has an acceptable safety profile, common side effects include neutropenia and diarrhea, and there is a risk of tumor lysis syndrome (TLS), which can be managed through careful dose ramp-up and patient education, leading to no reported TLS events in ongoing trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax: Management and Care for Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia . Brumbaugh Paradis, H., Alter, D., Llerandi, D.[2018]

Venetoclax is an effective oral treatment for relapsed or refractory chronic lymphocytic leukemia (CLL), showing durable responses and a manageable safety profile in clinical trials, including patients with poor prognostic factors.

In combination with rituximab, venetoclax significantly improved progression-free survival and achieved undetectable minimal residual disease compared to bendamustine plus rituximab, with benefits lasting for at least 36 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax: A Review in Relapsed/Refractory Chronic Lymphocytic Leukemia. Scott, LJ.[2020]

In the phase III CLL14 trial, a 12-month treatment with venetoclax combined with obinutuzumab significantly improved progression-free survival and rates of undetectable minimal residual disease compared to traditional chemoimmunotherapy with chlorambucil and obinutuzumab in patients with untreated chronic lymphocytic leukaemia.

Venetoclax + obinutuzumab is a well-tolerated, chemotherapy-free treatment option for CLL, with manageable side effects like neutropenia, making it suitable for patients who cannot undergo intensive chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax: A Review in Previously Untreated Chronic Lymphocytic Leukaemia. Blair, HA.[2021]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05536349

Study Details | NCT05536349 | Time-limited Triplet ... To learn if the combination of pirtobrutinib (also called LOXO-305), venetoclax, and obinutuzumab is safe and effective when given to patients with chronic ...

2. onlinelibrary.wiley.com onlinelibrary.wiley.com/doi/10.1002/cam4.70258

Efficacy and Effectiveness Outcomes of Treatments for ... This study highlights the limited clinical data on efficacy outcomes for double-exposed CLL/SLL patients. Pirtobrutinib, lisocabtagene ...

3. ashpublications.org ashpublications.org/blood/article/146/7/779/537595/Hitting-the-therapeutic-bull-s-eye-with-targeted

Hitting the therapeutic bull's-eye with targeted therapy for ... Although they both are highly effective at long-term disease control, they are not currently confirmed curative, and many patients are expected to develop ...

4. ash.confex.com ash.confex.com/ash/2024/webprogram/Paper211454.html

Combined Pirtobrutinib, Venetoclax, and Obinutuzumab As ... We report results of time-limited, combination therapy with non-covalent BTKi, pirtobrutinib with venetoclax and obinutuzumab as first-line treatment for pts ...

5. youtube.com youtube.com/watch?v=ArbZO-4-M2I

Results from a Phase II trial of pirtobrutinib, venetoclax, and ... Overall we think this is a very effective regimen which is leading to deep level of fissions for patients with CLL.

6. ashpublications.org ashpublications.org/blood/article/144/18/1924/516941/Venetoclax-obinutuzumab-for-previously-untreated

6-year results of the randomized phase 3 CLL14 study | Blood Key PointsOne-year fixed-duration Ven-Obi results in durable treatment-free remissions, with a 6-year PFS rate of 53% and TTNT rate of 65%, ...

7. cllsociety.org cllsociety.org/2025/03/first-line-pirtobrutinib-venetoclax-obinutuzumab-for-cll/

First-Line Pirtobrutinib-Venetoclax-Obinutuzumab for CLL A combination of pirtobrutinib, venetoclax, and obinutuzumab produces deep remissions in most patients with CLL as a first-line treatment.

8. healthtree.org healthtree.org/cll/community/articles/sponsorstudy-pirtobrutinib-venetoclax-cll-phase-1

Two-Year Pirtobrutinib + Venetoclax for R/R CLL Additionally, researchers found no drug interactions between pirtobrutinib and venetoclax, confirming their safety when taken together. Overall, ...

9. cancernetwork.com cancernetwork.com/view/pirtobrutinib-triplet-improves-mrd-outcomes-in-cll

Pirtobrutinib Triplet Improves MRD Outcomes in CLL Phase 2 results showed high undetectable MRD rates with pirtobrutinib, venetoclax, and obinutuzumab for patients with chronic lymphocytic leukemia.