Pirtobrutinib + Venetoclax for Chronic Lymphocytic Leukemia

Overseen By Alessandra Ferrajoli, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: M.D. Anderson Cancer Center

Must be taking: Venetoclax

Must not be taking: Warfarin, Strong CYP3A4 inducers

Disqualifiers: Richter's transformation, CNS involvement, others

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

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

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

Compensation: Varies

Number of Visits: Unknown

Duration: 24 cycles (each cycle is 4 weeks)

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if combining pirtobrutinib (a targeted therapy) and venetoclax (a medication that induces cancer cell death) can control chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) that has been previously treated. The trial focuses on individuals who have undergone at least 12 cycles of venetoclax and still exhibit signs of the disease. Ideal participants have a confirmed diagnosis of CLL or SLL and have not fully responded to prior venetoclax treatment. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new combination therapy.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, you cannot participate if you are on certain medications like strong CYP3A4 inducers or P-gp inhibitors, or if you require therapeutic anticoagulation with warfarin. It's best to discuss your current medications with the study team.

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

Research shows that combining pirtobrutinib and venetoclax is generally safe for patients. Studies have found that pirtobrutinib is effective and safe for individuals with chronic lymphocytic leukemia (CLL) who have tried other treatments. In these studies, patients did not experience severe side effects.

The FDA has already approved venetoclax for treating CLL, and it is considered safe. Although the combination of these two drugs is still under investigation, current research suggests promising safety outcomes. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Pirtobrutinib and Venetoclax for treating Chronic Lymphocytic Leukemia (CLL) because it offers a new approach to tackling the disease. Unlike standard CLL treatments that often target a single pathway, this combination therapy uses Pirtobrutinib, a next-generation BTK inhibitor, alongside Venetoclax, which targets BCL-2 proteins, to disrupt cancer cell survival on multiple fronts. This dual action could potentially improve treatment effectiveness and overcome resistance seen with existing therapies. Additionally, both drugs are taken orally, which can simplify treatment regimens for patients.

What evidence suggests that the combination of pirtobrutinib and venetoclax could be effective for chronic lymphocytic leukemia?

Research has shown that the combination of two drugs, pirtobrutinib and venetoclax, may help treat chronic lymphocytic leukemia (CLL) that has returned or hasn't responded to other treatments. Studies have found that pirtobrutinib works well and is easy for patients to handle, even if their cancer returned after previous treatments. Early results suggest this drug combination could be especially useful for patients who haven't had success with other options. The combination has shown promising early results, offering a new choice for those with limited options. Overall, while more research is needed, the initial evidence is encouraging for CLL patients. ^{2 5 6 7 8}

Who Is on the Research Team?

Alessandra Ferrajoli, MD

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

Adults with previously treated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) who have completed at least 12 cycles of venetoclax and still have detectable minimal residual disease. Participants must be in generally good health, with adequate organ function and blood counts, not pregnant or breastfeeding, willing to use effective contraception, and without certain heart conditions or other serious medical issues.

Inclusion Criteria

Activated partial thromboplastin time (aPTT) or partial thromboplastin time and prothrombin time (PT) or international normalized ratio (INR) not greater than 1.5 x ULN

Hemoglobin >= 8 mg/dL

Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3.0 x ULN, unless clearly due to documented disease involvement, in which case ALT and AST =< 5.0 x ULN

Exclusion Criteria

I haven't had a stem cell transplant or CAR-T therapy in the last 60 days and don't have active GVHD, need for anti-cytokine therapy, symptoms of neurotoxicity > grade 1, or uncontrolled auto-immune cytopenia.

I had a major bleeding event while on a BTK inhibitor.

I have been treated with a BTK inhibitor like nemtabrutinib before.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive pirtobrutinib and venetoclax orally once daily for up to 24 cycles

24 cycles (each cycle is 4 weeks)

Extended Treatment

Participants who do not achieve U-MRD4 continue receiving pirtobrutinib for up to 36 cycles

Additional 12 cycles (each cycle is 4 weeks)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks initially, then every 24 weeks for up to 5 years

What Are the Treatments Tested in This Trial?

Interventions

• Pirtobrutinib
• Venetoclax

Trial Overview The trial is testing the effectiveness of combining a new drug called pirtobrutinib (LOXO-305) with an existing treatment, venetoclax, to see if this combination can better control CLL/SLL after previous treatments. The goal is to eliminate any remaining cancer cells that were not cleared by prior therapy.

How Is the Trial Designed?

Group I: Pirtobrutinib+venetoclax Experimental Treatment 2 Interventions

Pirtobrutinib by mouth at the same time each day Venetoclax by mouth at the same time each day.

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

Approved in United States as Venclexta for:

• Chronic lymphocytic leukemia (CLL)
• Small lymphocytic lymphoma (SLL)
• Acute myeloid leukemia (AML)

Approved in European Union as Venclyxto for:

• Chronic lymphocytic leukemia (CLL)
• Small lymphocytic lymphoma (SLL)
• Acute myeloid leukemia (AML)

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

Published Research Related to This Trial

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]

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]

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]

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]

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]

Venetoclax is an oral medication that selectively inhibits the BCL-2 protein, which helps cancer cells survive, thereby restoring the ability of these malignant cells to undergo programmed cell death (apoptosis).

It has been approved in the USA for treating chronic lymphocytic leukaemia (CLL) in patients with a specific genetic marker (17p deletion) who have already undergone at least one prior therapy, and it is being studied for various other blood cancers and conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax: First Global Approval. Deeks, ED.[2018]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39344587/

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 maraleucel, and a ...

2. ascopubs.org ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.e19019

Efficacy outcomes of treatments for double exposed ... Conclusions: This study underscores the scarcity of clinical data addressing efficacy outcomes in double-exposed CLL/SLL patients. Treatments ...

3. ashpublications.org ashpublications.org/blood/article/142/Supplement%201/3269/504047/Fixed-Duration-Pirtobrutinib-Combined-with

Fixed-Duration Pirtobrutinib Combined with Venetoclax ... Here, we report the safety and efficacy of fixed-duration pirtobrutinib combined with venetoclax ± rituximab in pts with R/R CLL. Methods: Pts ...

4. haematologica.org haematologica.org/article/view/haematol.2023.284150

Pirtobrutinib <i>versus</i> venetoclax in covalent Bruton ... These results suggest that pirtobrutinib may also be considered as an effective and well-tolerated treatment for patients with relapsed CLL following cBTKi.

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

Two-Year Pirtobrutinib + Venetoclax for R/R CLL New study explores 2-year combo of pirtobrutinib + venetoclax ± rituximab for relapsed/refractory CLL. Promising early results.

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11141664/

Pirtobrutinib versus venetoclax in covalent Bruton tyrosine ... These results suggest that pirtobrutinib may also be considered as an effective and well-tolerated treatment for patients with relapsed CLL following cBTKi.

7. nejm.org nejm.org/doi/full/10.1056/NEJMoa2300696

Pirtobrutinib after a Covalent BTK Inhibitor in Chronic ... In this trial, pirtobrutinib showed efficacy in patients with heavily pretreated CLL or SLL who had received a covalent BTK inhibitor.

8. clinicaltrials.gov clinicaltrials.gov/study/NCT06466122

Pirtobrutinib (LOXO-305) and Venetoclax for the Treatment ... Giving pirtobrutinib and venetoclax may kill more cancer cells in patients with CLL or SLL that is resistant to covalent BTKi. Detailed Description. PRIMARY ...