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)

44 Participants Needed

Trial Summary

What is the purpose of this trial?

To learn if the combination of LOXO-305 (pirtobrutinib) and venetoclax can help to control previously treated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).

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.

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

Venetoclax has shown effectiveness in treating chronic lymphocytic leukemia (CLL), achieving high response rates and being effective in both previously untreated and relapsed cases. Pirtobrutinib, when compared to venetoclax, showed a higher response rate in patients who had been pre-treated with other similar drugs, suggesting potential effectiveness in CLL treatment. ^{1 2 3 4 5}

Is the combination of Pirtobrutinib and Venetoclax safe for treating Chronic Lymphocytic Leukemia?

Venetoclax has been shown to have an acceptable safety profile for patients with chronic lymphocytic leukemia, with manageable side effects like neutropenia (low white blood cell count). Pirtobrutinib, when compared to Venetoclax, showed fewer severe treatment-related side effects in studies. ^{2 3 4 5 6}

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

The combination of Pirtobrutinib and Venetoclax is unique because Pirtobrutinib is a highly selective, reversible Bruton tyrosine kinase inhibitor designed to overcome limitations of previous inhibitors, and when combined with Venetoclax, it may offer improved response rates and a manageable safety profile for patients with chronic lymphocytic leukemia who have been pre-treated with other inhibitors. ^{1 2 3 4 5}

Research Team

Alessandra Ferrajoli, MD

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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 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]

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 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]

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]

References

1. Austria pubmed.ncbi.nlm.nih.gov

Chronic lymphocytic leukemia at ASH 2017. [2020]

2. Italy pubmed.ncbi.nlm.nih.gov

Pirtobrutinib versus venetoclax in covalent Bruton tyrosine kinase inhibitor-pretreated chronic lymphocytic leukemia: a matching-adjusted indirect comparison. [2023]

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

Venetoclax: Management and Care for Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia . [2018]

4. New Zealand pubmed.ncbi.nlm.nih.gov

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

5. France pubmed.ncbi.nlm.nih.gov

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

6. New Zealand pubmed.ncbi.nlm.nih.gov

Venetoclax: First Global Approval. [2018]