Pirtobrutinib + Venetoclax for Mantle Cell Lymphoma

Overseen By Preetesh Jain, MD, DM, PhD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Strong CYP3A4 inhibitors

Disqualifiers: CNS involvement, Stroke, HIV, 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

Compensation: Varies

Number of Visits: 1

Duration: 12 months

30 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if a combination of pirtobrutinib (a targeted therapy) and venetoclax (a BCL-2 inhibitor) can control mantle cell lymphoma (MCL) that has returned or not responded to previous treatments. It is designed for individuals with MCL who can take oral medication and have previously tried other treatments. The study requires regular visits to monitor the condition and treatment effects. Participants must have MCL that has either recurred or not responded to other treatments. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial requires a 'washout period' (time without taking certain medications) for some treatments before starting the study. Specifically, you must stop taking targeted agents, investigational agents, therapeutic monoclonal antibodies, or cytotoxic chemotherapy for 5 half-lives or 2 weeks, whichever is shorter. Additionally, certain medications like strong CYP3A4 inhibitors or inducers and warfarin are not allowed during the study.

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

Research has shown that using pirtobrutinib and venetoclax together is promising for patients with mantle cell lymphoma (MCL) that has returned or not responded to treatment. Earlier studies demonstrated that pirtobrutinib alone was effective and tolerated by patients who had already tried many treatments, suggesting it might be safe even if other treatments have failed.

Venetoclax, when combined with other treatments like ibrutinib, has also proven safe and effective for previously untreated patients. So far, no specific reports of serious side effects have emerged from using pirtobrutinib and venetoclax together. However, as this trial is in an early stage, safety is still under investigation. Overall, the available evidence suggests that this combination is promising and might be safe for patients with relapsed or refractory MCL. ^{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 mantle cell lymphoma because these drugs work differently from the standard chemotherapy and immunotherapy options. Pirtobrutinib is a next-generation BTK inhibitor, which targets specific proteins involved in cancer cell growth, potentially offering a more precise and effective approach. Venetoclax, on the other hand, targets the BCL-2 protein that helps cancer cells survive, leading to their death. This combination aims to tackle the cancer cells from multiple angles, possibly enhancing treatment effectiveness and overcoming resistance seen with current therapies.

What evidence suggests that the combination of pirtobrutinib and venetoclax could be effective for mantle cell lymphoma?

Research has shown that combining pirtobrutinib and venetoclax, which participants in this trial will receive, may effectively treat mantle cell lymphoma, particularly when the disease has returned or hasn't responded to other treatments. Studies have found that this combination works well in lab tests and early patient trials. Pirtobrutinib alone has already demonstrated strong results and safety for patients whose lymphoma returned after other treatments. Adding venetoclax aims to enhance these results, potentially extending patients' lives and slowing cancer progression. These findings suggest this treatment could be a strong option for those with challenging cases of mantle cell lymphoma. ^{1 2 3 5 6}

Who Is on the Research Team?

Preetesh Jain, MD, PHD

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

Adults with relapsed or refractory Mantle Cell Lymphoma (MCL) who have measurable disease, an ECOG performance status of 2 or less, and adequate organ function. They must not be pregnant or breastfeeding, agree to use effective contraception, and cannot have central nervous system involvement by lymphoma, uncontrolled infections like HIV/HBV/HCV, significant heart issues, bleeding disorders, or other severe medical conditions.

Inclusion Criteria

I can take pills by mouth.

Adequate organ function as defined by the following laboratory values: Creatinine clearance. >=30 mL/min (by Cockcroft-Gault method, APPENDIX I); Total bilirubin ≤ 1.5 × ULN or ≤ 3 × ULN with documented liver involvement and/or Gilbert's Disease or controlled immune hemolysis or considered an effect of regular blood transfusions; Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <3 x ULN, or < 5 x upper limit of normal if hepatic metastases are present; Projected life expectancy of >12 weeks pertaining to lymphoma; Female patients must be surgically sterile, postmenopausal (for at least 1 year), or have confirmed negative results for a pregnancy test at screening, on a blood or urine sample obtained within 7 days prior to initiation of study treatment; Women of childbearing potential and men with female partners of childbearing potential must be willing to use an effective form of contraception for at least 6 months after the last dose of study treatment. Patient enrolled into the Pirtobrutinib+ venetoclax study should use an effective form of contraception for 6 months after the last dose of Pirtobrutinib in combination with venetoclax, whichever time period is longer. Recommended methods of highly effective birth control are: Hormonal contraception (birth control pills, patches, or rings); Intrauterine device (IUD); Birth control injections; Double barrier methods (diaphragm with spermicidal gel or condoms with birth control foam); Sterilization of participant or partner ('tubes tied' or vasectomy) Willingness of men and women of reproductive potential (defined as following menarche and not postmenopausal [and 2 years of non-therapy-induced amenorrhea] or surgically sterile) to observe conventional and highly effective birth control methods with failure rates of < 1% for the duration of treatment and for 6 months following the last dose of study treatment; this must include barrier methods such as condom or diaphragm with spermicidal gel. Women of reproductive potential are defined as following menarche and not postmenopausal (and 2 years of non-therapy-induced amenorrhea) or surgically sterile. For male subjects with a non-pregnant female partner of child-bearing potential and a woman of child-bearing potential one of the following highly effective birth control methods with a failure rate of less than 1% per year when used consistently and correctly are recommended: Combined estrogen and progestin containing hormonal contraception associated with inhibition of ovulation given orally, intravaginally, or trans dermally, progestin-only hormonal contraception associated with inhibition of ovulation given orally, by injection, or by implant, Intrauterine device (IUD) , Intrauterine hormone-releasing system (IUS), Bilateral tubal occlusion, Vasectomized partner, Sexual abstinence: considered a highly effective method only if defined as refraining from heterosexual intercourse during an entire period of risk associated with the study treatment. The reliability of sexual abstinence will be evaluated in relation to the duration of the study and to the usual lifestyle of the subject (CTFG 2014)

I can do most of my daily activities on my own.

Exclusion Criteria

With known allergies to xanthine oxidase inhibitors and/or rasburicase

Pregnant or lactating females

Pregnancy, lactation or plan to breastfeed during the study or within 6 months of the last dose of study treatment

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. Study visits occur every week during Cycle 1, then on Day 1 of every cycle for the first year.

12 months

Weekly visits during Cycle 1, then monthly visits for the first year

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 months

Long-term follow-up

Participants have study visits on Day 1 of every 2 cycles after the first year

Ongoing

What Are the Treatments Tested in This Trial?

Interventions

• Pirtobrutinib
• Venetoclax

Trial Overview The trial is testing the effectiveness of combining two drugs—Pirtobrutinib and Venetoclax—in treating MCL that has either returned after treatment or hasn't responded to previous therapies. The goal is to see if this drug combination can better control the disease.

How Is the Trial Designed?

Group I: Pirtobrutinib (LOXO-305) and Venetoclax (combination) Experimental Treatment 2 Interventions

Participants will have study visits every week during Cycle 1, and then on Day 1 of every cycle for the first year. After that, they will have study visits on Day 1 of every 2 cycles.

Pirtobrutinib is already approved in United States for the following indications:

Approved in United States as Jaypirca for:

• Mantle Cell Lymphoma
• Chronic Lymphocytic Leukemia
• Small Lymphocytic Lymphoma

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

Loxo Oncology

Collaborator

Trials

1

Recruited

30+

Published Research Related to This Trial

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]

The combination of venetoclax, ibrutinib, and obinutuzumab is well tolerated in patients with relapsed and untreated mantle cell lymphoma (MCL), with no dose-limiting toxicities reported and a maximum tolerated dose of 400 mg per day established for venetoclax.

High response rates were observed, with a complete response rate of 67% in relapsed patients and 86.6% in untreated patients, along with significant minimal residual disease clearance in 71.5% of relapsed and 100% of untreated patients after three cycles.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ibrutinib, obinutuzumab, and venetoclax in relapsed and untreated patients with mantle cell lymphoma: a phase 1/2 trial. Le Gouill, S., Morschhauser, F., Chiron, D., et al.[2021]

Venetoclax, a treatment for mantle cell lymphoma (MCL), faces challenges with resistance, but researchers identified mechanisms of this resistance, including increased levels of MCL-1 and AKT activation in resistant cell lines.

The dual inhibitor PIK-75 was found to effectively overcome venetoclax resistance in both cell lines and patient samples, showing promise as a new treatment option for patients with difficult-to-treat MCL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

PIK-75 overcomes venetoclax resistance via blocking PI3K-AKT signaling and MCL-1 expression in mantle cell lymphoma. Huang, S., Liu, Y., Chen, Z., et al.[2022]

The combination of venetoclax (VEN) and ibrutinib (IBR) showed a high overall response rate of 93.8% at the optimal dosing of VEN 200 mg and IBR 420 mg in treating relapsed mantle cell lymphoma (MCL) among 35 participants.

The study found that higher doses of VEN and IBR did not improve efficacy and were associated with increased toxicity, highlighting the importance of dose optimization in combination therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dose-finding study of ibrutinib and venetoclax in relapsed or refractory mantle cell lymphoma. Portell, CA., Wages, NA., Kahl, BS., et al.[2022]

Pirtobrutinib, a noncovalent Bruton tyrosine kinase inhibitor, has shown high response rates in patients with chronic lymphocytic leukemia and mantle cell lymphoma who are resistant to conventional covalent BTK inhibitors, addressing a significant unmet need in this population.

The early studies indicate that pirtobrutinib has a favorable toxicity profile, suggesting it may be suitable for use in combination therapies, and it has recently received accelerated FDA approval for use in mantle cell lymphoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pirtobrutinib: a new hope for patients with BTK inhibitor-refractory lymphoproliferative disorders. Thompson, PA., Tam, CS.[2023]

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 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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10153528/

Pirtobrutinib and venetoclax combination overcomes ... The pirtobrutinib-venetoclax combination exhibits enhanced efficacy against mantle cell lymphoma in vitro and in a dual ibrutinib/chimeric antigen receptor ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT05529069

Phase II Study of Pirtobrutinib With Venetoclax In Relapsed ... To evaluate the survival (including overall and progression-free survival) of the Pirtobrutinib plus venetoclax combination in relapsed refractory MCL patients.

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11106640/

Outcomes of pirtobrutinib for relapsed/refractory mantle cell ... Pirtobrutinib shows promising response rates in heavily pretreated MCL patients according to the approval study, but the real‐world data are scarce.

4. onclive.com onclive.com/view/pirtobrutinib-displays-activity-in-relapsed-refractory-mcl-following-covalent-btk-inhibitor-therapy

Pirtobrutinib Displays Activity in Relapsed/Refractory MCL ... Pirtobrutinib demonstrated promising efficacy and a tolerable safety profile in heavily pretreated patients with relapsed/refractory mantle cell lymphoma.

5. ascopubs.org ascopubs.org/doi/10.1200/JCO.23.00562

Pirtobrutinib in Covalent Bruton Tyrosine Kinase Inhibitor ... We report the safety and efficacy of pirtobrutinib in patients with covalent Bruton tyrosine kinase inhibitor (cBTKi) pretreated mantle-cell lymphoma (MCL).

6. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.7017

Efficacy and safety of first-line ibrutinib plus venetoclax in ... First-line Ibr+Ven showed promising efficacy with high CR rates and durable remissions in pts with TN MCL with and without TP53mut.