Pirtobrutinib + Venetoclax for Mantle Cell Lymphoma

Recruiting in Palo Alto (17 mi)

Overseen by Preetesh Jain, MD, PHD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Strong CYP3A4 inhibitors

Disqualifiers: CNS involvement, Stroke, HIV, others

No Placebo Group

Prior Safety Data

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

This trial is testing two drugs, pirtobrutinib and venetoclax, to treat patients with mantle cell lymphoma that has come back or not responded to other treatments. Pirtobrutinib stops cancer cells from growing, while venetoclax makes them die. Venetoclax has been previously studied in children with recurring or resistant cancers and in combination with other drugs for mantle cell lymphoma.

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.

What data supports the effectiveness of the drug combination Pirtobrutinib and Venetoclax for Mantle Cell Lymphoma?

Research shows that combining drugs like ibrutinib (similar to pirtobrutinib) and venetoclax has been effective in treating mantle cell lymphoma, with high response rates and manageable side effects. Additionally, venetoclax has shown benefits in treating other types of blood cancers, suggesting potential effectiveness in combination with pirtobrutinib for mantle cell lymphoma. ^{1 2 3 4 5}

Is the combination of Pirtobrutinib and Venetoclax safe for humans?

Both Pirtobrutinib and Venetoclax have been studied separately and have shown manageable safety profiles in clinical trials for conditions like chronic lymphocytic leukemia (CLL). Venetoclax, in particular, has been noted for its acceptable safety profile, though it can cause side effects like neutropenia (low white blood cell count), which can be managed with dose adjustments. ^{1 2 5 6 7}

What makes the drug combination of Pirtobrutinib and Venetoclax unique for treating Mantle Cell Lymphoma?

The combination of Pirtobrutinib and Venetoclax is unique because Pirtobrutinib is a non-covalent (reversible) Bruton tyrosine kinase inhibitor designed to overcome resistance to other BTK inhibitors, and Venetoclax targets BCL-2, a protein that helps cancer cells survive. This combination aims to address the unmet need for patients who are resistant to standard treatments, offering a novel approach by potentially overcoming resistance mechanisms in Mantle Cell Lymphoma. ^{1 2 4 5 8}

Research Team

Preetesh Jain, MD, PHD

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

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 am 18 years or older.

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)

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

Trial Timeline

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

Treatment Details

Interventions

• Pirtobrutinib (Bruton's Tyrosine Kinase (BTK) Inhibitor)
• Venetoclax (B-cell Lymphoma-2 (BCL-2) Inhibitor)

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.

Participant Groups

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.

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

Dr. Peter WT Pisters

M.D. Anderson Cancer Center

Chief Executive Officer since 2017

MD from University of Western Ontario

Dr. Jeffrey E. Lee

M.D. Anderson Cancer Center

Chief Medical Officer

MD from Stanford University School of Medicine

Loxo Oncology

Collaborator

Trials

1

Recruited

30+

Findings from Research

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]

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]

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]

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]

References

1. 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]

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

Dose-finding study of ibrutinib and venetoclax in relapsed or refractory mantle cell lymphoma. [2022]

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

Ibrutinib, obinutuzumab, and venetoclax in relapsed and untreated patients with mantle cell lymphoma: a phase 1/2 trial. [2021]

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

PIK-75 overcomes venetoclax resistance via blocking PI3K-AKT signaling and MCL-1 expression in mantle cell lymphoma. [2022]

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

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

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

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

Pirtobrutinib: a new hope for patients with BTK inhibitor-refractory lymphoproliferative disorders. [2023]