This prospective, open-label, phase 2 study will evaluate the efficacy and safety of lisaftoclax in combination with pirtobrutinib in adults with relapsed or refractory mantle cell lymphoma following failure of prior BTK-targeted therapy.

The study includes two cohorts. Cohort 1 will enroll participants who experienced stable disease, disease progression, or intolerance following treatment with a covalent BTK inhibitor. Cohort 2 is an exploratory cohort enrolling participants who experienced stable disease, disease progression, or intolerance following treatment with a non-covalent BTK inhibitor other than pirtobrutinib or a BTK degrader.

Participants will receive oral pirtobrutinib 200 mg once daily in combination with oral lisaftoclax. Lisaftoclax will be administered using a dose ramp-up schedule, followed by a target dose of 600 mg once daily. Treatment will continue until disease progression, unacceptable toxicity, withdrawal of consent.

Inclusion Criteria:

• Participants must meet all of the following criteria:

  1. Age 18 years or older.

  2. Histologically and immunophenotypically confirmed mantle cell lymphoma.

  3. At least one measurable lesion.

  4. Received at least one prior systemic treatment regimen that included a BTK-targeted therapy, including a covalent BTK inhibitor, non-covalent BTK inhibitor, or BTK degrader, and had stable disease, disease progression, or intolerance during or after the most recent BTK-targeted therapy.

  5. Eastern Cooperative Oncology Group performance status of 0 to 2.

  6. Adequate hepatic, renal, and bone marrow function, defined as all of the following:

     * Aspartate aminotransferase and alanine aminotransferase ≤3 × upper limit of normal;

     • Total bilirubin ≤1.5 × upper limit of normal;
     • Creatinine clearance ≥30 mL/min;
     • Absolute neutrophil count ≥0.5 × 10^9/L;
     • Platelet count ≥30 × 10^9/L. Supportive treatment is permitted.

  7. Participants of reproductive potential must agree to use effective contraception during study treatment and for 3 months after the last dose of study treatment.

  8. Willing and able to comply with study procedures and follow-up assessments.

  9. Able to understand and voluntarily sign the informed consent form before screening.

Exclusion Criteria:

• 1. Known hypersensitivity to pirtobrutinib, lisaftoclax, or any component or excipient of either study drug.

  2. Concurrent participation in another clinical study. 3. Prior treatment with any BCL-2 inhibitor. 4. Active central nervous system involvement, including parenchymal or leptomeningeal disease.

  5. Clinically significant uncontrolled cardiac or cardiovascular disease, or a history of myocardial infarction within 6 months before the planned initiation of pirtobrutinib.

  6. Uncontrolled active severe systemic bacterial, viral, fungal, or parasitic infection.

  7. Current treatment with strong CYP3A4 inhibitors or inducers and/or strong P-glycoprotein inhibitors.

  8. Positive human immunodeficiency virus test. 9. Active hepatitis B or hepatitis C infection, except:

  • Participants with detectable hepatitis B virus DNA whose disease is controlled may be enrolled at the investigator's discretion, provided that concurrent antiviral therapy is administered;

  • Participants with a history of hepatitis C virus infection who have completed antiviral treatment and have a viral load below the lower limit of quantification may be enrolled.

    10. Pregnant or breastfeeding women. 11. Unable to complete protocol-required study visits or procedures, including follow-up visits, or unable to comply with study requirements.

    12. Any other clinically significant current or prior medical condition that, in the investigator's judgment, may pose a risk to participant safety or interfere with study assessments, procedures, or completion.