Lisaftoclax Plus Pirtobrutinib in Relapsed or Refractory Mantle Cell Lymphoma After BTK-Targeted Therapy

Official title

A Prospective Phase 2 Study of Lisaftoclax Plus Pirtobrutinib in Patients With Relapsed or Refractory Mantle Cell Lymphoma After Failure of BTK-Targeted Therapy

Overview

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.

Interventions

• Drug Lisaftoclax
  Lisaftoclax will be administered orally once daily. During Cycle 1, participants will undergo dose ramp-up with 20 mg on Day 1, 50 mg on Day 2, 100 mg on Day 3, 200 mg on Day 4, and 400 mg on Day 5. The target dose of 600 mg once daily will begin on Day 6 and continue thereafter. Each treatment cycle is 28 days. Treatment will continue until disease progression, unacceptable toxicity, withdrawal of consent, or another protocol-defined reason for discontinuation.
• Drug Pirtobrutinib
  Pirtobrutinib will be administered orally at a dose of 200 mg once daily beginning on Day 1 of Cycle 1. Each treatment cycle is 28 days. Treatment will continue until disease progression, unacceptable toxicity, withdrawal of consent, or another protocol-defined reason for discontinuation.

Primary outcome measures

• Complete Response Rate at 6 Months in Cohort 1 [Time frame: At 6 months after initiation of study treatment]
• Overall Response Rate in Cohort 2 [Time frame: From the first dose of study treatment until disease progression, assessed up to 36 months]

Secondary outcome measures (5)

• Duration of Response [Time frame: From the first documented response until disease progression or death, whichever came first, assessed up to 36 months]
• Progression-Free Survival [Time frame: From the first dose of study treatment until disease progression or death, whichever came first, assessed up to 36 months]
• Overall Survival [Time frame: From the first dose of study treatment until death from any cause, assessed up to 36 months]
• Minimal Residual Disease Negativity Rate [Time frame: At baseline, assessed up to 4 weeks. Interim response assessment, from the first dose of study treatment till 3 cycles. End of induction treatment, from the first dose of study treatment till 3 cycles. Following period, every 6 months during follow-up.]
• Number of Participants With Treatment-Emergent Adverse Events [Time frame: From the first dose of study treatment through 30 days after the last dose]

Eligibility criteria

Inclusion criteria

• Participants must meet all of the following criteria:

• Age 18 years or older.
• Histologically and immunophenotypically confirmed mantle cell lymphoma.
• At least one measurable lesion.
• 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.
• Eastern Cooperative Oncology Group performance status of 0 to 2.
• 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.
• Participants of reproductive potential must agree to use effective contraception during study treatment and for 3 months after the last dose of study treatment.
• Willing and able to comply with study procedures and follow-up assessments.
• 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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• Henan Cancer Hospital — Zhengzhou

Identifiers

NCT: NCT07684950 · 2026-204

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗