Phase 2 Study of Disease Risk Mutation-Guided Finite Acalabrutinib+Venetoclax for Relapsed CLL Post-1L Finite cBTKi+BCL2i ± Obinutuzumab (MAVRiC)

AstraZeneca

Status and phase: Not yet enrolling; Phase 2

Conditions: Small Lymphocytic Lymphoma (SLL); Chronic Lymphocytic Leukemia (CLL)

Treatments: Drug: Acalabrutinib; Drug: Venetoclax

Study type: Interventional

Funder types: Industry

Identifiers

NCT07024706

D8220C00036

Details and patient eligibility

About

This study will evaluate the efficacy and safety of finite-duration acalabrutinib plus venetoclax therapy in patients with relapsed CLL or SLL, and have previously responded to first line (1L) cBTKi + BCL2i therapy (± obinutuzumab) and maintained a response for at least two years post-treatment.

Full description

The purpose of this study is to explore the use of second line (2L) treatment with AV after relapse following first line (1L) cBTKi + BCL2i by assessment of ORR in participants with CLL/SLL. This study will generate efficacy and safety data needed to understand outcomes associated with AV in patients who initially responded with partial remission (PR) or better for a minimum of 2 years from the end of 1L cBTKi + BCL2i combination treatment and are experiencing clinical relapse requiring further treatment. MAVRiC explores AV as second-line (2L) CLL/SLL treatment after relapse on first-line (1L) cBTKi + BCL-2 by assessment of overall response rate (ORR)

• The study duration for each participant will be up to 5 year.
• The study consists of screening, treatment, and post-intervention follow-up periods.
• Participants will be grouped into low or high risk cohorts based on disease risk determined by IGHV mutation and TP53 aberrancy.

Enrollment: 80 estimated patients

Sex: All

Ages: 18 to 130 years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

Main Inclusion Criteria:

1. Participant must be ≥ 18 years at the time of signing informed consent.

2. Diagnosis of CLL/SLL according to iwCLL guidelines 2018 (Hallek et al. 2018)

3. Participants must have received first line treatment with fixed duration covalent BTKi plus BCL2i therapy (± obinutuzumab) with a response ≥ PR (i.e., CR, CRi, nPR, or PR) with a minimum of 2 years since the end of the prior 1L treatment.

4. The following data must be available or at least the appropriate samples drawn/acquired prior to dosing:

   1. IGHV (mutated vs. unmutated)
   2. del(17p) (present or absent)
   3. TP53 mutation (present or absent)

5. ECOG performance status 0, 1 or 2

6. Adequate organ and bone marrow (BM) function.

Main Exclusion Criteria:

1. Any evidence of diseases that, in the investigator's opinion, makes it undesirable for patient to participate in the study.
2. Significant cardiovascular or cerebrovascular disease.
3. Active bleeding or history of bleeding diathesis (e.g., hemophilia or von Willebrand disease).
4. Child-Pugh B/C liver cirrhosis.
5. History of prior or current malignancy.
6. HIV positive
7. History of progressive multifocal leukoencephalopathy (PML).
8. Active hepatitis B or C infection:
9. Corticosteroid use > 20 mg within 1 week before the first dose of study intervention.
10. History of hypersensitivity or anaphylaxis to study intervention(s).
11. Requires treatment with a strong CYP3A4 inhibitor/inducer.
12. Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonists.
13. Major surgical procedure within 30 days of the first dose of study intervention.

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Single Group Assignment

Masking: None (Open label)

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80 participants in 1 patient group

Acalabrutinib and Venetoclax

Experimental group

Description:

For Cohort 1, each participant will be in the study for approximately 5 years (60 months) counting from C1D1, starting with 2 cycles of acalabrutinib lead-in treatment, followed by 12 cycles of AV combination treatment, and 4 years of follow-up. For Cohort 2, each participant will be in the study for approximately 5 years (60 months) counting from C1D1 starting with 2 cycles of acalabrutinib lead-in treatment, followed by 22 cycles of AV combination treatment, and 3 years of follow-up.

Treatment:

Drug: Venetoclax

Drug: Acalabrutinib