Chronic Lymphocytic Leukemia (CLL), Small Lymphocytic Lymphoma (SLL)
Conditions
Keywords
Chronic Lymphocytic Leukemia (CLL), Small Lymphocytic Lymphoma (SLL), Relapsed CLL, Refractory CLL, Acalabrutinib
Brief summary
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.
Detailed 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.
Interventions
DRUGAcalabrutinib
Acalabrutinib is an orally available cBTKi that inhibits the activity of BTK and prevents the activation of the B-cell antigen receptor (BCR) signaling pathway.
DRUGVenetoclax
Venetoclax is an orally bioavailable inhibitor of the anti-apoptotic protein BCL-2
Sponsors
AstraZeneca
AbbVie
Genentech, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 130 Years
Healthy volunteers
No
Inclusion 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) | ORR assessed at multiple timepoints during treatment period (each cycle is 28 days). Timepoint for primary analysis is at completion of cycle 14 | ORR, defined as the proportion of participants who achieve best response of CR, CRi, nPR, or PR per iwCLL criteria as assessed by the investigator. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) | PFS will be assessed from Cycle 3 to Cycle 24 during treatment period (each cycle is 28 days) | PFS is defined as time from date of the first dose until progression per iwCLL criteria or death due to any cause in the absence of progression. |
| Duration of Response (DoR) | DoR will be assessed from Cycle 3 to Cycle 24 during treatment period (each cycle is 28 days) | DoR is defined as the time from the date of first documented response until date of documented progression per iwCLL criteria or death due to any cause. |
| Event Free Survival (EFS) | EFS will be assessed from Cycle 3 to Cycle 24 during treatment period (each cycle is 28 days) | EFS is defined as the time from date of the first dose until the first occurrence of disease progression, initiation of subsequent CLL/SLL therapy, or death due to any cause. |
| Time to Next Treatment (TTNT) | TTNT will be assessed from Cycle 3 to Cycle 24 during treatment period (each cycle is 28 days) | TTNT is defined as the time from date of the first dose to the initiation of subsequent CLL/SLL therapy or death due to any cause |
| Overall Survival (OS) | OS will be assessed every 3 months through the study completion, for 5 years | OS is defined as the time from date of the first dose until the date of death due to any cause. |
| Rate of undetectable Minimal Residual Disease (uMRD) | uMRD will be measured at 3 months after last treatment | Rate of peripheral blood (PB) uMRD, defined as proportion of participants achieving remission based on a clonoSEQ® assay result of \<1 CLL cell per 100,000 leukocytes (\< 10-5). |
| Treatment-Emergent Adverse Events (safety and tolerability) of second-line (2L) treatment with Acalabrutinib and Venetoclax after relapse following 1L cBTKi + BCL2i | Safety and tolerability will be evaluated throughout the study for 5 years | Safety and tolerability will be evaluated in terms of AEs/SAEs, AEs leading to treatment discontinuation and deaths, and relevant clinical laboratory results. |
Countries
Austria, Brazil, Czechia, Ireland, Italy, Poland, Spain, United States
Contacts
CONTACTAstraZeneca Clinical Study Information Center
Outcome results
None listed