Study of Acalabrutinib Plus Venetoclax and Rituximab in Participants with Treatment Naïve Mantle Cell Lymphoma

Overview

Sponsor-declared trial summary

Key facts

Sponsor

AstraZeneca AB

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

21 Feb 2024 → ongoing

Decision date (initial)

2023-12-21

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

AstraZeneca AB

External identifiers

EU CT number

2023-505205-16-00

ClinicalTrials.gov

NCT05951959

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

To assess the efficacy of AVR by assessment of MRD-negative CR rate at the end of AVR induction, i.e., following completion of Cycle 13

Secondary objectives 4

1. 1. To assess the efficacy of AVR by assessment of MRD-negative CR rate at any time during the study
2. 2. To assess the efficacy of AVR by assessment of overall response rate (ORR), CR rate, duration of response (DoR), time to next treatment (TTNT), progression-free survival (PFS), event-free survival (EFS), and overall survival (OS)
3. 3. To assess the efficacy of continued acalabrutinib treatment compared to observation, in participants achieving MRD-negative CR after AVR induction by assessment of post randomisation time to first occurrence of relapse or death, EFS, and TTNT
4. 4. To assess the safety and tolerability of AVR with continued acalabrutinib or observation until disease progression

Conditions and MedDRA coding

Treatment Naïve Mantle Cell Lymphoma

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 10

1. 1. Participant must be ≥ 18 years or the legal age of consent in the jurisdiction in which the study is taking place, whichever is greater, at the time of signing the informed consent.
2. 2. Histologically documented MCL based on criteria established by the World Health Organization with documentation of chromosomal translocation t(11;14) (q13;q32) and/or overexpression of cyclin D1 in association with other relevant markers (e.g., CD5, CD19, CD20 or PAX5).
3. 3. Clinical Stage II, III, or IV by Ann Arbor Classification and requiring systemic treatment in the opinion of the treating clinician.
4. 4. At least 1 measurable site of disease per Lugano Classification for NHL (Appendix K). The site of disease must be > 1.5 cm in the long axis regardless of short axis measurement or > 1.0 cm in the short axis regardless of long axis measurement, and clearly measurable in 2 perpendicular dimensions, as assessed by diagnostic quality CT (MRI may be used for participants who are either allergic to CT contrast media or have renal insufficiency that per institutional guidelines restricts the use of CT contrast media). OR Participant with leukemic non-nodal MCL presentation with splenomegaly (spleen > 13 cm in length cranial to caudal) and Bone Marrow (BM) involvement.
5. 5. Eastern Cooperative Oncology Group PS of 0, 1, or 2 and ECOG PS of 3 if poor PS is due to lymphoma.
6. 6. Confirmed availability of sufficient FFPE tumour samples for central laboratory genomic profiling, including TP53 and clone identification for MRD testing per clonoSEQ® assay. Participants with leukemic non-nodal MCL may be enrolled with available BM tissue. For non-nodal leukaemic MCL participants and when nodal or extranodal tissue is not easily accessible and an invasive biopsy will cause a significant risk to the participant, the participant can be enrolled without a tissue biopsy if MCL BM involvement is confirmed by a BM biopsy and sufficient BM biopsy and aspirate provided for TP53 testing, tumour profiling and clone identification for MRD testing.
7. 7. Adequate organ and bone marrow function.
8. 8. Male and/or female Contraceptive use by males or females should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. (a) Male participants: - Male participants with a female partner of child-bearing potential should use a condom from enrolment, throughout the study until 90 days following the last dose of venetoclax or rituximab, whichever is longer. - For non-pregnant potentially childbearing partners, contraception recommendations should also be considered. A male participant must agree to refrain from sperm donation throughout the study until 90 days following the last dose of venetoclax or rituximab, whichever is longer. (b) Female participants: - Women of childbearing potential must have negative serum pregnancy test result prior to the start of study intervention (Cycle 1 Day 1) and agree to abstain from breastfeeding during study participation and at least 12 months after the last drug administration. - Female participants of childbearing potential who are sexually active with a nonsterilized male partner must agree to use at least one highly effective form of birth control from enrolment, throughout the study and at least 2 days after the last dose of acalabrutinib, at least 6 months after the last dose of venetoclax, and at least 12 months after the last dose of rituximab, whichever is longer. Cessation of contraception after this point should be discussed with a responsible physician.
9. 9. Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the ICF and in this protocol
10. 10. Provision of signed and dated written Optional Genetic Research Information informed consent prior to collection of samples for optional genetic research that supports the Genomic Initiative.

Exclusion criteria 24

1. 1. Active CNS involvement by lymphoma or leptomeningeal disease.
2. 2. Current or previous active malignancies requiring anticancer therapy (except: - adequately treated basal cell or squamous cell skin cancer, in situ cancer, history of cancer with no evidence of recurrence for ≥ 2 years before enrolment, local radiotherapy with a field that does not overlap with sites of current MCL disease and given at least 3 months prior to the screening PET-CT scan and the participant had recovered from any associated toxicity. Anti-hormonal therapies are permitted after discussion with the sponsor's medical monitor)
3. 3. Participants for whom the goal of therapy is tumour debulking before ASCT
4. 4. Any severe or life-threatening illness, medical condition (e.g., uncontrolled hypertension, bleeding diathesis), or organ system dysfunction which, in the investigator' opinion, could compromise the participant safety, interfere with the absorption or metabolism of study intervention (acalabrutinib, rituximab, venetoclax) or put the study outcomes at undue risk
5. 5. Clinically significant cardiovascular disease such as uncontrolled or untreated symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or any Class 3 (moderate) or Class 4 (severe) cardiac disease as defined by the New York Heart Association Functional Classification, or QTc > 480 msec at screening. Exception: Participants with controlled, asymptomatic atrial fibrillation during screening may enroll.
6. 6. Any active uncontrolled infection (bacterial, viral, fungal, or other infection including tuberculosis), defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment, which in the investigator's opinion makes it undesirable or pose a safety risk for the participant to participate in the study.
7. 7. Participants with active HIV infection (i.e., with detectable viral load by PCR)
8. 8. Serologic status reflecting active hepatitis B or C. (a) Participants who are HBsAg positive or HBV-DNA PCR positive will not be eligible. Participants who are anti-HBc IgG antibody positive and who are HBsAg negative will need to have a negative PCR result before enrolment. Participants who have protective titres of HBsAb after vaccination will be eligible. (b) Participants who are hepatitis C antibody positive and are HCV-PCR positive will not be eligible.
9. 9. History or ongoing confirmed progressive multifocal leukoencephalopathy.
10. 10. History of stroke or intracranial haemorrhage within 6 months prior to the first dose of study intervention
11. 11. Uncontrolled autoimmune haemolytic anaemia or idiopathic thrombocytopenic purpura.
12. 12. Active bleeding from a gastrointestinal ulcer, except incidental finding identified on endoscopy that is attributable to MCL
13. 13. Participants with a known hypersensitivity to acalabrutinib, venetoclax, or rituximab or any of the excipients of the product.
14. 14. Known allergy to uric acid lowering agents
15. 15. Severe prior reactions to monoclonal antibodies
16. 16. Known glucose-6-phosphate dehydrogenase deficiency
17. 17. Malabsorption syndrome, disease significantly affecting gastrointestinal function, resection of the stomach, extensive small bowel resection that is likely to affect absorption, symptomatic inflammatory bowel disease, partial or complete bowel obstruction, or gastric restrictions and bariatric surgery, such as gastric bypass or inability to swallow the formulated product (tablets).
18. 18. Currently pregnant (confirmed with positive pregnancy test) or breast feeding
19. 19. Any prior therapies for the treatment of MCL with the exception of involved site radiotherapy given at least 3 months prior to screening PET-CT scan and where the radiotherapy field does not overlap areas of current disease activity
20. 20. Requiring continued treatment with a strong CYP3A4 inhibitor/inducer or its use within 7 days prior to the first dose (Cycle 1 Day 1) of acalabrutinib or venetoclax
21. 21. Requiring continued anticoagulation with warfarin or equivalent vitamin K antagonists. Exceptions are DOACs rivaroxaban, apixaban, edoxaban and dabigatran
22. 22. Requiring ongoing immunosuppressive therapy, including systemic or enteric corticosteroids (except: Topical or inhaled corticosteroids or low-dose oral steroids (≤ 20 mg of prednisone or equivalent per day) as a therapy for comorbid conditions, short courses of glucocorticoids in excess of 20 mg prednisone for no more than 14 days for comorbid conditions and systemic use of corticosteroids as a prephase to control MCL manifestations) (up to approximately 100 mg prednisolone or equivalent daily) for up to 10 days.
23. 23. Received major surgery (excluding placement of vascular access or for diagnosis) within 28 days of first dose of study intervention
24. 24. Receipt of live, attenuated vaccine within 28 days before the first dose of study intervention.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. MRD-negative CR rate

Secondary endpoints 14

1. MRD-negative CR rate o MRD-negative CR rate is defined as the proportion of participants who achieved MRD-negativity in peripheral blood by NGS at a threshold of 10-5 while in CR per the Lugano Classification for NHL at any time during the study.
2. Overall Response Rate (ORR) o ORR is defined as the proportion of participants with a CR or PR, as determined by the investigator.
3. Complete Response (CR) rate o CR rate is defined as the proportion of participants with a best response of CR.
4. Duration of Response (DoR) o The DoR is defined as the time from the date of first documented response (CR-PR) until the date of documented progression per the Lugano Classification for NHL or death (by any cause in the absence of disease progression), whichever occurs first.
5. Time to Next Treatment (TTNT) o TTNT or death is defined as the time from the start of AVR induction until the start of the next anti-lymphoma therapy (including local radiotherapy, unless pre-planned at baseline) or death due to any cause, whichever comes first.
6. Progression-free Survival (PFS) o PFS is defined as the time from the start of AVR induction until the date of documented objective disease progression or death (by any cause in the absence of progression), regardless of whether the participant withdraws from therapy or receives another anti-cancer therapy prior to progression.
7. Event Free Survival (EFS) o EFS is defined as the time from the start of AVR induction to any of the following events: disease progression, or initiation of systemic anti-lymphoma treatment and or unplanned radiation, or death due to any cause, whichever occurs first.
8. Overall Survival (OS) o OS is defined as the time from the start of AVR induction until death due to any cause.
9. Post randomization time to first occurrence of relapse or death, EFS and TTNT in continued acalabrutinib arm compared to observation arm.
10. o Time to first occurrence of relapse or death is defined as the time from Cycle 15 Day 1 until date of progression per the Lugano Classification for NHL as assessed by investigator, or death due to any cause, whichever occurs first.
11. o Event-free survival is defined as the time from Cycle 15 Day 1 until any of the following events: disease progression, or initiation of subsequent systemic anti‑lymphoma treatment and/or unplanned radiation, or death due to any cause, whichever occurs first.
12. o Time to next therapy or death is defined as the time from Cycle 15 Day 1 until the start of the next anti-lymphoma therapy (including local radiotherapy, unless pre-planned at baseline) or death due to any cause, whichever comes first.
13. Number of participants with any Adverse Events (AE), Serious Adverse Events (SAE), Adverse Event of Special Interest (AESI) and AEs leading to study treatment discontinuation or dose modification
14. o Adverse events will be graded by the investigator according to the NCI-CTCAE v5.0. Each AE verbatim term will be coded to a system organ class and a preferred term using the MedDRA.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Auxiliary 5

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

AstraZeneca AB

Sponsor organisation

AstraZeneca AB

Address

Astraallen Gartuna, Karlebyhus Byggnad 674 Karlebyhus Byggnad 674

City

Sodertalje

Postcode

151 85

Country

Sweden

Scientific contact point

Organisation

AstraZeneca AB

Contact name

Clinical Study Information Center

Public contact point

Organisation

AstraZeneca AB

Contact name

Clinical Study Information Center

Locations

2 EU/EEA countries · 6 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 8 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

4 submissions — initial application plus substantial / non-substantial modifications