Efficacy Evaluation of Acalabrutinib, Venetoclax, and Rituximab in Treatment-Naïve Mantle Cell Lymphoma: A Phase II Multicenter Open-Label Study
- Trial ID
- 2023-505205-16-00
- Protocol
- D822GC00001
- Sponsor
- AstraZeneca AB
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **efficacy** of the combination therapy of acalabrutinib, venetoclax, and rituximab (AVR) in participants with treatment-naïve Mantle Cell Lymphoma by assessing the rate of complete response (CR) with minimal residual disease (MRD) negativity at the end of AVR induction, specifically after the completion of Cycle 13. This is clinically relevant as achieving MRD-negative CR is associated with improved long-term outcomes and may indicate a deeper remission in patients.
Secondary objectives include:
- Assessing the efficacy of AVR by evaluating the MRD-negative CR rate at any time during the study.
- Evaluating the 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).
- Comparing the efficacy of continued acalabrutinib treatment versus observation in participants achieving MRD-negative CR after AVR induction, by assessing the time to first occurrence of relapse or death, EFS, and TTNT post-randomization.
- Assessing the safety and tolerability of AVR with continued acalabrutinib or observation until disease progression.
Participants
The clinical trial involves a total of **59 participants** diagnosed with **treatment-naïve Mantle Cell Lymphoma**. The study population includes both male and female subjects, aged 18 years and older, who are capable of providing informed consent. Participants were selected based on specific inclusion criteria, including histologically documented Mantle Cell Lymphoma with chromosomal translocation t(11;14) and/or overexpression of cyclin D1, and a clinical stage of II, III, or IV by Ann Arbor Classification. The trial population is characterized by adequate organ and bone marrow function and an Eastern Cooperative Oncology Group performance status of 0, 1, or 2, with an allowance for a status of 3 if due to lymphoma. Lifestyle considerations such as contraceptive use are required, consistent with local regulations, to ensure safety during the study. The trial includes a vulnerable population, ensuring that all ethical guidelines are strictly adhered to. Participants are required to have at least one measurable site of disease or specific clinical presentations, and sufficient tumor samples must be available for genomic profiling and MRD testing. The study does not specify any particular dietary or physical activity requirements for participants.
Plans and Procedures
The clinical trial is designed as a **Phase II**, open-label study to evaluate the efficacy of a combination therapy involving **acalabrutinib**, **venetoclax**, and **rituximab** in participants with treatment-naïve mantle cell lymphoma. The trial aims to assess the efficacy of this combination by measuring the MRD-negative complete response (CR) rate at the end of the induction phase, following the completion of Cycle 13. The study is expected to run until December 2028, with recruitment starting in September 2023.
Participants will be involved in the trial for a maximum treatment period of 309 days for rituximab, 67 days for acalabrutinib, and 48 days for venetoclax. The trial includes several key visits: an initial screening visit to confirm eligibility based on criteria such as histologically documented mantle cell lymphoma and adequate organ function, followed by regular follow-up visits to monitor response and safety. The end-of-study visit will conclude the participant's involvement, assessing the final outcomes and any adverse events.
Participants may be withdrawn from the study early if they experience significant adverse events, fail to comply with the study protocol, or if the investigator deems it in the participant's best interest. The trial will measure primary and secondary endpoints, including MRD-negative CR rate, overall response rate, duration of response, progression-free survival, and overall survival. Adverse events will be monitored and graded according to the NCI-CTCAE v5.0 standards.
Treatment
The clinical trial involves the administration of several treatments, including **Rituximab**, **Acalabrutinib**, and **Venetoclax**, to evaluate their efficacy in participants with treatment-naïve Mantle Cell Lymphoma. **Rituximab** is provided as a concentrate for solution for infusion. It is administered via infusion, with a maximum treatment period of 309 days. The specific dosage and frequency of administration are determined based on the study protocol, and participant compliance is monitored throughout the trial.
**Acalabrutinib** is administered in the form of film-coated tablets, marketed under the name Calquence. Each tablet contains 100 mg of the active substance. The route of administration is oral, and the maximum treatment period is 67 days. The clinical supply of Acalabrutinib is provided in HDPE bottles, differing from the standard blister packaging, and is sourced from different manufacturing sites for the clinical supply chain. Participant adherence to the dosing schedule is closely monitored to ensure compliance.
**Venetoclax** is available in film-coated tablets of varying strengths: 10 mg, 50 mg, and 100 mg, marketed under the name Venclyxto. The tablets are administered orally, with a maximum treatment period of 48 days. The dosing schedule is tailored to the study protocol, and participant compliance is assessed regularly. Venetoclax is classified as an orphan drug, and its administration is integral to the study's objective of assessing the efficacy of the combination therapy.
Throughout the trial, participant compliance with the dosing schedules for all medications is monitored to ensure adherence to the study protocol. The trial does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatment. The study is designed to evaluate the efficacy of the combination therapy in achieving MRD-negative complete response rates at the end of the induction phase.
Efficacy
The efficacy of the clinical trial will be assessed by evaluating the **MRD-negative CR rate** at the end of the AVR induction, specifically following the completion of Cycle 13. The primary endpoint is the MRD-negative CR rate, which is defined as the proportion of participants who achieve minimal residual disease (MRD) negativity in peripheral blood by next-generation sequencing (NGS) at a threshold of 10^-5 while in complete response (CR) per the Lugano Classification for Non-Hodgkin Lymphoma (NHL) at any time during the study.
Secondary endpoints include several measures: Overall Response Rate (ORR), which is the proportion of participants with a CR or partial response (PR) as determined by the investigator; Complete Response (CR) rate, defined as the proportion of participants with a best response of CR; Duration of Response (DoR), which is the time from the first documented response (CR-PR) until documented progression or death; Time to Next Treatment (TTNT), defined as the time from the start of AVR induction until the start of the next anti-lymphoma therapy or death; Progression-free Survival (PFS), which is the time from the start of AVR induction until disease progression or death; Event Free Survival (EFS), defined as the time from the start of AVR induction to disease progression, initiation of systemic anti-lymphoma treatment, or death; and Overall Survival (OS), which is the time from the start of AVR induction until death due to any cause.
Additional assessments include post-randomization time to first occurrence of relapse or death, EFS, and TTNT in the continued acalabrutinib arm compared to the observation arm. Adverse events will also be monitored, graded according to the NCI-CTCAE v5.0, and coded using MedDRA. These efficacy parameters will be measured and analyzed at specified timepoints throughout the study to ensure comprehensive evaluation of the treatment's impact on participants with treatment-naïve Mantle Cell Lymphoma.
Inclusion and Exclusion Criteria
Inclusion Criteria
- 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.
- 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).
- Clinical Stage II, III, or IV by Ann Arbor Classification and requiring systemic treatment in the opinion of the treating clinician.
- 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.
- Eastern Cooperative Oncology Group PS of 0, 1, or 2 and ECOG PS of 3 if poor PS is due to lymphoma.
- 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.
- Adequate organ and bone marrow function.
- 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.
- Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the ICF and in this protocol
- 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
- Active CNS involvement by lymphoma or leptomeningeal disease.
- 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)
- Participants for whom the goal of therapy is tumour debulking before ASCT
- 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
- 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.
- 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.
- Participants with active HIV infection (i.e., with detectable viral load by PCR)
- 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.
- History or ongoing confirmed progressive multifocal leukoencephalopathy.
- History of stroke or intracranial haemorrhage within 6 months prior to the first dose of study intervention
- Uncontrolled autoimmune haemolytic anaemia or idiopathic thrombocytopenic purpura.
- Active bleeding from a gastrointestinal ulcer, except incidental finding identified on endoscopy that is attributable to MCL
- Participants with a known hypersensitivity to acalabrutinib, venetoclax, or rituximab or any of the excipients of the product.
- Known allergy to uric acid lowering agents
- Severe prior reactions to monoclonal antibodies
- Known glucose-6-phosphate dehydrogenase deficiency
- 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).
- Currently pregnant (confirmed with positive pregnancy test) or breast feeding
- 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
- 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
- Requiring continued anticoagulation with warfarin or equivalent vitamin K antagonists. Exceptions are DOACs rivaroxaban, apixaban, edoxaban and dabigatran
- 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.
- Received major surgery (excluding placement of vascular access or for diagnosis) within 28 days of first dose of study intervention
- Receipt of live, attenuated vaccine within 28 days before the first dose of study intervention.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Poland | Not Recruiting | 28 Sept 2023 | 30 |
 Spain | Not Recruiting | 28 Sept 2023 | 11 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Venclyxto 100 mg film-coated tablets | Other | FILM-COATED TABLETS | ORAL USE | 00 | 48 | PRD6353834 |
RITUXIMAB | Other | — | INFUSION | 00 | 309 | SUB12570MIG |
Calquence 100 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL USE | 00 | 67 | PRD10242587 |
Venclyxto 50 mg film-coated tablets | Other | FILM-COATED TABLETS | ORAL USE | 00 | 48 | PRD6353826 |
RITUXIMAB | Other | — | INFUSION | 00 | 309 | SUB12570MIG |
Venclyxto 10 mg film-coated tablets | Other | FILM-COATED TABLETS | ORAL USE | 00 | 48 | PRD6353818 |