Acalabrutinib and Rituximab in Previously Untreated Mantle Cell Lymphoma

Study Overview
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Brief Summary
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This is a phase II, single-arm, open-label, multicentre study of acalabrutinib and rituximab for elderly or frail patients with previously untreated mantle cell lymphoma.

Detailed Description
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This is a Phase II, multicentre, single arm, open label pilot study to assess the safety and efficacy of acalabrutinib in combination with rituximab for previously untreated elderly frail mantle cell lymphoma patients. 26 patients will be recruited from 12 UK centres over 18 months. Patients will receive acalabrutinib and rituximab for up to six cycles. The cycle length is 28 days. Specifically, patients will receive acalabrutinib, orally, at a dose of 100 mg twice daily for 28 days and rituximab 375 mg/m2 intravenously on day 1 (+/-3) of each cycle.* Patients with any degree of response at the Week 12 (end of cycle 3) and Week 24 assessments (end of cycle 6) will continue with acalabrutinib monotherapy at a dose of 100 mg twice daily until disease progression, the development of unacceptable toxicity or any other reason (whichever occurs sooner). * Note: Acalabrutinib may be administered at a dose of 100 mg od po for cycle 1 day 1-7 at the local investigator's discretion. The dose should be escalated to full dose (100 mg bd) by day 8, cycle 1 if no toxicity (see dose modification section). Rituximab may be administered subcutaneously at a flat dose of 1400 mg from cycle 2 onwards following an intravenous dose of 375 mg/m2 in cycle 1. Consider splitting the first dose of rituximab at cycle 1 in the minority of MCL patients presenting with a white cell count of >25 x 109/L. Consider splitting 25mg/m2 on Day 1 and 350mg/m2 on Day 2 of cycle 1. All patients will be followed up for a minimum of 2 years following being registered into the trial. For patients that have been in follow-up for more than 2 years, annual survival and disease status follow-up will continue until the end of the trial.

Official Title
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Phase II Study of Acalabrutinib and Rituximab for Elderly or Frail Patients With Previously Untreated Mantle Cell Lymphoma

Conditions
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Mantle Cell Lymphoma

Intervention / Treatment
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* Drug: Acalabrutinib
* Drug: Rituximab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and women ≥ 60 years of age. Pathologically confirmed MCL, with documentation of monoclonal B cells that have a chromosome translocation t(11;14)(q13;q32) and/or overexpress cyclin D1. Stage II-IV MCL and requiring treatment in the opinion of the treating clinician. Eastern Cooperative Oncology Group (ECOG) performance status 0-3 ( One or more of the following: Age 80 years or more Cumulative Illness Rating Scale for Geriatrics (CIRS-G) score 6 or greater Left ventricular ejection fraction (LVEF) less than or equal to 50% as assessed by echocardiogram or multi-gated coronary angiography (MUGA) Significant co-morbidities or cardiac risk factors making anthracycline-containing chemotherapy inadvisable Heart failure clinically determined by the presence of New York Heart Association (NYHA) failure grade II due to a cause other than MCL Impaired respiratory function with DLCO and/or FVC/FEV1 ratio less than 75% of predicted due to a cause other than MCL Significant respiratory illness e.g., moderate or severe COPD / bronchiectasis Other co-morbidities that in the Investigator's opinion which would preclude the use of standard immuno-chemotherapy (to be discussed on a case-by-case basis with the TMG, via UCL CTC) Willing and able to participate in all required evaluations and procedures in this study protocol including swallowing capsules without difficulty. Negative serum or urine pregnancy test for women of childbearing potential (WOCBP). Willing to comply with the contraceptive requirements of the trial (see section 6.3.4). Written informed consent. Exclusion Criteria: Any prior therapy (including targeted inhibitors) for MCL (other than prior localised radiotherapy, a 10-day pulse of high dose steroids or ongoing continuous prednisolone above 20mg od for symptom control). Patients considered fit enough to receive standard, full dose cytotoxic immunochemotherapy as treatment for non-transplant eligible MCL e.g., full dose R-CHOP, VR-CAP, R-DHAP, R-Bendamustine, R-FC. Prior malignancy (or any other malignancy requiring active treatment), except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, localised prostate cancer or other cancer from which the subject has been disease free for ≥ 2 years or which will not limit survival to < 5 years. Clinically significant cardiovascular disease such as uncontrolled arrhythmias, or myocardial infarction within 6 months of screening, or any Class 3 or 4 cardiac disease as defined by the New York Heart Association (NYHA) Functional Classification, or corrected QT interval (QTc) > 480 msec at screening. Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel 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. Known history of infection with HIV or any uncontrolled active systemic infection (e.g., bacterial, viral or fungal). Known history of drug-specific hypersensitivity or anaphylaxis to any study drug (including active product or excipient components). Active bleeding or history of bleeding diathesis (e.g. haemophilia or von Willebrand disease. Uncontrolled AIHA (autoimmune haemolytic anaemia) or ITP (idiopathic thrombocytopenic purpura). Known presence of a gastrointestinal ulcer diagnosed by endoscopy within 3 months before screening. Requires treatment with a strong cytochrome P450 3A4 (CYP3A4) inhibitor/inducer. Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonists (e.g. phenprocoumon) within 7 days of first dose of study drug. Prothrombin time (PT)/INR or aPTT (in the absence of lupus anticoagulant) > 2 x upper limit of normal (ULN). Requires treatment with proton pump inhibitors (e.g. omeprazole, esomeprazole, lansoprazole, rabeprazole, or pantoprazole). Subjects receiving proton pump inhibitors who switch to H2-receptor antagonists or antacids are eligible for enrolment to this study. History of significant cerebrovascular disease/event, including stroke or intracranial haemorrhage, within 6 months before the first dose of study drug. Major surgical procedure within 28 days of first dose of study drug. Note: If a subject had major surgery, they must have recovered adequately from any toxicity and/or complications from the intervention before the first dose of study drug. Hepatitis B or C serologic status: subjects who are hepatitis B core antibody (anti-HB core) positive and who are surface antigen negative will need to have a negative polymerase chain reaction (PCR) test. Those who are hepatitis B surface antigen (HbsAg) positive or hepatitis B PCR positive will be excluded. Those who are hepatitis C antibody or PCR positive will be excluded (those who are hepatitis C antibody positive and PCR negative will not be excluded). Absolute neutrophil count <1.0 x 109/L (or requires growth factor support to maintain absolute neutrophil count >1.0 x 109/L) and/or platelets <75 x109/L independent of growth factor support, unless related to bone marrow infiltration or splenomegaly due to underlying MCL (where platelets between 50-75 x109/L are acceptable) Total bilirubin > 1.5 x ULN, unless due to Gilbert's syndrome or of non-hepatic origin. AST and/or ALT > 3 x ULN. Calculated creatinine clearance <30 mL/min. Breastfeeding or pregnant. Concurrent participation in another therapeutic clinical trial. Live vaccine within 28 days of first study dose

Ages Eligible for Study
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Minimum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Acalabrutinib and rituximab<br>Patients with untreated mantle cell lymphoma will receive acalabrutinib and rituximab for up to six cycles. Each cycle will comprise of acalabrutinib 100mg twice daily orally for 28 days and rituximab 375mg/m2 IV on day 1 (+/1 3 days) of every cycle. | Drug: Acalabrutinib<br>* Patients will receive acalabrutinib 100mg twice daily for up to six 28 day cycles. Patients can receive 100mg once daily for cycle 1, day 1 to day 7, according to the investigator's discretion.<br>Drug: Rituximab<br>* Patient will receive rituximab 375 mg/m2 IV on day 1 (+/- 3 days) of each cycle, for a maximum of 6 cycles<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall response rate | To determine the efficacy of acalabrutinib in combination with rituximab in terms of disease response. | 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression free survival | Progression free survival measured from the date of first dose of acalabrutinib until the date of first documented progression or date of death from any cause. | From the date of first dose of acalabrutinib until the date of progression or death. Assessed up to 42 months. | 
| Overall survival | Overall survival measured from the date of first dose of acalabrutinib until the date of death from any cause. | From the date of first dose of acalabrutinib until the date of death. Assessed up to 42 months. | 
| Quality of life up to 24 months | The EORTC QLQ-C30 will be used to measure participant-assessed quality of life | At baseline, week 12, week 24, month 12 and month 24 | 
| Incidence and frequency of grade 1-2 and 3+ adverse events seen in both treatment arms. | Safety and toxicity will be characterised in terms of adverse events as assessed by CTCAE v5.0. The incidence and frequency of adverse events during treatment and after treatment will be assessed. | Between the start of study treatment and 30 calendar days post last IMP administration. |