Treatment With Acalabrutinib Post Blood or Marrow Transplantation in Subjects With Mantle Cell Lymphoma

Single Arm, Phase II Study of Acalabrutinib as Post-Autologous Blood or Marrow Transplant (BMT) Maintenance Therapy in Subjects With Mantle Cell Lymphoma

This is a phase II study to evaluate efficacy of Acalabrutinib as a maintenance therapy following blood or marrow transplant (BMT) in patients who have been diagnosed with mantle cell lymphoma.

Mantle cell lymphoma (MCL) is one of approximately 100 different types of non-Hodgkin's lymphoma (NHL). Due to the aggressive and heterogeneous nature of MCL, majority of patients are diagnosed with advanced stage disease that requires immediate, diverse and aggressive courses of therapy to improve the outcome of the disease. The addition of blood or bone marrow transplantation (BMT) to the chemotherapy regimens is a critical factor to prolong duration of response in patients, however, the benefit of combination chemotherapy followed by BMT is often temporary as patients experience disease progression and mortality and this underscores the need for novel therapies as well as additional maintenance therapy strategies to prevent relapse post-BMT.

Acalabrutinib, a selective, irreversible small molecule inhibitor of Bruton's tyrosine kinase (BTK) is approved for the treatment of adult patients with MCL who have received at least 1 prior therapy

This study is a single arm, multi-center, phase 2 study of participants who will receive acalabrutinib as maintenance therapy post-BMT. Participants will undergo a standard of care BMT with conditioning regimen determined by the treating physician per institutional guidelines.The BMT procedure is not considered part of this study. Following completion of the BMT, maintenance therapy with acalabrutinib will begin on Day 100 in 28-day cycles. Participants will self-administer 129 mg acalabrutinib twice daily (BID) until they reach 2 years post-BMT (approximately 22 cycles). Participants will be followed for up to 5 years post-BMT for Progression Free Survival.

Inclusion Criteria:

Inclusion Criteria for Initial Enrollment (Screening #1):

Patients must meet all of the following criteria in order to be included in this research study:

1. Written informed consent, according to local guidelines, signed by the subject or by a legal guardian prior to the performance of any study-related screening procedures.

2. Men and women ≥18 years-of-age at the time of signature of the informed consent form (ICF).

3. A diagnosis of MCL confirmed by one of the following:

   • t(11;14) detected by fluorescence in situ hybridization (FISH), conventional cytogenetics, or other molecular evaluation
   • expression of cyclin D1 confirmed by immunohistochemistry.

4. Subject must have completed induction chemotherapy and plan to and be eligible to receive their first BMT per standard of care.

5. Availability of an archival paraffin-embedded tumor block for MRD testing.

6. The Investigator anticipates that the subject will meet the appropriate lab requirements listed in Screening #2 by Day 100.

7. Patients who received prior therapy with a BTK inhibitor are eligible to enroll.

Inclusion Criteria Post-BMT, Prior to Day 100 (Screening #2):

1. Adequate organ system function defined as:

   • Absolute neutrophil count (ANC) ≥1,000/mm3.
   • Total bilirubin ≤1.5 x the upper limit of normal (ULN) (except for previously documented Gilbert's syndrome)
   • Platelet count ≥75,000/mm3. Platelet infusions to meet eligibility criteria are not allowed within 3 days of study enrollment.
   • Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) ≤2.5 x ULN
   • Calculated creatinine clearance (CrCl) ≥30 mL/min as calculated by the CockcroftGault method. Estimated CrCl (glomerular filtration rate [GFR]) = (140-age [years]) x (weight [kg]) x Fa /(72 x serum creatinine [mg/dL]) a where F = 0.85 for females and F = 1 for males

2. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.

3. Subjects who did not receive an anti-cancer therapy (including surgery, radiotherapy, chemotherapy, immunotherapy, or investigational therapy) during the time between their transplant and the start of study therapy. Subjects must have recovered (e.g., Grade ≤1 or baseline) from AEs associated with prior cancer therapy. Note: Subjects with Grade ≤2 neuropathy or Grade ≤2 alopecia are an exception to the latter criterion and may qualify for the study.

4. Woman of childbearing potential (WoCBP) who are sexually active with male partners must use highly effective methods of contraception during treatment and for 2 days after the last dose of acalabrutinib. For male subjects with a pregnant or non-pregnant WoCBP partner, no contraception measures are required. A WoCBP must have a negative pregnancy test (urine or serum) at the time of screening and 72 hours before starting the study drug or have evidence of non-childbearing potential by fulfilling one of the following criteria:

   • Post-menopausal women, defined as either women aged >50 years and amenorrheic for ≥12 months following cessation of all exogenous hormonal treatments or women <50 years old who have been amenorrheic for ≥12 months following the cessation of exogenous hormonal treatments, and have serum follicle- stimulating hormone (FSH) and luteinizing hormone (LH) levels in the post- menopausal range for the institution.
   • Documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy or bilateral salpingectomy, but not tubal ligation
   • Medically confirmed, irreversible premature ovarian failure.

5. Willing and able to participate in all required evaluations and procedures in this study protocol including swallowing capsules without difficulty.

6. Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information (PHI).

Exclusion Criteria:

Patients who meet any of the following criteria will be excluded from study entry:

1. Subjects who have relapsed or progressed at any time prior to BM

2. Subjects with known mutations that confer resistance to a BTK inhibitor.

3. Confirmed clinical PD since the time of BMT

4. Prior malignancy (or any other malignancy requiring active treatment), except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or other cancer from which the subject has been disease free for ≥2 years or that will not limit survival to <2 years. The exceptions are:

   • Subjects treated with curative intent >2 years prior to enrollment and have a low probability of recurrence.

5. Clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification.

6. Malabsorption syndrome, disease significantly affecting gastrointestinal function, 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.

7. Known history of infection with human immunodeficiency virus (HIV) or any uncontrolled active systemic bacterial, fungal, parasitic or viral infection. Infections are considered controlled if appropriate therapy has been instituted and, at the time of screening, no signs of infection progression are present.

8. Known history of drug-specific hypersensitivity or anaphylaxis to study drug (including active product or excipient components).

9. Active bleeding or history of bleeding diathesis (e.g., hemophilia or von Willebrand disease).

10. Uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenic purpura.

11. Requires treatment with a strong CYP3A4 inhibitor/inducer

12. Requires or is receiving anticoagulation treatment with warfarin or equivalent vitamin K antagonists (e.g., phenprocoumon) within 7 days of first dose of study drug.

13. Prothrombin time (PT)/ international normalized ratio (INR) or activated partial thromboplastin time (aPTT) >2 x ULN (in the absence of lupus anticoagulant).

14. Requires treatment with proton-pump inhibitors (e.g., omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole). Subjects receiving proton pump inhibitors who switch to H2-receptor antagonists or antacids are eligible for enrollment to this study.

15. History of significant cerebrovascular disease/event, including stroke or intracranial hemorrhage, within 6 months before the first dose of study drug.

16. 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.

17. Hepatitis B or C serologic status: subjects who are hepatitis B core antibody (anti-HBc) positive and who are hepatitis B surface antigen (HbsAg) negative will need to have a negative PCR result. Those who are HbsAg positive or hepatitis B PCR positive will be excluded. Subjects who are hepatitis C antibody positive will need to have a negative PCR result. Those who are hepatitis C PCR positive will be excluded.

18. Breastfeeding or pregnant.

19. Concurrent participation in another therapeutic clinical trial.

20. Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol and/or follow-up procedures outlined in the protocol.

21. The inability to swallow capsules.