Acalabrutinib With Bendamustine / Rituximab Followed by Cytarabine / Rituximab for Untreated Mantle Cell Lymphoma
Condition: Mantle Cell Lymphoma
MeSH terms: Lymphoma; Lymphoma, Mantle-Cell
Intervention: Bendamustine; Rituximab; Acalabrutinib; Cytarabine; Leukapheresis; Peripheral blood; Oral rinse; Bone marrow collection
Intervention description: Bendamustine will be administered at a dose of 90 mg/m^2 IV over 30 minutes on Days 1 and 2 of Cycles 1-3; In Cycle 1, rituximab will be administered at a dose of 375 mg/m^2 IV on Day 1 or 2 at the investigator's discretion in order to reduce the risk of a first infusion reaction. Rituximab will be given on Day 1 of Cycles 1 through 6.; The capsules should be swallowed intact with water and with or without food.; On Days 1 and 2 of Cycles 4-6, following rituximab dosing, cytarabine will be administered IV every 12 hours for a total of 4 doses.; Until collection of ≥ 2 x 106 CD34+ stem cells / kg; -Baseline, end of Cycle 3, 4-6 weeks after Cycle 6 Day 1, and if the patient discontinues protocol therapy prior to completion of Cycle 6; -Baseline; -Bone marrow will be collected at baseline if the patient requires a marrow for staging purposes and at end of treatment if the patient requires a marrow for restaging.
Intervention MeSH terms: Cytarabine; Rituximab; Bendamustine Hydrochloride; Acalabrutinib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 13.0
Sex: All
Minimum age: 18 Years
Maximum age: 70 Years
Healthy volunteers: No

Summary:

      This study is designed to evaluate the efficacy and safety of acalabrutinib plus bendamustine
      and rituximab followed by acalabrutinib plus cytarabine and rituximab in subjects with
      treatment naïve mantle cell lymphoma (MCL), as a preparation for a larger cooperative group
      trial with the goal of achieving a standard induction regimen for MCL in transplant eligible
      patients. The investigators hypothesize that the addition of acalabrutinib to BR/CR regimen
      will prove safe and increase the complete response (CR) rate as well as minimal residual
      disease (MRD) negativity pre-transplant, thus improving clinical outcomes.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Histologically confirmed mantle cell lymphoma with documented expression of Cyclin D1
             by immune-histochemical stains and/or t(11;14) by cytogenetics or FISH.

          -  Presence of evaluable disease by PET imaging per the Lugano classification.

          -  Eligible for autologous stem cell transplantation.

          -  Between 18 and 70 years of age, inclusive.

          -  ECOG performance status ≤ 2

          -  Normal bone marrow and organ function as defined below:

               -  Absolute neutrophil count ≥ 1,000/mcL unless, in the opinion of the treating
                  physician, neutropenia is due to splenomegaly or bone marrow involvement

               -  Platelets ≥ 100,000/mcL unless, in the opinion of the treating physician,
                  thrombocytopenia is due to splenomegaly or bone marrow involvement

               -  Total bilirubin ≤ 2.0 x IULN and AST(SGOT)/ALT(SGPT) ≤ 3.0 x IULN except when, in
                  the opinion of the treating physician, elevation is due to direct involvement of
                  lymphoma (e.g. hepatic infiltration or biliary obstruction due to lymphoma) or
                  Gilbert's disease

               -  Creatinine ≤ IULN OR creatinine clearance ≥ 40 mL/min for patients with
                  creatinine levels above institutional normal

          -  Women of childbearing potential and men must agree to use adequate contraception
             (hormonal or barrier method of birth control, abstinence) prior to study entry and for
             the duration of study participation. Should a woman become pregnant or suspect she is
             pregnant while participating in this study, she must inform her treating physician
             immediately.

          -  Ability to understand and willingness to sign an IRB approved written informed consent
             document (or that of legally authorized representative, if applicable).

        Exclusion Criteria:

          -  Any previous chemotherapy or radiation for mantle cell lymphoma. Short course of
             steroids for symptom relief prior to presentation is permissible.

          -  Symptomatic meningeal or parenchymal brain lymphoma.

          -  Prior exposure to a BTK inhibitor.

          -  Currently receiving any other investigational agents.

          -  A history of allergic reactions attributed to compounds of similar chemical or
             biologic composition to acalabrutinib, rituximab, cytarabine, bendamustine, or other
             agents used in the study.

          -  Received a live virus vaccination within 28 days of first dose of study drug.

          -  Uncontrolled active systemic fungal, bacterial, viral, or other infection (defined as
             exhibiting ongoing signs/symptoms related to the infection and without improvement,
             despite appropriate antibiotics or other treatment), or intravenous anti-infective
             treatment within 2 weeks before first dose of study drug.

          -  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, or corrected QT interval (QTc) > 480 msec at
             screening. Exception: subjects with controlled, asymptomatic atrial fibrillation
             during screening are allowed to enroll on study.

          -  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.

          -  Active bleeding or history of bleeding diathesis (eg, hemophilia or von Willebrand
             disease).

          -  Uncontrolled AIHA (autoimmune hemolytic anemia) or ITP (idiopathic thrombocytopenic
             purpura).

          -  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) >2x ULN.
             Exception: Subjects receiving warfarin are excluded; however, those receiving other
             anticoagulant therapy who have a higher INR/aPTT may be permitted to enroll to this
             study after discussion with the PI.

          -  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.

          -  History of significant cerebrovascular disease/event, including stroke or intracranial
             hemorrhage, 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.

          -  Subjects with serologic status reflecting active viral hepatitis B or C infection.
             Subjects who are hepatitis B core antibody positive but surface antigen negative will
             need negative polymerase chain reaction (PCR) prior to enrollment. Hepatitis B surface
             antigen positive or PCR positive patients will be excluded. Subjects who are hepatitis
             C antibody positive will need negative PCR prior to enrollment. Subjects with positive
             hepatitis C PCR will be excluded.

          -  Pregnant and/or breastfeeding. Women of childbearing potential must have a negative
             serum pregnancy test within 14 days of study entry.

          -  Known HIV-positivity on combination antiretroviral therapy because of the potential
             for pharmacokinetic interactions with acalabrutinib. In addition, these patients are
             at increased risk of lethal infections when treated with marrow-suppressive therapy