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Acalabrutinib With Alternating Cycles of Bendamustine / Rituximab and Cytarabine / Rituximab for Untreated Mantle Cell Lymphoma

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ClinicalTrials.gov Identifier: NCT03623373
Recruitment Status : Not yet recruiting
First Posted : August 9, 2018
Last Update Posted : October 17, 2018
Sponsor:
Collaborator:
Acerta Pharma BV
Information provided by (Responsible Party):
Washington University School of Medicine

Brief Summary:
This study is designed to evaluate the efficacy and safety of acalabrutinib plus bendamustine and rituximab and cytarabine and rituximab (BR/CR) 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.

Condition or disease Intervention/treatment Phase
Mantle Cell Lymphoma Drug: Bendamustine Drug: Rituximab Drug: Acalabrutinib Drug: Cytarabine Procedure: Leukapheresis Procedure: Peripheral blood Phase 1

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 15 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Pilot Study of Acalabrutinib With Alternating Cycles of Bendamustine / Rituximab and Cytarabine / Rituximab for Untreated Mantle Cell Lymphoma
Estimated Study Start Date : October 31, 2018
Estimated Primary Completion Date : April 30, 2021
Estimated Study Completion Date : October 31, 2025


Arm Intervention/treatment
Experimental: Bendamustine/Rituximab/Acalabrutinib/Cytarabine
  • Patients will receive (6) 28 day cycles
  • Odd-numbered cycles (1, 3, and 5) will consist of bendamustine on Days 1 and 2, rituximab on Day 1, and acalabrutinib twice per day (BID) on Days 1 through 28.
  • Even-numbered cycles (2, 4, and 6) will consist of rituximab on Day 1, cytarabine every 12 hours on Days 1 and 2, acalabrutinib BID on Days 1 through 7 and 22 through 28 (one week on, two weeks off, one week on), and growth factors as per institutional standard
  • After Cycle 6, patients will undergo leukapheresis
Drug: Bendamustine
Bendamustine will be administered at a dose of 90 mg/m2 IV over 30 minutes on Days 1 and 2 of Cycles 1, 3, and 5.
Other Names:
  • Treanda
  • Bendeka

Drug: Rituximab
In Cycle 1, rituximab will be administered at a dose of 375 mg/m2 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 2 through 6.
Other Names:
  • Rituxan
  • Rituxan Hycela

Drug: Acalabrutinib
The capsules should be swallowed intact with water and with or without food.
Other Name: Calquence®

Drug: Cytarabine
On Days 1 and 2 of Cycles 2, 4, and 6, following rituximab dosing, cytarabine will be administered IV every 12 hours for a total of 4 doses.
Other Name: Cytosar-U

Procedure: Leukapheresis
Until collection of ≥ 2 x 106 CD34+ stem cells / kg

Procedure: Peripheral blood
Baseline and end of treatment restaging visit




Primary Outcome Measures :
  1. Stem cell mobilization success rate in subjects with MCL treated with acalabrutinib and an alternating regimen of bendamustine and rituximab with cytarabine and rituximab [ Time Frame: Through 5 courses of apheresis (up to 5 days) ]
    -Stem cell mobilization success is defined as a yield of >2x10^6 CD34+ stem cells/kg with a maximum of 5 courses of apheresis


Secondary Outcome Measures :
  1. Safety and tolerability of acalabrutinib plus BR/CR in subjects with MCL as measured by treatment related non-hematologic toxicity of grade 3 or higher [ Time Frame: 30 days following completion of treatment (estimated to be 7 months) ]
  2. Overall response rate (ORR = complete response (CR) + partial response (PR)) of subjects with MCL treated with acalabrutinib plus BR/CR [ Time Frame: Through completion of treatment (estimated to be 6 months) ]
    -For definitions of CR and PR please refer to the Recommendations for Initial Evaluation, Staging and Response Assessment of Hodgkin and Non-Hodgkin Lymphoma: The Lugano Classification

  3. Pre-transplant complete response rate of subjects with MCL treated with acalabrutinib plus BR/CR [ Time Frame: Through completion of treatment (estimated to be 6 months) ]
    -For definitions of CR, please refer to the Recommendations for Initial Evaluation, Staging and Response Assessment of Hodgkin and Non-Hodgkin Lymphoma: The Lugano Classification

  4. Progression-free survival (PFS) of subjects with MCL treated with acalabrutinib plus BR/CR [ Time Frame: Through 5 years ]
    • PFS is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first
    • London Deauville score of 4 or 5 in individual target nodes/masses with an increase in intensity of uptake from the baseline and/or new FDG avid foci consistent with lymphoma at interim or end of treatment assessment; New FDG avid foci of extranodal disease consistent with lymphoma. If there is concern regarding the etiology of the new lesions, biopsy or interval scan may be considered; New or recurrent FDG avid foci in the bone marrow

  5. Overall survival (OS) of subjects with MCL treated with acalabrutinib plus BR/CR [ Time Frame: Through 5 years ]
    -OS=time from study registration until death from any cause



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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 65 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03623373


Contacts
Contact: Brad S Kahl, M.D. (314) 747-6250 bkahl@wustl.edu

Locations
United States, Missouri
Washington University School of Medicine Not yet recruiting
Saint Louis, Missouri, United States, 63110
Contact: Brad S Kahl, M.D.    314-747-6250    bkahl@wustl.edu   
Principal Investigator: Brad S Kahl, M.D.         
Sub-Investigator: Nancy Bartlett, M.D.         
Sub-Investigator: Amanda F Cashen, M.D.         
Sub-Investigator: Todd Fehniger, M.D., Ph.D.         
Sub-Investigator: Armin Ghobadi, M.D.         
Sub-Investigator: Daniel Guy, M.D.         
Sub-Investigator: Neha Mehta-Shah, M.D.         
Sub-Investigator: Kathryn Trinkaus, Ph.D.         
Sponsors and Collaborators
Washington University School of Medicine
Acerta Pharma BV
Investigators
Principal Investigator: Brad S Kahl, M.D. Washington University School of Medicine

Additional Information:
Responsible Party: Washington University School of Medicine
ClinicalTrials.gov Identifier: NCT03623373     History of Changes
Other Study ID Numbers: 201809111
First Posted: August 9, 2018    Key Record Dates
Last Update Posted: October 17, 2018
Last Verified: October 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes

Additional relevant MeSH terms:
Lymphoma
Lymphoma, Mantle-Cell
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Lymphoma, Non-Hodgkin
Rituximab
Cytarabine
Bendamustine Hydrochloride
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antiviral Agents
Anti-Infective Agents
Immunosuppressive Agents
Antineoplastic Agents, Alkylating
Alkylating Agents