Clinical Trials /

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

NCT03623373

Description:

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.

Related Conditions:
  • Mantle Cell Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

    <li>Brief Title: Acalabrutinib With Alternating Cycles of Bendamustine / Rituximab and Cytarabine / Rituximab for Untreated Mantle Cell Lymphomali><li>Official Title: A Pilot Study of Acalabrutinib With Alternating Cycles of Bendamustine / Rituximab and Cytarabine / Rituximab for Untreated Mantle Cell Lymphomali>

Clinical Trial IDs

    <li>ORG STUDY ID: 18-x233li><li>NCT ID: NCT03623373li>

Conditions

    <li>Mantle Cell Lymphomali>

Interventions

<td>Bendamustinetd><td>Treanda, Bendekatd><td>Bendamustine/Rituximab/Acalabrutinib/Cytarabinetd><td>Rituximabtd><td>Rituxan, Rituxan Hycelatd><td>Bendamustine/Rituximab/Acalabrutinib/Cytarabinetd><td>Acalabrutinibtd><td>Calquence®td><td>Bendamustine/Rituximab/Acalabrutinib/Cytarabinetd><td>Cytarabinetd><td>Cytosar-Utd><td>Bendamustine/Rituximab/Acalabrutinib/Cytarabinetd>
DrugSynonymsArms

Purpose

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.

Trial Arms

<td>Bendamustine/Rituximab/Acalabrutinib/Cytarabinetd><td>Experimentaltd><td>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 leukapheresistd><td>
    <li>Bendamustineli><li>Rituximabli><li>Acalabrutinibli><li>Cytarabineli>
td>
NameTypeDescriptionInterventions

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 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
      
<td>Maximum Eligible Age:td><td>65 Yearstd><td>Minimum Eligible Age:td><td>18 Yearstd><td>Eligible Gender:td><td>Alltd><td>Healthy Volunteers:td><td>Notd>

Primary Outcome Measures

<td>Measure:td><td>Stem cell mobilization success rate in subjects with MCL treated with acalabrutinib and an alternating regimen of bendamustine and rituximab with cytarabine and rituximabtd><td>Time Frame:td><td>Through 5 courses of apheresis (up to 5 days)td><td>Safety Issue:td><td/><td>Description:td><td>-Stem cell mobilization success is defined as a yield of >2x10^6 CD34+ stem cells/kg with a maximum of 5 courses of apheresistd>

Secondary Outcome Measures

<td>Measure:td><td>Safety and tolerability of acalabrutinib plus BR/CR in subjects with MCLas measured by treatment related non-hematologic toxicity of grade 3 or highertd><td>Time Frame:td><td>30 days following completion of treatment (estimated to be 7 months)td><td>Safety Issue:td><td/><td>Description:td><td/>
<td>Measure:td><td>Overall response rate (ORR = complete response (CR) + partial response (PR)) of subjects with MCL treated with acalabrutinib plus BR/CRtd><td>Time Frame:td><td>Through completion of treatment (estimated to be 6 months)td><td>Safety Issue:td><td/><td>Description:td><td>-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 Classificationtd>
<td>Measure:td><td>Pre-transplant complete response rate of subjects with MCL treated with acalabrutinib plus BR/CRtd><td>Time Frame:td><td>Through completion of treatment (estimated to be 6 months)td><td>Safety Issue:td><td/><td>Description:td><td>-For definitions of CR, please refer to the Recommendations for Initial Evaluation, Staging and Response Assessment of Hodgkin and Non-Hodgkin Lymphoma: The Lugano Classificationtd>
<td>Measure:td><td>Progression-free survival (PFS) of subjects with MCL treated with acalabrutinib plus BR/CRtd><td>Time Frame:td><td>Through 5 yearstd><td>Safety Issue:td><td/><td>Description:td><td>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 lymphomaat 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 marrowtd>
<td>Measure:td><td>Overall survival (OS) of subjects with MCL treated with acalabrutinib plus BR/CRtd><td>Time Frame:td><td>Through 5 yearstd><td>Safety Issue:td><td/><td>Description:td><td>-OS=time from study registration until death from any causetd>

Details

<td>Phase:td><td>Phase 1td><td>Primary Purpose:td><td>Interventionaltd><td>Overall Status:td><td>Not yet recruitingtd><td>Lead Sponsor:td><td>Washington University School of Medicinetd>

Last Updated

<p/>