Clinical Trials /

Acalabrutinib for the Treatment of Ibrutinib-Intolerant Mantle Cell Lymphoma

NCT04189757

Description:

This phase II trial studies how well acalabrutinib works in treating patients with mantle cell lymphoma that cannot tolerate ibrutinib. Acalabrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Related Conditions:
  • Mantle Cell Lymphoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Acalabrutinib for the Treatment of Ibrutinib-Intolerant Mantle Cell Lymphoma
  • Official Title: A Phase II Study of Acalabrutinib in Ibrutinib-Intolerant Mantle Cell Lymphoma

Clinical Trial IDs

  • ORG STUDY ID: 2019-0421
  • SECONDARY ID: NCI-2019-07927
  • SECONDARY ID: 2019-0421
  • SECONDARY ID: P30CA016672
  • NCT ID: NCT04189757

Conditions

  • Mantle Cell Lymphoma

Interventions

DrugSynonymsArms
AcalabrutinibACP-196, Bruton Tyrosine Kinase Inhibitor ACP-196, CalquenceTreatment (acalabrutinib)

Purpose

This phase II trial studies how well acalabrutinib works in treating patients with mantle cell lymphoma that cannot tolerate ibrutinib. Acalabrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Detailed Description

      PRIMARY OBJECTIVE:

      I. To assess the overall response rate (ORR) at the end of 3 cycles of acalabrutinib.

      SECONDARY OBJECTIVES:

      I. To assess the proportion of patients that are progression free without any of the
      following toxicities at the end of 3 cycles:

      Ia. Recurrence of intolerable toxicities previously noted on ibrutinib. Ib. The occurrence of
      intolerable toxicities related to acalabrutinib defined as: grade 4 neutropenia or
      thrombocytopenia lasting greater than 7 days or any grade more or equal to 3 non-hematologic
      toxicity as assessed by the investigator to be related to study drug).

      II. To determine the efficacy of acalabrutinib, progression free survival (PFS) and duration
      of response (DOR) in patients.

      III. To assess the safety profile of acalabrutinib in patient's intolerant to ibrutinib.

      EXPLORATORY OBJECTIVE:

      I. Sequential peripheral blood (PB)/plasma/tissue fine-needle aspiration (FNA) will be stored
      for evaluation of:

      Ia. Clonal evolution with targeted sequencing (seq) and/or whole exome sequencing (WES) in
      sequential samples.

      Ib. Pattern of mutation changes with acalabrutinib. Ic. Response predictors - mutations,
      cytokine-chemokines. Id. Minimal residual disease (MRD) assay using flow cytometry (FC) and
      circulating tumor-derived deoxyribonucleic acid (ctDNA) analysis.

      Ie. Sequential immunologic studies with cytokines/chemokines, T cells and immunoglobulins.

      OUTLINE:

      Patients receive acalabrutinib orally (PO) twice daily (BID) on days 1-28. Treatment repeats
      every 28 days for up to 36 cycles in the absence of disease progression or unacceptable
      toxicity.

      After completion of study treatment, patients are followed up every 4 months for 2 years,
      every 6 months for 1 years, then annually for up to 3 years.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (acalabrutinib)ExperimentalPatients receive acalabrutinib PO BID on days 1-28. Treatment repeats every 28 days for up to 36 cycles in the absence of disease progression or unacceptable toxicity.
  • Acalabrutinib

Eligibility Criteria

        Inclusion Criteria:

          -  Confirmed diagnosis of mantle cell lymphoma with CD20 positivity and chromosome
             translocation t(11;14), (q13;q32) and/or overexpress cyclin D1 in tissue biopsy

          -  Prior treatment with ibrutinib discontinued for reasons other than progression

          -  Intolerable ibrutinib-related adverse event (AE) defined as subjects who cannot
             tolerate ibrutinib therapy due to adverse reactions associated with treatment; AEs
             (must be other than hypersensitivity or anaphylactic reaction or progressive disease
             [PD] [see exclusion criteria #3]), defined as subjects who cannot tolerate ibrutinib
             therapy due to adverse reactions associated with treatment. Subjects are considered
             ibrutinib intolerant (at any dose/or duration) if they have discontinued ibrutinib
             therapy due to grade 3 or 4 AEs that persisted in spite of optimal supportive care
             measures or if they had grade 2 AEs related to ibrutinib therapy, in spite of optimal
             supportive care measures, that persisted for more or equal to 2 weeks or that recurred
             for more or equal to 2 times, even if the dose was reduced or discontinued (related is
             any adverse event on the ibrutinib drug-label or any other AE that the investigator
             considers as associated with ibrutinib treatment)

          -  Understand and voluntarily sign an Institutional Review Board (IRB)-approved informed
             consent form

          -  Bi-dimensional measurable disease using the Cheson criteria (measurable disease by
             positron emission tomography [PET]-computed tomography [CT] scan defined as at least 1
             lesion that measures more or equal to 1.5 cm in single dimension). Gastrointestinal,
             bone marrow or spleen only patients are allowable

          -  Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less

          -  Absolute neutrophil count (ANC) more than 1,000/mm^3

               -  Patients who have bone marrow infiltration by mantle cell lymphoma (MCL) are
                  eligible if their ANC is more or equal to 500/mm^3 (growth factor allowed) or
                  their platelet level is equal to or more than 20,000/mm^3. These patients should
                  be discussed with either the principal investigator (PI) or co-PI of the study
                  for final approval

          -  Platelet count more than 75,000/mm^3

               -  Patients who have bone marrow infiltration by MCL are eligible if their ANC is
                  more or equal to 500/mm^3 (growth factor allowed) or their platelet level is
                  equal to or more than 20,000/mm^3. These patients should be discussed with either
                  the PI or co-PI of the study for final approval

          -  Serum bilirubin less than 1.5 mg/dl

          -  Creatinine (Cr) clearance more or equal to 20 mL/min

          -  Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and
             alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) less
             than 2.5 x upper limit of normal or less than 5 x upper limit of normal if hepatic
             metastases are present. Gilbert's disease is allowed

          -  Disease free of prior malignancies with exception of currently treated basal cell,
             squamous cell carcinoma of the skin, carcinoma "in situ" of the cervix or breast, or
             other malignancies in remission (including prostate cancer patients in remission from
             radiation therapy, surgery or brachytherapy), not actively being treated with life
             expectancy of more than 3 years. PI can use clinical judgement in the best interest of
             patients

          -  Women of childbearing potential (WOBP) must have a negative serum or urine pregnancy
             test. WOBP and males must be willing to use highly effective methods of birth control
             prior to starting therapy and for 2 days after the last dose of study drug

        Exclusion Criteria:

          -  Prior treatment with acalabrutinib

          -  History of BTK mutations conferring resistance to BTK inhibitors. Known mutations in
             the BTK gene that confer resistance to ibrutinib

          -  Progressive disease while on Ibrutinib therapy. Patients who progressed while on
             ibrutinib therapy will be excluded from the study, patients who discontinue ibrutinib
             due to anaphylaxis or hypersensitivity reaction related to ibrutinib will be excluded
             from participation in the study

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

          -  Pregnant or breast-feeding females

          -  Known human immunodeficiency virus (HIV) infection

          -  Patients with active hepatitis B infection. Those with prior hepatitis (hep)-B
             vaccination (i.e., anti-HBs antibody positive) or natural immunity as evidenced by the
             presence of anti-HBs and anti-HBc positivity are eligible to enroll. (Known hepatitis
             C infection is allowed as long as there is no active disease and is cleared by
             gastrointestinal [GI] consultation)

          -  Central nervous system involvement with mantle cell lymphoma or with suspected or
             confirmed progressive multifocal leukoencephalopathy (PML)

          -  Active bleeding, history of bleeding diathesis (such as hemophilia or Von-Willebrand
             disease), Any history of intracranial bleed or stroke within 6 months of first dose of
             study drug

          -  Uncontrolled AIHA (autoimmune hemolytic anemia) or ITP (idiopathic thrombocytopenic
             purpura)

          -  Ongoing adverse events from prior ibrutinib therapy (except persistent hematologic
             toxicity if meeting entry criteria). The PI should determine if AEs are an ongoing
             sequel of prior BTK therapy such as fungal infections, skin rash, diarrhea, fatigue,
             cramps and colitis or if the patient has resolved AE and is free of these adverse
             events more or equal to 2 months after stopping ibrutinib)

          -  Malabsorption syndrome, disease significantly affecting gastrointestinal function, or
             resection of the stomach or small bowel or ulcerative colitis, symptomatic
             inflammatory bowel disease, or partial or complete bowel obstruction, or any other
             gastrointestinal condition that could interfere with the absorption and metabolism of
             acalabrutinib

          -  Presence of a gastrointestinal ulcer diagnosed by endoscopy within 3 months before
             first dose of study drug

          -  Major surgery within 4 weeks of initiation of therapy

          -  Requires anticoagulation with warfarin or equivalent vitamin K antagonist

          -  Concomitant use of corticosteroids at more than 10 mg prednisone or equivalent per day

          -  Requires treatment with strong CYP3A inhibitors or inducers

          -  Any of the following cardiac related conditions: New York Heart Association (NYHA)
             class III and IV heart failure, active/symptomatic coronary artery disease, myocardial
             infarction in the preceding 6 months, significant conduction abnormalities, including
             but not limited to: left bundle branch block, 2nd degree atrioventricular (AV) block
             type II, 3rd degree block, QT prolongation (corrected QT interval [QTc] > 500 msec),
             sick sinus syndrome, ventricular tachycardia, symptomatic bradycardia (heart rate < 50
             bpm), persistent and uncontrolled atrial fibrillation. Uncontrolled hypertension,
             hypotension, light headedness and syncope

          -  Acute infection requiring systemic anti-microbial treatment (systemic antibiotics,
             antivirals, or antifungals) within 14 days prior to initiation of therapy

          -  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

          -  Any other serious medical condition including, but not limited to, uncontrolled
             diabetes mellitus, chronic obstructive pulmonary disease (COPD), renal failure,
             psychiatric illness or social circumstances that, in the investigator's opinion places
             the patient at unacceptable risk and would prevent the subject from signing the
             informed consent form or complying with study procedures
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall response rate (complete response + partial response)
Time Frame:At the end of cycle 3 (each cycle is 28 days)
Safety Issue:
Description:The primary end point will be met if > 50% patients attain response (half of patients responding without intolerance). Logistic regression may be utilized to assess the effect of patient prognostic factors on the response rate. Intent-to-treat analysis will be applied to the eligible patients.

Secondary Outcome Measures

Measure:Progression free survival
Time Frame:Up to 6 years
Safety Issue:
Description:The distribution of time-to-event endpoints including progression free survival will be estimated using the method of Kaplan and Meier. Comparison of time-to-event endpoints by important subgroups will be made using the log-rank test.
Measure:Overall survival
Time Frame:Up to 6 years
Safety Issue:
Description:The distribution of time-to-event endpoints including overall survival will be estimated using the method of Kaplan and Meier. Comparison of time-to-event endpoints by important subgroups will be made using the log-rank test.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:M.D. Anderson Cancer Center

Last Updated

December 4, 2019