Clinical Trials /

Venetoclax and Acalabrutinib in Treating Patients With Relapsed or Refractory Mantle Cell Lymphoma

NCT03946878

Description:

This phase II trial studies how well venetoclax and acalabrutinib work in treating patients with mantle cell lymphoma that did not respond to previous treatment or has come back. Venetoclax may cause cancer cell death by blocking the mechanism that cancer cells use to stay alive. Acalabrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving venetoclax and acalabrutinib together may kill more cancer cells in patients with mantle cell lymphoma.

Related Conditions:
  • Mantle Cell Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Venetoclax and Acalabrutinib in Treating Patients With Relapsed or Refractory Mantle Cell Lymphoma
  • Official Title: An Open Label, Phase II Investigator Initiated Study of Venetoclax and Acalabrutinib in Previously Treated Relapsed/Refractory Patients With Mantle Cell Lymphoma (MCL)

Clinical Trial IDs

  • ORG STUDY ID: 2018-0935
  • SECONDARY ID: NCI-2019-02354
  • SECONDARY ID: 2018-0935
  • SECONDARY ID: P30CA016672
  • NCT ID: NCT03946878

Conditions

  • Blastoid Variant Mantle Cell Lymphoma
  • CCND1 Protein Overexpression
  • CD20 Positive
  • CD5 Positive
  • FCER2 Negative
  • Pleomorphic Variant Mantle Cell Lymphoma
  • Recurrent Mantle Cell Lymphoma
  • Refractory Mantle Cell Lymphoma
  • t(11;14)(q13;q32)

Interventions

DrugSynonymsArms
AcalabrutinibACP-196, Bruton Tyrosine Kinase Inhibitor ACP-196, CalquenceTreatment (acalabrutinib, venetoclax)
VenetoclaxABT-0199, ABT-199, ABT199, GDC-0199, RG7601, VenclextaTreatment (acalabrutinib, venetoclax)

Purpose

This phase II trial studies how well venetoclax and acalabrutinib work in treating patients with mantle cell lymphoma that did not respond to previous treatment or has come back. Venetoclax may cause cancer cell death by blocking the mechanism that cancer cells use to stay alive. Acalabrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving venetoclax and acalabrutinib together may kill more cancer cells in patients with mantle cell lymphoma.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To evaluate the efficacy of a combination of venetoclax and acalabrutinib, in patients
      with previously treated relapsed/refractory mantle cell lymphoma (MCL).

      SECONDARY OBJECTIVES:

      I. To evaluate the efficacy of this combination regimen in previously treated subjects with
      relapsed/refractory MCL with overall response rate (ORR), duration of response (DOR), event
      free survival (EFS), progression free survival (PFS), and overall survival (OS).

      II. To evaluate the safety and tolerability of venetoclax and acalabrutinib in previously
      treated subjects with relapsed/refractory MCL.

      CORRELATIVE/TRANSLATIONAL COMPONENT OBJECTIVES:

      I. Sequential peripheral blood (PB)/plasma/tissue fine needle aspirate will be stored.

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

      III. Pattern of mutation changes with Bruton tyrosine kinase inhibitor (BTKi) or with
      venetoclax resistance.

      IV. Response predictors - mutations, cytokine-chemokines, clonal evolution (CE).

      V. Minimal residual disease (MRD) assay using circulating tumor deoxyribonucleic acid (ctDNA)
      analysis, flow cytometry at various time points from peripheral blood (PB)/ bone marrow (BM).

      VI. Sequential immunologic studies with cytokines/chemokines, T cell numbers, and
      immunoglobulins (Ig).

      VII. Tissue microenvironmental studies with simultaneous assessment of PB, BM and lymph nodes
      for gene expression profiling (GEP), single cell seq, ribonucleic acid (RNA) seq and clonal
      heterogeneity and the impact of acalabrutinib - venetoclax (A-V) treatment.

      OUTLINE: This is a dose escalation study of venetoclax.

      Patients receive acalabrutinib orally (PO) twice daily (BID) on days 1-28. Starting cycle 2
      day 1, patients also receive venetoclax PO daily. Cycles repeat every 28 days in the absence
      of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up within 30 days, then every 4
      months for 2 years, then every 6 months for the next 2 years, and then annually thereafter.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (acalabrutinib, venetoclax)ExperimentalPatients receive acalabrutinib PO BID on days 1-28. Starting cycle 2 day 1, patients also receive venetoclax PO daily. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Acalabrutinib
  • Venetoclax

Eligibility Criteria

        Inclusion Criteria:

          -  Confirmed diagnosis of previously treated relapsed/refractory patients MCL with CD5+,
             CD23-, CD20+ and chromosome translocation t(11;14), (q13;q32) and/or overexpress
             cyclin D1 in tissue biopsy (blastoid/pleomorphic morphology, complex karyotype is
             acceptable).

          -  Disease had relapsed after or been refractory to >= 1 prior therapy for MCL and now
             requires further treatment.

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

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

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

          -  Absolute neutrophil count (ANC) > 1,000/mm^3 independent of growth factor support.

          -  Platelet count >= 100,000/mm^3 or >= 50,000/mm^3 if bone marrow involved with
             lymphoma, independent of transfusion support in either situation.

          -  Creatinine (Cr) =< 2 or Cr clearance >= 30 mL/min.

          -  Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3 x upper limit
             of normal (ULN).

          -  Serum bilirubin < 1.5 mg/dl, unless due to Gilbert's syndrome, documented liver
             involvement with lymphoma, or of non-hepatic origin.

          -  Prothrombin time (PT)/international normalized ratio (INR) =< 1.5 x ULN and partial
             thromboplastin time (PTT) =< 1.5 x ULN.

          -  Disease free of prior malignancies other than MCL 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 > 3 years. Principal investigator (PI) can use
             clinical judgement in the best interest of patients.

          -  Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy
             test and willing to use highly effective methods of birth control. A female of
             childbearing potential is a sexually mature woman who:

               -  Has not undergone a hysterectomy or bilateral oophorectomy; or

               -  Has not been naturally postmenopausal for at least 24 consecutive months (i.e.,
                  has had menses at any time in the preceding 24 consecutive months).

        Exclusion Criteria:

          -  Any serious medical condition including but not limited to, uncontrolled hypertension,
             uncontrolled diabetes mellitus, active/symptomatic coronary artery disease, chronic
             obstructive pulmonary disease, renal failure, active hemorrhage, or psychiatric
             illness that, in the investigator's opinion places the patient at unacceptable risk
             and would prevent the subject from signing the ICF.

          -  Pregnant or breast-feeding females.

          -  Known human immunodeficiency virus (HIV) infection.

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

          -  Patients with active hepatitis B infection (not including patients with prior
             hepatitis B vaccination; or positive serum hepatitis B antibody). Known hepatitis C
             infection is allowed as long as there is no active disease and is cleared by
             gastrointestinal (GI) consultation.

          -  Central nervous system (CNS) disease with serious significance.

          -  Malabsorption syndrome, disease significantly affecting GI 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 GI condition that
             could interfere with the absorption and metabolism of acalabrutinib or venetoclax.

          -  Major surgery or a wound that has not fully healed within 4 weeks of initiation of
             therapy.

          -  Known bleeding diathesis (e.g., von Willebrand's disease) or hemophilia.

          -  History of stroke or intracranial hemorrhage within 6 months prior to study entry.

          -  Requires anticoagulation with warfarin or equivalent vitamin K antagonist.

          -  Vaccinated with live, attenuated vaccines within 4 weeks of study entry.

          -  Concurrent systemic immunosuppressant therapy (e.g., cyclosporine, tacrolimus, etc.,
             or chronic administration of > 10 mg/day of prednisone or equivalent) within 28 days
             of the first dose of study drug.

          -  Requires treatment with strong CYP3A inhibitors or inducers or strong CYP1A2
             inhibitors.

          -  Refractory to prior ibrutinib or BTK mutation or previous exposure to ibrutinib.

          -  Patients with New York Heart Association (NYHA) class III and IV heart failure,
             myocardial infarction in the preceding 6 months, and significant conduction
             abnormalities, including but not limited to left bundle branch block, 2nd degree
             atrioventricular (AV) block type II, 3rd degree block, sick sinus syndrome,
             ventricular tachycardia, symptomatic bradycardia (heart rate < 50 beats per minute
             [bpm]), hypotension, light headedness and syncope, persistent and uncontrolled atrial
             fibrillation.

          -  Recent placement of a stent (within last 12 months) and by recommendation of their
             cardiologist need to stay on anticoagulants such as warfarin or equivalent vitamin K
             antagonist or anti-platelet agents.

          -  Exclude patients with active ongoing infections requiring intravenous (IV)
             antimicrobials.

          -  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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Complete response (CR)
Time Frame:16 weeks
Safety Issue:
Description:Assessed by Lugano criteria - positron emission tomography (PET)-computed tomography, and in a subset of patients by bone marrow flow cytometry, circulating tumor deoxyribonucleic acid and endoscopy if at baseline there is gut involvement. Response will be calculated separately with and without knowledge of the PET result by International Working Group criteria, in order to provide context in relation to historical control data. Will estimate the CR along with the 95% credible interval.

Secondary Outcome Measures

Measure:Overall response rate
Time Frame:5 years
Safety Issue:
Description:
Measure:Duration of response
Time Frame:5 years
Safety Issue:
Description: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:Event free survival
Time Frame:5 years
Safety Issue:
Description: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:Progression free survival
Time Frame:5 years
Safety Issue:
Description: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:5 years
Safety Issue:
Description: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:Incidence of adverse events
Time Frame:5 years
Safety Issue:
Description:Safety data will be summarized by frequency tables for all patients. Per-treated analysis will be performed to include any patient who received the treatment regardless of the eligibility nor the duration or dose of the treatment received.

Details

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

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