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

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ClinicalTrials.gov Identifier: NCT03946878
Recruitment Status : Recruiting
First Posted : May 13, 2019
Last Update Posted : August 22, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
M.D. Anderson Cancer Center

Tracking Information
First Submitted Date  ICMJE May 9, 2019
First Posted Date  ICMJE May 13, 2019
Last Update Posted Date August 22, 2019
Actual Study Start Date  ICMJE August 13, 2019
Estimated Primary Completion Date February 8, 2024   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 9, 2019)
Complete response (CR) [ Time Frame: 16 weeks ]
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.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03946878 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: May 9, 2019)
  • Overall response rate [ Time Frame: 5 years ]
  • Duration of response [ Time Frame: 5 years ]
    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.
  • Event free survival [ Time Frame: 5 years ]
    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.
  • Progression free survival [ Time Frame: 5 years ]
    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.
  • Overall survival [ Time Frame: 5 years ]
    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.
  • Incidence of adverse events [ Time Frame: 5 years ]
    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.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Venetoclax and Acalabrutinib in Treating Patients With Relapsed or Refractory Mantle Cell Lymphoma
Official Title  ICMJE An Open Label, Phase II Investigator Initiated Study of Venetoclax and Acalabrutinib in Previously Treated Relapsed/Refractory Patients With Mantle Cell Lymphoma (MCL)
Brief Summary 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • 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)
Intervention  ICMJE
  • Drug: Acalabrutinib
    Given PO
    Other Names:
    • ACP-196
    • Bruton Tyrosine Kinase Inhibitor ACP-196
    • Calquence
  • Drug: Venetoclax
    Given PO
    Other Names:
    • ABT-0199
    • ABT-199
    • ABT199
    • GDC-0199
    • RG7601
    • Venclexta
Study Arms  ICMJE Experimental: Treatment (acalabrutinib, venetoclax)
Patients 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.
Interventions:
  • Drug: Acalabrutinib
  • Drug: Venetoclax
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: May 9, 2019)
50
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE February 8, 2024
Estimated Primary Completion Date February 8, 2024   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Luhua (Michael) Wang, MD,MS 713-792-2860 miwang@mdanderson.org
Contact: Preetesh Jain, MD,DM, PHD 713-745-8432 pjain@mdanderson.org
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03946878
Other Study ID Numbers  ICMJE 2018-0935
NCI-2019-02354 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
2018-0935 ( Other Identifier: M D Anderson Cancer Center )
P30CA016672 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party M.D. Anderson Cancer Center
Study Sponsor  ICMJE M.D. Anderson Cancer Center
Collaborators  ICMJE National Cancer Institute (NCI)
Investigators  ICMJE
Principal Investigator: Luhua (Michael) Wang M.D. Anderson Cancer Center
PRS Account M.D. Anderson Cancer Center
Verification Date August 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP