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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT03946878
Recruitment Status : Recruiting
First Posted : May 13, 2019
Last Update Posted : March 24, 2020
National Cancer Institute (NCI)
Information provided by (Responsible Party):
M.D. Anderson Cancer Center

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.

Condition or disease Intervention/treatment Phase
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) Drug: Acalabrutinib Drug: Venetoclax Phase 2

Detailed Description:


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


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.


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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 50 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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)
Actual Study Start Date : August 13, 2019
Estimated Primary Completion Date : February 8, 2024
Estimated Study Completion Date : February 8, 2024

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lymphoma

Arm Intervention/treatment
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.
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

Primary Outcome Measures :
  1. 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.

Secondary Outcome Measures :
  1. Overall response rate [ Time Frame: 5 years ]
  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. 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.

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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

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.

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 identifier (NCT number): NCT03946878

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Contact: Luhua (Michael) Wang, MD,MS 713-792-2860
Contact: Preetesh Jain, MD,DM, PHD 713-745-8432

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United States, Texas
M D Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Luhua (Michael) Wang, MD,MS    713-792-2860      
Contact: Preetesh Jain, MD,DM,PhD    713-745-8432      
Principal Investigator: Luhua (Michael) Wang         
Sponsors and Collaborators
M.D. Anderson Cancer Center
National Cancer Institute (NCI)
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Principal Investigator: Luhua (Michael) Wang M.D. Anderson Cancer Center
Additional Information:
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Responsible Party: M.D. Anderson Cancer Center Identifier: NCT03946878    
Other Study ID Numbers: 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 )
First Posted: May 13, 2019    Key Record Dates
Last Update Posted: March 24, 2020
Last Verified: March 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Lymphoma, Mantle-Cell
Neoplasms by Histologic Type
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Lymphoma, Non-Hodgkin
Antineoplastic Agents