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A Comparison of Three Chemotherapy Regimens for the Treatment of Patients With Newly Diagnosed Mantle Cell Lymphoma

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ClinicalTrials.gov Identifier: NCT04115631
Recruitment Status : Recruiting
First Posted : October 4, 2019
Last Update Posted : November 5, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Eastern Cooperative Oncology Group ( ECOG-ACRIN Cancer Research Group )

Brief Summary:
This phase II trial compares three chemotherapy regimens consisting of bendamustine, rituximab, high dose cytarabine, and acalabrutinib and studies how well they work in treating patients with newly diagnosed mantle cell lymphoma. Drugs used in chemotherapy, such as bendamustine and cytarabine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Monoclonal antibodies, such as rituximab, may interfere with the ability of cancer cells to grow and spread. Acalabrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. This study is being done to find out if one the drug combinations of bendamustine, rituximab, high dose cytarabine, and acalabrutinib is better or worse than the usual approach for mantle cell lymphoma.

Condition or disease Intervention/treatment Phase
Liver Lymphoma Mantle Cell Lymphoma Drug: Acalabrutinib Drug: Bendamustine Drug: Bendamustine Hydrochloride Drug: Cytarabine Biological: Rituximab Phase 2

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 369 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Randomized 3-Arm Phase II Study Comparing 1.) Bendamustine, Rituximab and High Dose Cytarabine (BR/CR) 2.) Bendamustine, Rituximab, High Dose Cytarabine and Acalabrutinib (BR/CR-A), and 3.) Bendamustine, Rituximab and Acalabrutinib (BR-A) in Patients </= 70 Years Old With Untreated Mantle Cell Lymphoma
Actual Study Start Date : October 3, 2019
Estimated Primary Completion Date : March 31, 2024
Estimated Study Completion Date : March 31, 2025


Arm Intervention/treatment
Experimental: Arm A (bendamustine, rituximab, cytarabine)
Patients receive bendamustine IV on days 1 and 2 and rituximab IV on day 1 or 2. Treatment repeats every 28 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity. Beginning cycle 4, patients receive rituximab IV on day 1 and cytarabine IV every Q12 hours on days 1 and 2. Treatment repeats every 28 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity.
Drug: Bendamustine
Given IV
Other Name: SDX-105

Drug: Bendamustine Hydrochloride
Given IV
Other Names:
  • Bendamustin Hydrochloride
  • Bendeka
  • Cytostasan Hydrochloride
  • Levact
  • Ribomustin
  • SyB L-0501
  • Treanda

Drug: Cytarabine
Given IV
Other Names:
  • .beta.-Cytosine arabinoside
  • 1-.beta.-D-Arabinofuranosyl-4-amino-2(1H)pyrimidinone
  • 1-.beta.-D-Arabinofuranosylcytosine
  • 1-Beta-D-arabinofuranosyl-4-amino-2(1H)pyrimidinone
  • 1-Beta-D-arabinofuranosylcytosine
  • 1.beta.-D-Arabinofuranosylcytosine
  • 2(1H)-Pyrimidinone, 4-Amino-1-beta-D-arabinofuranosyl-
  • 2(1H)-Pyrimidinone, 4-amino-1.beta.-D-arabinofuranosyl-
  • Alexan
  • Ara-C
  • ARA-cell
  • Arabine
  • Arabinofuranosylcytosine
  • Arabinosylcytosine
  • Aracytidine
  • Aracytin
  • Aracytine
  • Beta-cytosine Arabinoside
  • CHX-3311
  • Cytarabinum
  • Cytarbel
  • Cytosar
  • Cytosine Arabinoside
  • Cytosine-.beta.-arabinoside
  • Cytosine-beta-arabinoside
  • Erpalfa
  • Starasid
  • Tarabine PFS
  • U 19920
  • U-19920
  • Udicil
  • WR-28453

Biological: Rituximab
Given IV
Other Names:
  • ABP 798
  • BI 695500
  • C2B8 Monoclonal Antibody
  • Chimeric Anti-CD20 Antibody
  • CT-P10
  • IDEC-102
  • IDEC-C2B8
  • IDEC-C2B8 Monoclonal Antibody
  • MabThera
  • Monoclonal Antibody IDEC-C2B8
  • PF-05280586
  • Rituxan
  • Rituximab ABBS
  • Rituximab Biosimilar ABP 798
  • Rituximab Biosimilar BI 695500
  • Rituximab Biosimilar CT-P10
  • Rituximab Biosimilar GB241
  • Rituximab Biosimilar IBI301
  • Rituximab Biosimilar JHL1101
  • Rituximab Biosimilar PF-05280586
  • Rituximab Biosimilar RTXM83
  • Rituximab Biosimilar SAIT101
  • rituximab biosimilar TQB2303
  • rituximab-abbs
  • RTXM83
  • Truxima

Experimental: Arm B (acalabrutinib, bendamustine, rituximab, cytarabine)
Patients receive PO BID on days 1-28, bendamustine IV on days 1 and 2, and rituximab IV on day 1 or 2. Treatment repeats every 28 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity. Beginning cycle 4, patients receive acalabrutinib PO BID on days 1-7 and 22-28, rituximab IV on day 1, and cytarabine IV Q12 hours on days 1 and 2. Treatment repeats every 28 days for up to 3 cycles 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: Bendamustine
Given IV
Other Name: SDX-105

Drug: Bendamustine Hydrochloride
Given IV
Other Names:
  • Bendamustin Hydrochloride
  • Bendeka
  • Cytostasan Hydrochloride
  • Levact
  • Ribomustin
  • SyB L-0501
  • Treanda

Drug: Cytarabine
Given IV
Other Names:
  • .beta.-Cytosine arabinoside
  • 1-.beta.-D-Arabinofuranosyl-4-amino-2(1H)pyrimidinone
  • 1-.beta.-D-Arabinofuranosylcytosine
  • 1-Beta-D-arabinofuranosyl-4-amino-2(1H)pyrimidinone
  • 1-Beta-D-arabinofuranosylcytosine
  • 1.beta.-D-Arabinofuranosylcytosine
  • 2(1H)-Pyrimidinone, 4-Amino-1-beta-D-arabinofuranosyl-
  • 2(1H)-Pyrimidinone, 4-amino-1.beta.-D-arabinofuranosyl-
  • Alexan
  • Ara-C
  • ARA-cell
  • Arabine
  • Arabinofuranosylcytosine
  • Arabinosylcytosine
  • Aracytidine
  • Aracytin
  • Aracytine
  • Beta-cytosine Arabinoside
  • CHX-3311
  • Cytarabinum
  • Cytarbel
  • Cytosar
  • Cytosine Arabinoside
  • Cytosine-.beta.-arabinoside
  • Cytosine-beta-arabinoside
  • Erpalfa
  • Starasid
  • Tarabine PFS
  • U 19920
  • U-19920
  • Udicil
  • WR-28453

Biological: Rituximab
Given IV
Other Names:
  • ABP 798
  • BI 695500
  • C2B8 Monoclonal Antibody
  • Chimeric Anti-CD20 Antibody
  • CT-P10
  • IDEC-102
  • IDEC-C2B8
  • IDEC-C2B8 Monoclonal Antibody
  • MabThera
  • Monoclonal Antibody IDEC-C2B8
  • PF-05280586
  • Rituxan
  • Rituximab ABBS
  • Rituximab Biosimilar ABP 798
  • Rituximab Biosimilar BI 695500
  • Rituximab Biosimilar CT-P10
  • Rituximab Biosimilar GB241
  • Rituximab Biosimilar IBI301
  • Rituximab Biosimilar JHL1101
  • Rituximab Biosimilar PF-05280586
  • Rituximab Biosimilar RTXM83
  • Rituximab Biosimilar SAIT101
  • rituximab biosimilar TQB2303
  • rituximab-abbs
  • RTXM83
  • Truxima

Experimental: Arm C (acalabrutinib, bendamustine, rituximab)
Patients receive acalabrutinib PO BID on days 1-28, bendamustine IV on days 1 and 2, and rituximab IV on day 1 or 2. Treatment repeats every 28 days for up to 6 cycles 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: Bendamustine
Given IV
Other Name: SDX-105

Drug: Bendamustine Hydrochloride
Given IV
Other Names:
  • Bendamustin Hydrochloride
  • Bendeka
  • Cytostasan Hydrochloride
  • Levact
  • Ribomustin
  • SyB L-0501
  • Treanda

Biological: Rituximab
Given IV
Other Names:
  • ABP 798
  • BI 695500
  • C2B8 Monoclonal Antibody
  • Chimeric Anti-CD20 Antibody
  • CT-P10
  • IDEC-102
  • IDEC-C2B8
  • IDEC-C2B8 Monoclonal Antibody
  • MabThera
  • Monoclonal Antibody IDEC-C2B8
  • PF-05280586
  • Rituxan
  • Rituximab ABBS
  • Rituximab Biosimilar ABP 798
  • Rituximab Biosimilar BI 695500
  • Rituximab Biosimilar CT-P10
  • Rituximab Biosimilar GB241
  • Rituximab Biosimilar IBI301
  • Rituximab Biosimilar JHL1101
  • Rituximab Biosimilar PF-05280586
  • Rituximab Biosimilar RTXM83
  • Rituximab Biosimilar SAIT101
  • rituximab biosimilar TQB2303
  • rituximab-abbs
  • RTXM83
  • Truxima




Primary Outcome Measures :
  1. Composite of positron emission tomography (PET)/computed tomography (CT) complete response (CR) and peripheral blood (PB) minimal residual disease (MRD) negative rate [ Time Frame: Up to 8 weeks post treatment ]
    MRD status is defined as positive, negative, or indeterminate as measured from PB specimens following completion of treatment. Measures of frequencies and proportion, and location and dispersion will be used to describe categorical, and continuous variables respectively; 90% confidence intervals around these estimates will be computed. Kaplan-Meier method will be used to describe time-to-event endpoints and log-rank test to assess difference in time-to-event endpoints by levels of a categorical predictor. Cox proportional hazards (PH) regression model would be used to model the impact of baseline and other relevant variables on time-to-event endpoints.


Secondary Outcome Measures :
  1. Progression-free survival (PFS) [ Time Frame: From randomization to earliest of disease progression or death, assessed at 36 months ]
  2. Incidence of adverse events [ Time Frame: Up to 10 years post randomization ]
    Assessed by Common Terminology Criteria for Adverse Events (CTCAE). The cumulative dose of high dose cytarabine and proportion of patients that discontinued treatment due to toxicity will be assessed.

  3. Objective response rate (ORR) [ Time Frame: Up to 10 years post randomization ]
    ORR is defined as the proportion of patients achieving a best response to treatment of complete response (CR) or partial response (PR). ORR and PET/CT CR will be estimated in each treatment arm in the efficacy population, as well as among all treated patients, regardless of informative tissue status.

  4. Overall survival (OS) [ Time Frame: From randomization to death, assessed at 36 months ]
    Patients that are alive will be censored at the time of last follow-up. OS will be described using the Kaplan-Meier method and log-rank test will be used to compare survival by treatment arm.

  5. Mobilization failure rate [ Time Frame: Up to 10 years post randomization ]
    Defined as a yield < 2 x10^6 CD34+ stem cells/kg with a maximum of 4 course of apheresis will be summarized as a categorical variable, and compared, between treatment arms using Z- test.


Other Outcome Measures:
  1. PET/CT negative rate between the three arms [ Time Frame: Up to 10 years post randomization ]
  2. PET quantitative assessment (qPET) [ Time Frame: At end of treatment (within 6 months after the "8 weeks post treatment" timeframe) ]
    Will evaluate the association between baseline qPET and MRD status.

  3. Change of qPET parameters [ Time Frame: Baseline to end of treatment (within 6 months after the "8 weeks post treatment" timeframe) ]
    Will evaluate the association between the change of qPET parameters and MRD and compare this association across all 3 arms.

  4. Incremental prognostic value of baseline qPET to standard risk markers (Mantle Cell Lymphoma International Prognostic Index [MIPI]) [ Time Frame: At end of treatment (within 6 months after the "8 weeks post treatment" timeframe) ]
    Will assess the incremental prognostic value of baseline to standard risk markers (MIPI) in predicting MRD status.

  5. Interim PET status [ Time Frame: At end of treatment (within 6 months after the "8 weeks post treatment" timeframe) ]
    Interim PET status both qualitatively (Deauville) and quantitatively will be correlated with MRD status. Will fit a logistic regression model to evaluate this aim with binary MRD status at end of treatment (EOT) as the response variable and interim PET status as the predictor.

  6. Incremental prognostic value of interim qPET to standard risk markers (MIPI) [ Time Frame: At end of treatment (within 6 months after the "8 weeks post treatment" timeframe) ]
    Will assess the incremental prognostic value of interim qPET to standard risk markers (MIPI) in predicting MRD status.

  7. Incremental prognostic value of interim qPET to Ki67 [ Time Frame: At end of treatment (within 6 months after the "8 weeks post treatment" timeframe) ]
    Will assess the incremental prognostic value of interim qPET to Ki67 in predicting MRD status.

  8. Incremental prognostic value of baseline qPET to Ki67 [ Time Frame: At end of treatment (within 6 months after the "8 weeks post treatment" timeframe) ]
    Will assess the incremental prognostic value of baseline qPET to Ki67 in predicting MRD status.



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 to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Baseline measurements and evaluations must be obtained within 6 weeks of randomization to the study. Abnormal PET or CT scans may constitute evaluable disease. Patient must have at least one objective measurable disease parameter. Measurable disease in the liver is required if the liver is the only site of lymphoma.
  • MIPI score must be calculated and entered in Oncology Patient Enrollment Network (OPEN).
  • Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status score of 0-2.
  • Patients must have untreated histologically confirmed mantle cell lymphoma, with cyclin D1 (BCL1) expression by immunohistochemical stains and/or t(11;14) by cytogenetics or fluorescent in situ hybridization (FISH). The diagnosis must be confirmed by formal hematopathology review at the enrolling center.
  • Patients being treated with gastric reducing agents proton pump inhibitors must be switched to an alternative drug before starting acalabrutinib.
  • Absolute neutrophil count (ANC) >= 1,000/mcL (obtained with 14 days of randomization). If disease includes marrow involvement or hypersplenism, please reference the below revised ANC requirement:

    • ANC >= 500/mcL
  • Platelets >= 75,000 mcL (obtained with 14 days of randomization). If disease includes involvement or hypersplenism, please reference the below revised platelet requirement:

    • Platelets >= 25,000/mcL
  • Total bilirubin =< 2 x institutional upper limit of normal (ULN) (obtained with 14 days of randomization). If disease includes hepatic infiltration or is causing biliary obstruction, or if elevated bilirubin is due to Gilbert's disease, please reference the below revised bilirubin requirements:

    • Bilirubin =< 3 x institutional ULN
  • Aspartate aminotransferase (AST) and alanine transaminase (ALT) =< 2.5 x institutional ULN (obtained with 14 days of randomization). If disease includes hepatic infiltration or is causing biliary obstruction, or if elevated bilirubin is due to Gilbert's disease, please reference the below revised AST/ALT requirements:

    • AST/ALT =< 5 x institutional ULN
  • Prothrombin time (PT)/international normalized ratio (INR) or partial thromboplastin time (aPTT) in the absence of lupus anticoagulant) < 2 x institutional ULN (obtained with 14 days of randomization). Patients receiving anticoagulant therapy (other than warfarin or equivalent vitamin K antagonists which are excluded), higher INR/aPTT may be permitted to enroll to this study after discussion with the primary investigator (PI).
  • Creatinine =< institutional ULN, OR glomerular filtration rate (GFR) >= 40 mL/min/1.73 m^2 (obtained with 14 days of randomization).
  • Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial.
  • For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.
  • Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load.
  • Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.
  • Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional classification. To be eligible for this trial, patients should be class 2B or better.
  • Patients must have a QT interval (QTc) =< 480 msec obtained within 14 days of randomization.
  • Women must not be pregnant or breast-feeding due to the potential harm to an unborn fetus and possible risk for adverse events in nursing infants with the treatment regimens being used. Patients must also not expect to conceive or father children from the time of registration, while on study treatment, and until 12 months after the last dose of study treatment. All females of childbearing potential must have a blood test or urine study within 2 weeks prior to randomization to rule out pregnancy. A female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: has achieved menarche at some point, has not undergone a hysterectomy or bilateral oophorectomy; or has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months).
  • Women of childbearing potential and sexually active males must agree to use accepted and effective method(s) of contraception or to abstain from sexual intercourse for the duration of their participation in the study and for 12 months after treatment ends.
  • Patients are not eligible if they require treatment with a strong cytochrome P450 (CYP) 3A inhibitor.
  • Patients may not have received the following within 7 days prior to the first dose of study drug:

    • Strong and moderate CYP3A inhibitors
    • Strong and moderate CYP3A inducers
  • Patients are ineligible if they have any of the following:

    • Malabsorption syndrome or disease significantly affecting gastrointestinal function.
    • Active bleeding or history of bleeding diathesis (e.g. hemophilia or von Willebrand disease).
    • Uncontrolled AIHA (autoimmune hemolytic anemia) or ITP (idiopathic thrombocytopenia purpura).
    • Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonists (e.g. phenprocoumon) within 7 days of first dose of study drug.
    • History of significant cerebrovascular disease/event, including stroke or intracranial hemorrhage, within 6 months before the first dose of study drug.
    • Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infections at study enrollment (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment).
    • History of severe allergic reaction attributed to compounds of similar chemical or biologic composition to rituximab, bendamustine, cytarabine, or acalabrutinib.
  • Patients must be able to fulfill one of the following eligibility requirements pertaining to biospecimen availability for submission following randomization:

    • Archived formalin-fixed paraffin-embedded (FFPE) tumor tissue specimen from the original diagnostic biopsy is available for submission OR,
    • If tumor tissue is not available, peripheral blood collected prior to initiation of protocol therapy will be submitted

      • NOTE: Biospecimens must be submitted within 60 days following randomization to Adaptive Biotechnologies for ClonoSEQ ID molecular marker identification of unique clonal immunoglobulin deoxyribonucleic acid (DNA) sequence. If peripheral blood will be submitted, Adaptive Biotechnologies should be contacted prior to patient randomization for guidance pertaining to collection and submission requirements.

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 ClinicalTrials.gov identifier (NCT number): NCT04115631


  Show 67 Study Locations
Sponsors and Collaborators
ECOG-ACRIN Cancer Research Group
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Nina D Wagner-Johnston ECOG-ACRIN Cancer Research Group

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Responsible Party: ECOG-ACRIN Cancer Research Group
ClinicalTrials.gov Identifier: NCT04115631     History of Changes
Other Study ID Numbers: EA4181
NCI-2019-05536 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
EA4181 ( Other Identifier: ECOG-ACRIN Cancer Research Group )
EA4181 ( Other Identifier: CTEP )
U10CA180820 ( U.S. NIH Grant/Contract )
First Posted: October 4, 2019    Key Record Dates
Last Update Posted: November 5, 2019
Last Verified: October 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Additional relevant MeSH terms:
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Lymphoma
Lymphoma, Mantle-Cell
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Lymphoma, Non-Hodgkin
Cytarabine
Rituximab
Antineoplastic Agents, Immunological
Bendamustine Hydrochloride
Antibodies
Immunoglobulins
Antibodies, Monoclonal
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents
Antirheumatic Agents
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antiviral Agents
Anti-Infective Agents
Immunosuppressive Agents
Antineoplastic Agents, Alkylating
Alkylating Agents