Try the modernized ClinicalTrials.gov beta website. Learn more about the modernization effort.
Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu
Trial record 1 of 1 for:    A051301
Previous Study | Return to List | Next Study

Ibrutinib Before and After Stem Cell Transplant in Treating Patients With Relapsed or Refractory Diffuse Large B-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.
 
ClinicalTrials.gov Identifier: NCT02443077
Recruitment Status : Recruiting
First Posted : May 13, 2015
Last Update Posted : June 22, 2022
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Study Description
Go to 
Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information
Brief Summary:
This randomized phase III trial studies ibrutinib to see how well it works compared to placebo when given before and after stem cell transplant in treating patients with diffuse large B-cell lymphoma that has returned after a period of improvement (relapsed) or does not respond to treatment (refractory). Before transplant, stem cells are taken from patients and stored. Patients then receive high doses of chemotherapy to kill cancer cells and make room for healthy cells. After treatment, the stem cells are then returned to the patient to replace the blood-forming cells that were destroyed by the chemotherapy. Ibrutinib is a drug that may stop the growth of cancer cells by blocking a protein that is needed for cell growth. It is not yet known whether adding ibrutinib to chemotherapy before and after stem cell transplant may help the transplant work better in patients with relapsed or refractory diffuse large B-cell lymphoma.

Condition or disease Intervention/treatment Phase
Recurrent Diffuse Large B-Cell Lymphoma Activated B-Cell Type Refractory Diffuse Large B-Cell Lymphoma Activated B-Cell Type Procedure: Autologous Bone Marrow Transplantation Procedure: Autologous Hematopoietic Stem Cell Transplantation Drug: Carmustine Drug: Cyclophosphamide Drug: Cytarabine Drug: Etoposide Drug: Ibrutinib Other: Laboratory Biomarker Analysis Drug: Melphalan Other: Pharmacogenomic Study Other: Placebo Administration Phase 3

Show Show detailed description
Study Design
Go to 
Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 302 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: A Randomized Double-Blind Phase III Study of Ibrutinib During and Following Autologous Stem Cell Transplantation Versus Placebo in Patients With Relapsed or Refractory Diffuse Large B-Cell Lymphoma of the Activated B-Cell Subtype
Actual Study Start Date : July 6, 2016
Estimated Primary Completion Date : October 7, 2022
Estimated Study Completion Date : October 7, 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lymphoma
Drug Information available for: Ibrutinib

Arms and Interventions
Go to 
Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Arm Intervention/treatment
Experimental: Arm I (ibrutinib, chemotherapy, autoHCT)

CONDITIONING REGIMEN: Investigators may choose to use either the BEAMi or CBVi regimen.

BEAMi: Patients receive ibrutinib PO on days -6 to -1 or days -7 to -2 if a day of rest is planned, carmustine IV over 2 hours on day -6, etoposide IV BID over 1-2 hours and cytarabine IV BID over 1-2 hours on days -5 to -2, and melphalan IV over 20-30 minutes on day -1.

CBVi: Patients receive ibrutinib PO on days -6 to -1 or days -7 to -2 if a day of rest is planned, carmustine IV over 2 hours on day -6, etoposide IV over 4 hours on day -4, and cyclophosphamide IV on day -2.

TRANSPLANT: In both arms, patients undergo autologous hematopoietic progenitor cell or bone marrow transplant on day 0.

CONTINUATION REGIMEN: Beginning 30-60 days after transplant, patients receive ibrutinib PO on days 1-28. Treatment repeats every 28 days for 12 cycles in the absence of disease progression or unacceptable toxicity.

 Procedure: Autologous Bone Marrow Transplantation
Undergo autologous hematopoietic progenitor cells or bone marrow transplant

Procedure: Autologous Hematopoietic Stem Cell Transplantation
Undergo autologous hematopoietic progenitor cells or bone marrow transplant

Drug: Carmustine
Given IV

Drug: Cyclophosphamide
Given IV

Drug: Cytarabine
Given IV

Drug: Etoposide
Given IV

Drug: Ibrutinib
Given PO

Other: Laboratory Biomarker Analysis
Correlative studies

Drug: Melphalan
Given IV

Other: Pharmacogenomic Study
Correlative studies
Placebo Comparator: Arm II (placebo, chemotherapy, autoHCT)

CONDITIONING REGIMEN: Patients receive placebo PO on days -6 to -1 and receive 1 of the 2 conditioning regimens as in Arm I.

TRANSPLANT: Patients undergo autologous hematopoietic progenitor cell or bone marrow transplant on day 0.

CONTINUATION REGIMEN: Beginning 30-60 days after transplant, patients receive placebo PO on days 1-28. Treatment repeats every 28 days for 12 cycles in the absence of disease progression or unacceptable toxicity. Patients experiencing disease progression may crossover Arm I.

 Procedure: Autologous Bone Marrow Transplantation
Undergo autologous hematopoietic progenitor cells or bone marrow transplant

Procedure: Autologous Hematopoietic Stem Cell Transplantation
Undergo autologous hematopoietic progenitor cells or bone marrow transplant

Drug: Carmustine
Given IV

Drug: Cyclophosphamide
Given IV

Drug: Cytarabine
Given IV

Drug: Etoposide
Given IV

Other: Laboratory Biomarker Analysis
Correlative studies

Drug: Melphalan
Given IV

Other: Pharmacogenomic Study
Correlative studies

Other: Placebo Administration
Given PO


Outcome Measures
Go to 
Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Primary Outcome Measures :
  1. 24-month progression-free survival (PFS), defined as the proportion of patients who are alive and progression-free 2 years from randomization [ Time Frame: Time between registration and disease progression or death, whichever comes first, assessed at 24 months ]
    Will be assessed using the Lugano classification.


Secondary Outcome Measures :
  1. Overall survival (OS) [ Time Frame: The time between randomization and death from any cause, assessed up to 5 years (60 months) ]
    For each arm, the distribution of OS will be estimated using the Kaplan-Meier method. OS will be compared between the two arms using the log-rank test and Cox regression method adjusting for the known predictors.

  2. Time to hematopoietic engraftment [ Time Frame: First day of one week without platelet transfusion, assessed up to 5 years ]
    Will be defined as platelet count greater than or equal to 20,000/uL following nadir.

  3. PFS [ Time Frame: Time between registration and disease progression or death, whichever comes first, assessed up to 5 years (60 months) ]
    For each arm, the distribution of PFS will be estimated using the Kaplan-Meier method. PFS will be compared between the two arms using the log-rank test and Cox regression method adjusting for the known predictors.

  4. Response rate using the Lugano classification [ Time Frame: Up to 60 months ]
    The metabolic response proportion following AutoHCT will be compared between the two arms using chi-squared test.

  5. Treatment-related mortality [ Time Frame: Up to 60 months ]
    Treatment-related mortality will be summarized using contingency tables.

  6. Incidence of hematologic toxicity of ibrutinib therapy [ Time Frame: Up to 60 months ]
    Hematologic toxicity will be summarized using contingency tables.

  7. Incidence of secondary malignancies [ Time Frame: Up to 60 months ]
    Incidence of secondary malignancies will be summarized using contingency tables.


Other Outcome Measures:
  1. Fludeoxyglucose positron emission tomography (FDG-PET) imaging results [ Time Frame: Baseline ]
    PFS and OS will be compared between PET/computed tomography (CT) positive and negative groups using the two-sample log-rank test with a 2-sided alpha of 5%. A Cox regression model will be conducted to regress PFS and OS on PET/CT positivity. Deauville criteria analyses will be conducted with cutoffs at scores of 2 and 3, and quantitative measurements, e.g. delta standard uptake value (SUV), %SUV decline and %MTV decline, in place of the dichotomous FDG-PET/CT outcome. Positive/negative predictive values, sensitivity and specificity of PET/CT further estimated by dichotomizing the PFS and OS at 2 years.

  2. GSTT1 null allele expression [ Time Frame: Baseline ]
    GSTT1 null allele expression will be associated with carmustine toxicity. Quantified using the standard Common Terminology Criteria for Adverse Events and changes in diffusing capacity of the lungs for carbon monoxide from baseline.

  3. Single-nuclear polymorphisms (SNPs) in the BCNU metabolism or damage repair pathways [ Time Frame: Baseline ]
    All SNPs will be evaluated for deviation from Hardy-Weinberg. In the absence of a hypothesized effect, analyses will be powered for allele dosing (i.e., additive) effects. The Cochran-Armitage test (for binary endpoints), Jonkheere-Terpstra test (for quantitative traits including biomarker or gene expressions in serum or tumor ribonucleic acid) and the Cox score test (for censored time-to-event outcomes) will be used to quantify marginal associations. Multivariable models, with molecular, clinical and demographic variables, will be constructed using conditional inference trees and random forests.

  4. BCR pathway mutations [ Time Frame: Baseline ]
    The mutation of CD79a/b, caspase recruitment domain family, member 11 (CARD11), tumor necrosis factor, alpha-induced protein 3 TNFAIP3), and myeloid differentiation primary response 88 (MYD88) will be associated with each outcome in the ibrutinib arm (Arm A) using the chi-squared test for response rate and the log-rank test for each censored outcome. Similar analyses will be conducted for the placebo arm (Arm B) to show that the association between mutation and the outcomes observed in the ibrutinib arm is not observed in the placebo arm.

  5. BCL2, MYC, and Ki67 expression in tissue samples by immunohistochemistry (IHC) [ Time Frame: Baseline ]
    The expression of BCL2, MYC, and Ki67 will be analyzed to assess whether they affect clinical outcomes.

  6. MYC translocations [ Time Frame: Baseline ]
    Translocations in MYC with or without BCL2, and BCL6 will be analyzed to determine whether they are related to poor outcomes and whether ibrutinib modifies the prognosis.


Eligibility Criteria
Go to 
Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

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.


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

Inclusion Criteria:

  • PRE-REGISTRATION ELIGIBILITY CRITERIA (STEP 0)
  • Patients must have paraffin tissue from the diagnostic or relapse biopsy available to be submitted for central pathology review; this review is mandatory prior to registration to confirm eligibility and should be initiated as soon as possible
  • ELIGIBILITY CRITERIA (STEP 1)
  • Diagnosis of World Health Organization (WHO) diffuse large B-cell lymphoma, non-GCB by central review confirmation
  • Patient must be deemed eligible to proceed with high-dose chemotherapy and autologous stem cell transplantation by local transplant center
  • New York Heart Association class I or less; ordinary physical activity does not cause undue fatigue, palpitations, dyspnea, or angina pain; patients 60 years or older must have a left ventricular ejection fraction (LVEF) at rest >= 40% measured by echocardiogram or multi-gated acquisition (MUGA)
  • Diffusion capacity of the lung for carbon monoxide (DLCO) >= 40% of predicted (corrected or uncorrected for hemoglobin per institutional standards)
  • Forced expiratory volume in 1 second (FEV1) >= 40% of predicted (corrected or uncorrected for hemoglobin per institutional standards)
  • Forced vital capacity (FVC) >= 40% of predicted (corrected or uncorrected for hemoglobin per institutional standards)
  • Total bilirubin =< 1.5 x upper limit of normal (ULN) unless isolated hyperbilirubinemia attributed to Gilbert's syndrome
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3 x upper limit of normal (ULN)
  • Creatinine =< 2.0 mg/dL OR creatinine clearance (calculated clearance permitted) >= 40 mL/min by Cockcroft-Gault formula
  • Prothrombin time (PT)/ international normalized ration (INR) < 1.5 x ULN and partial thromboplastin time (PTT) (activated [a]PTT) < 1.5 x ULN
  • Patient must have progressed or be refractory to prior anthracycline-containing chemotherapy (e.g. rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine, and prednisone [R-CHOP], dose adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab [DA-EPOCH-R], etc)
  • No more than 3 prior regimens for large cell component (e.g. one induction and two salvage therapies); monoclonal antibody alone or involved field/involved site radiotherapy do not count as lines of therapy. Prior CART therapy is allowed and counts as one line of therapy
  • Prior use of ibrutinib is allowed unless patient has had disease progression while receiving ibrutinib
  • Patient must have chemosensitive disease as defined by at least a partial response to salvage therapy at their latest assessment
  • No major surgery =< 7 days prior to registration and no minor surgery =< 3 days prior to registration (with the exception of intravenous access placement, e.g. Hickman or peripherally inserted central catheter [PICC])

  • Not pregnant and not nursing, because this study involves an agent that has known genotoxic, mutagenic and teratogenic effects; therefore, for women of childbearing potential only, a negative serum pregnancy test must be obtained within 14 days prior to registration

    • Women of childbearing potential must use adequate contraception from study start to one month after the last dose of protocol therapy; adequate contraception is defined as hormonal birth control, intrauterine device, double barrier method or total abstinence; men must practice complete abstinence or agree to use an adequate contraception method from study start to one month after the last dose of protocol therapy
  • Age >= 18 years
  • Patients should not require chronic use of strong CYP3A inhibitors or strong CYP3A inducers
  • Patients should not require concurrent therapeutic doses of steroids (> 20 mg of prednisone/day or equivalent) unless they need them for the indications; steroids should be discontinued for 14 days before starting protocol treatment

  • Human immunodeficiency virus (HIV) infected patients are eligible provided they meet all other eligibility criteria, and:

    • There is no prior history of acquired immunodeficiency syndrome (AIDS) defining conditions other than historically low CD4+ T-cell count or B-cell lymphoma
    • In the opinion of an expert in HIV disease, prospects for long-term survival are excellent were it not for the diagnosis of lymphoma
    • Use of HIV protease inhibitors as part of the anti-HIV regimen OR as a pharmacologic booster is not allowed
    • Zidovudine is not allowed
    • Once daily combination pills for HIV containing a pharmacologic booster such as cobicistat are not allowed
    • Patients with multi-drug resistant HIV are not eligible

  • Patients cannot have:

    • Active central nervous system or meningeal involvement by lymphoma; patients with a history of central nervous system (CNS) or meningeal involvement must be in a documented remission by cerebrospinal fluid (CSF) evaluation and contrast-enhanced magnetic resonance imaging (MRI) imaging for at least 91 days prior to registration
    • Evidence of myelodysplasia or cytogenetic abnormality indicative of myelodysplasia on any bone marrow biopsy prior to initiation of therapy
    • A known bleeding diathesis
    • Requirement for warfarin or similar vitamin K antagonists; these drugs are prohibited 28 days prior to the first treatment and throughout the trial
    • History of stroke or intracranial hemorrhage =< 6 months before treatment
    • Currently active, clinically significant hepatic impairment (Child-Pugh class B or C according to the Child Pugh classification
    • History of allergic reactions attributed to compounds of similar chemical or biologic composition to ibrutinib or other agents used in study
    • Serologic status reflecting active hepatitis B or C infection; patients that are positive for hepatitis B core antibody, hepatitis B surface antigen (HBsAg), or hepatitis C antibody must have a negative polymerase chain reaction (PCR) prior to enrollment; (PCR positive patients will be excluded)
  • Eastern Cooperative Oncology Group (ECOG) performance status must be =< 2
Contacts and Locations
Go to 
Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

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): NCT02443077


Locations
Show Show 283 study locations
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
Layout table for investigator information
Principal Investigator: Charalambos B Andreadis Alliance for Clinical Trials in Oncology
More Information
Go to 
Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information
Layout table for additonal information
Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT02443077    
Other Study ID Numbers: NCI-2015-00668
NCI-2015-00668 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
BMT CTN 1201
A051301
A051301 ( Other Identifier: Alliance for Clinical Trials in Oncology )
A051301 ( Other Identifier: CTEP )
U10CA180821 ( U.S. NIH Grant/Contract )
First Posted: May 13, 2015    Key Record Dates
Last Update Posted: June 22, 2022
Last Verified: May 2022
Additional relevant MeSH terms:
Layout table for MeSH terms
Lymphoma
Lymphoma, B-Cell
Lymphoma, Large B-Cell, Diffuse
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Lymphoma, Non-Hodgkin
Cytarabine
Cyclophosphamide
Melphalan
Carmustine
Etoposide
 Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antineoplastic Agents, Phytogenic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Antimetabolites, Antineoplastic
Antimetabolites