Clinical Trials /

Ibrutinib Before and After Stem Cell Transplant in Treating Patients With Relapsed or Refractory Diffuse Large B-cell Lymphoma

NCT02443077

Description:

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.

Related Conditions:
  • B-Cell Non-Hodgkin Lymphoma
  • Diffuse Large B-Cell Lymphoma
  • Diffuse Large B-Cell Lymphoma, Not Otherwise Specified
  • Mediastinal B-Cell Lymphoma, Unclassifiable, with Features Intermediate between Diffuse Large B-Cell Lymphoma and Classical Hodgkin Lymphoma
Recruiting Status:

Suspended

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Ibrutinib Before and After Stem Cell Transplant in Treating Patients With Relapsed or Refractory Diffuse Large B-cell Lymphoma
  • 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

Clinical Trial IDs

  • ORG STUDY ID: NCI-2015-00668
  • SECONDARY ID: NCI-2015-00668
  • SECONDARY ID: BMT CTN 1201
  • SECONDARY ID: A051301
  • SECONDARY ID: A051301
  • SECONDARY ID: A051301
  • SECONDARY ID: U10CA180821
  • NCT ID: NCT02443077

Conditions

  • Activated B-Cell-Like Diffuse Large B-Cell Lymphoma
  • B-Cell Lymphoma, Unclassifiable, With Features Intermediate Between Diffuse Large B-Cell Lymphoma and Burkitt Lymphoma
  • Diffuse Large B-Cell Lymphoma, Not Otherwise Specified
  • Recurrent Diffuse Large B-Cell Lymphoma
  • Refractory Diffuse Large B-Cell Lymphoma

Interventions

DrugSynonymsArms
CarmustineBCNU, Becenum, Becenun, BiCNU, Bis(chloroethyl) Nitrosourea, Bis-Chloronitrosourea, Carmubris, Carmustin, Carmustinum, FDA 0345, Gliadel, N,N'-Bis(2-chloroethyl)-N-nitrosourea, Nitrourean, Nitrumon, SK 27702, SRI 1720, WR-139021Arm I (ibrutinib, chemotherapy, autoHCT)
Cyclophosphamide(-)-Cyclophosphamide, 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate, Carloxan, Ciclofosfamida, Ciclofosfamide, Cicloxal, Clafen, Claphene, CP monohydrate, CTX, CYCLO-cell, Cycloblastin, Cycloblastine, Cyclophospham, Cyclophosphamid monohydrate, Cyclophosphamidum, Cyclophosphan, Cyclophosphane, Cyclophosphanum, Cyclostin, Cyclostine, Cytophosphan, Cytophosphane, Cytoxan, Fosfaseron, Genoxal, Genuxal, Ledoxina, Mitoxan, Neosar, Revimmune, Syklofosfamid, WR- 138719Arm I (ibrutinib, chemotherapy, autoHCT)
Cytarabine.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, Cytosar-U, Cytosine Arabinoside, Cytosine-.beta.-arabinoside, Cytosine-beta-arabinoside, Erpalfa, Starasid, Tarabine PFS, U 19920, U-19920, Udicil, WR-28453Arm I (ibrutinib, chemotherapy, autoHCT)
EtoposideDemethyl Epipodophyllotoxin Ethylidine Glucoside, EPEG, Lastet, Toposar, Vepesid, VP 16-213, VP-16, VP-16-213Arm I (ibrutinib, chemotherapy, autoHCT)
IbrutinibBTK Inhibitor PCI-32765, CRA-032765, Imbruvica, PCI-32765Arm I (ibrutinib, chemotherapy, autoHCT)
MelphalanAlanine Nitrogen Mustard, CB-3025, L-PAM, L-Phenylalanine mustard, L-Sarcolysin, L-Sarcolysin Phenylalanine mustard, L-Sarcolysine, Melphalanum, Phenylalanine Mustard, Phenylalanine Nitrogen Mustard, Sarcoclorin, Sarkolysin, WR-19813Arm I (ibrutinib, chemotherapy, autoHCT)

Purpose

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.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To evaluate the ability of ibrutinib to improve 24-month progression free survival (PFS)
      compared to placebo.

      SECONDARY OBJECTIVES:

      I. To evaluate the ability of ibrutinib to improve overall survival (OS) compared to placebo.

      II. To evaluate the ability of ibrutinib to improve progression free survival (PFS) compared
      to placebo.

      III. To evaluate the ability of ibrutinib to improve post-transplant response rates compared
      to placebo.

      IV. To evaluate time to hematopoietic recovery in the two arms. V. To evaluate the safety and
      tolerability of ibrutinib compared to placebo. VI. To evaluate the incidence of secondary
      malignancies in the two arms. VII. To evaluate immune reconstitution in the two arms.

      TERTIARY OBJECTIVES:

      I. To assess whether pre-autologous hematopoietic stem cell transplantation (AutoHCT)
      positive fludeoxyglucose F-18 (FDG)-positron emission tomography (PET) is associated with
      inferior 24-month PFS as well as PFS and OS.

      II. To assess whether pre-AutoHCT FDG-PET results are differentially associated with 24-month
      PFS, PFS and OS in the ibrutinib versus placebo arms.

      III. To evaluate the application of the Lugano criteria and change in quantitative
      measurements between pre-AutoHCT and post AutoHCT (e.g. delta standard uptake variable [SUV],
      %SUV decline and %metabolic tumor volume [MTV] decline, and other available applicable
      quantitative measurements) to assess the association between changes in these variables and
      outcomes, such as PFS and OS.

      IV. To assess whether the glutathione S-transferase theta 1 (GSTT1) null polymorphism is
      correlated with pulmonary toxicity after BCNU (carmustine)-containing conditioning regimens
      as part of autologous stem cell transplantation.

      V. To assess whether other polymorphisms in the BCNU metabolism pathway or BCNU damage repair
      pathway(s) are associated with pulmonary toxicity after BCNU-containing conditioning regimens
      as part of autologous stem cell transplantation.

      VI. To evaluate whether any of the proposed deoxyribonucleic acid (DNA) polymorphisms are
      associated with other toxicities.

      VII. To assess whether activating mutations in the breakpoint cluster region (BCR) pathway
      are associated with response to ibrutinib and with clinical outcomes in patients treated on
      this protocol.

      VIII. To assess whether there are any phenotypic associations with immunohistochemistry (IHC)
      markers (particularly v-myc avian myelocytomatosis viral oncogene homolog [MYC] protein
      expression level) and presence of these mutations.

      IX. To assess whether B-cell chronic lymphocytic leukemia (CLL)/lymphoma 2 (BCL2), MYC, and
      antigen Ki67 (Ki67) expression by IHC affect clinical outcomes in patients treated on this
      protocol.

      X. To assess whether translocations in MYC with or without BCL2 and BC6 have poor outcomes in
      patients treated on this protocol and whether ibrutinib modifies the prognosis.

      OUTLINE: Patients are randomized to 1 of 2 treatment arms.

      CONDITIONING REGIMEN:

      ARM I: Investigators may choose to use either the BEAMi (carmustine, etoposide, cytarabine,
      melphalan, ibrutinib) or CBVi (cyclophosphamide, carmustine, etoposide, ibrutinib) regimen.

      BEAMi: Patients receive ibrutinib orally (PO) on days -6 to -1, carmustine intravenously (IV)
      over 2 hours on day -6, etoposide IV twice daily (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, carmustine IV over 2 hours on day -6,
      etoposide IV over 4 hours on day -4, and cyclophosphamide IV on day -2.

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

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

      CONTINUATION REGIMEN:

      ARM I: Beginning 30-36 days after transplant, patients receive ibrutinib PO on days 1-28.
      Treatment repeats every 28 days for 12 courses in the absence of disease progression or
      unacceptable toxicity.

      ARM II: Beginning 30-36 days after transplant, patients receive placebo PO on days 1-28.
      Treatment repeats every 28 days for 12 courses in the absence of disease progression or
      unacceptable toxicity. Patients experiencing disease progression may crossover Arm I.

      After completion of treatment, patients are followed up periodically for 60 months from
      registration.
    

Trial Arms

NameTypeDescriptionInterventions
Arm I (ibrutinib, chemotherapy, autoHCT)ExperimentalCONDITIONING REGIMEN: Investigators may choose to use either the BEAMi or CBVi regimen. BEAMi: Patients receive ibrutinib PO on days -6 to -1, 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, 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 30-36 days after transplant, patients receive ibrutinib PO on days 1-28. Treatment repeats every 28 days for 12 courses in the absence of disease progression or unacceptable toxicity.
  • Carmustine
  • Cyclophosphamide
  • Cytarabine
  • Etoposide
  • Ibrutinib
  • Melphalan
Arm II (placebo, chemotherapy, autoHCT)Placebo ComparatorCONDITIONING 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 30-36 days after transplant, patients receive placebo PO on days 1-28. Treatment repeats every 28 days for 12 courses in the absence of disease progression or unacceptable toxicity. Patients experiencing disease progression may crossover Arm I.
  • Carmustine
  • Cyclophosphamide
  • Cytarabine
  • Etoposide
  • Melphalan

Eligibility 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 and integral molecular subtyping; this
             review is mandatory prior to registration to confirm eligibility and should be
             initiated as soon as possible; determination of cell-of-origin subtype will be
             performed using the lymphoma subtyping test (LST) assay

          -  ELIGIBILITY CRITERIA (STEP 1)

          -  Diagnosis of World Health Organization (WHO) diffuse large B-cell lymphoma, high grade
             B-cell lymphoma not otherwise specified, or B-cell lymphoma, unclassifiable, with
             features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma

          -  Determination of activated B-cell-like (ABC) subtype by pre-registration central
             review

          -  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 for hemoglobin)

          -  Forced expiratory volume in 1 second (FEV1) >= 40% of predicted (corrected for
             hemoglobin)

          -  Forced vital capacity (FVC) >= 40% of predicted (corrected for hemoglobin)

          -  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. R-CHOP, 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 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; 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

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

Primary Outcome Measures

Measure:24-month progression-free survival (PFS), defined as the proportion of patients who are alive and progression-free 2 years from randomization
Time Frame:At 24 months
Safety Issue:
Description:Will be assessed using the Lugano classification.

Secondary Outcome Measures

Measure:Incidence of hematologic toxicity of ibrutinib therapy
Time Frame:Up to 60 months
Safety Issue:
Description:Hematologic toxicity will be summarized using contingency tables.
Measure:Incidence of secondary malignancies
Time Frame:Up to 60 months
Safety Issue:
Description:Incidence of secondary malignancies will be summarized using contingency tables.
Measure:Overall survival (OS)
Time Frame:The time between randomization and death from any cause, assessed up to 5 years (60 months)
Safety Issue:
Description: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.
Measure:PFS
Time Frame:Time between registration and disease progression or death, whichever comes first, assessed up to 5 years (60 months)
Safety Issue:
Description: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.
Measure:Response rate using the Lugano classification
Time Frame:Up to 60 months
Safety Issue:
Description:The metabolic response proportion following AutoHCT will be compared between the two arms using chi-squared test.
Measure:Time to hematopoietic engraftment
Time Frame:First day of one week without platelet transfusion, assessed up to 5 years
Safety Issue:
Description:Will be defined as platelet count greater than or equal to 20,000/uL following nadir.
Measure:Treatment-related mortality
Time Frame:Up to 60 months
Safety Issue:
Description:Treatment-related mortality will be summarized using contingency tables.

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

Last Updated

September 13, 2017