Skip to Main Content
Phase III

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

  • Study HIC#:2000020994
  • Last Updated:11/11/2022

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.

  • Start Date11/29/2017
  • End Date10/07/2022

Trial Purpose and Description


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


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.

Eligibility Criteria

Inclusion Criteria:

  • 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
  • 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

For more information about this study, contact: