PRIMARY OBJECTIVE:
I. To evaluate the ability of ibrutinib to improve 24-month progression free survival (PFS)
compared to placebo in patients with non-germinal center B-cell-like (GCB) diffuse large
B-cell lymphoma (DLBCL) as determined by immunohistochemistry (IHC).
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.
CORRELATIVE SCIENCE 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 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 DLBCL subtype based on the lymphoma subtyping test (LST) is associated
with 24-month PFS, PFS, and OS with ibrutinib compared to placebo in patients treated on this
protocol.
VIII. To assess whether activating mutations in the BCR pathway are associated with response
to ibrutinib and with clinical outcomes in patients treated on this protocol.
IX. To assess whether there are any phenotypic associations with IHC markers (particularly
MYC protein expression level) and presence of these mutations.
X. To assess whether BCL2, MYC, and Ki67 expression by IHC affect clinical outcomes in
patients treated on this protocol.
XI. 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. Optionally,
if a day of rest is planned, patients may receive BEAMi on days -7 to -2.
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. Optionally, if a day
of rest is planned, patients may receive CBVi on days -7 to -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 30-60 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.
ARM II: 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.
After completion of treatment, patients are followed up every 6 months for up to 60 months
from registration.