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

Recurrent Diffuse Large B-Cell Lymphoma Activated B-Cell Type Clinical Trial

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 Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02443077
• Other study ID #: NCI-2015-00668
• Secondary ID: NCI-2015-00668BM
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: October 12, 2016
• Est. completion date: May 10, 2025

Study information

• Verified date: May 2024
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Description:

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 302
• Est. completion date: May 10, 2025
• Est. primary completion date: May 10, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Lymphoma
• Lymphoma, B-Cell
• Lymphoma, Large B-Cell, Diffuse
• Recurrent Diffuse Large B-Cell Lymphoma Activated B-Cell Type
• Refractory Diffuse Large B-Cell Lymphoma Activated B-Cell Type

Intervention

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

Drug:
• Carmustine
Given IV
• Cyclophosphamide
Given IV
• Cytarabine
Given IV
• Etoposide
Given IV
• Ibrutinib
Given PO

Other:
• Laboratory Biomarker Analysis
Correlative studies

Drug:
• Melphalan
Given IV

Other:
• Pharmacogenomic Study
Correlative studies
• Placebo Administration
Given PO

Locations

Country	Name	City	State
Saudi Arabia	King Faisal Specialist Hospital and Research Centre	Riyadh
United States	Providence Regional Cancer System-Aberdeen	Aberdeen	Washington
United States	American Fork Hospital / Huntsman Intermountain Cancer Center	American Fork	Utah
United States	Community Hospital of Anaconda	Anaconda	Montana
United States	Cancer Care Center at Island Hospital	Anacortes	Washington
United States	Alaska Breast Care and Surgery LLC	Anchorage	Alaska
United States	Alaska Oncology and Hematology LLC	Anchorage	Alaska
United States	Alaska Women's Cancer Care	Anchorage	Alaska
United States	Anchorage Associates in Radiation Medicine	Anchorage	Alaska
United States	Anchorage Oncology Centre	Anchorage	Alaska
United States	Anchorage Radiation Therapy Center	Anchorage	Alaska
United States	Katmai Oncology Group	Anchorage	Alaska
United States	Providence Alaska Medical Center	Anchorage	Alaska
United States	University of Michigan Comprehensive Cancer Center	Ann Arbor	Michigan
United States	Emory University Hospital/Winship Cancer Institute	Atlanta	Georgia
United States	Northside Hospital	Atlanta	Georgia
United States	Augusta University Medical Center	Augusta	Georgia
United States	Rocky Mountain Cancer Centers-Aurora	Aurora	Colorado
United States	The Medical Center of Aurora	Aurora	Colorado
United States	UCHealth University of Colorado Hospital	Aurora	Colorado
United States	Johns Hopkins University/Sidney Kimmel Cancer Center	Baltimore	Maryland
United States	Baton Rouge General Medical Center	Baton Rouge	Louisiana
United States	Hematology/Oncology Clinic PLLC	Baton Rouge	Louisiana
United States	Bronson Battle Creek	Battle Creek	Michigan
United States	Nebraska Medicine-Bellevue	Bellevue	Nebraska
United States	PeaceHealth Saint Joseph Medical Center	Bellingham	Washington
United States	Saint Charles Health System	Bend	Oregon
United States	Billings Clinic Cancer Center	Billings	Montana
United States	Saint Vincent Frontier Cancer Center	Billings	Montana
United States	Saint Vincent Healthcare	Billings	Montana
United States	Prisma Health Cancer Institute - Spartanburg	Boiling Springs	South Carolina
United States	Saint Alphonsus Cancer Care Center-Boise	Boise	Idaho
United States	Saint Luke's Cancer Institute - Boise	Boise	Idaho
United States	Boulder Community Foothills Hospital	Boulder	Colorado
United States	Boulder Community Hospital	Boulder	Colorado
United States	Rocky Mountain Cancer Centers-Boulder	Boulder	Colorado
United States	Bozeman Health Deaconess Hospital	Bozeman	Montana
United States	Children's Hospital at Montefiore	Bronx	New York
United States	Montefiore Medical Center - Moses Campus	Bronx	New York
United States	Montefiore Medical Center-Einstein Campus	Bronx	New York
United States	Montefiore Medical Center-Weiler Hospital	Bronx	New York
United States	Roswell Park Cancer Institute	Buffalo	New York
United States	Providence Saint Joseph Medical Center/Disney Family Cancer Center	Burbank	California
United States	Aurora Cancer Care-Southern Lakes VLCC	Burlington	Wisconsin
United States	Saint Alphonsus Cancer Care Center-Caldwell	Caldwell	Idaho
United States	Sandra L Maxwell Cancer Center	Cedar City	Utah
United States	Providence Regional Cancer System-Centralia	Centralia	Washington
United States	Christiana Care Health System-Concord Health Center	Chadds Ford	Pennsylvania
United States	Cancer Center of Kansas - Chanute	Chanute	Kansas
United States	UNC Lineberger Comprehensive Cancer Center	Chapel Hill	North Carolina
United States	Medical University of South Carolina	Charleston	South Carolina
United States	University of Virginia Cancer Center	Charlottesville	Virginia
United States	Cheyenne Regional Medical Center-West	Cheyenne	Wyoming
United States	Northwestern University	Chicago	Illinois
United States	Rush University Medical Center	Chicago	Illinois
United States	University of Chicago Comprehensive Cancer Center	Chicago	Illinois
United States	University of Illinois	Chicago	Illinois
United States	Marshfield Clinic-Chippewa Center	Chippewa Falls	Wisconsin
United States	University of Cincinnati Cancer Center-UC Medical Center	Cincinnati	Ohio
United States	Clackamas Radiation Oncology Center	Clackamas	Oregon
United States	Providence Cancer Institute Clackamas Clinic	Clackamas	Oregon
United States	Case Western Reserve University	Cleveland	Ohio
United States	Cleveland Clinic Foundation	Cleveland	Ohio
United States	Prisma Health Cancer Institute - Laurens	Clinton	South Carolina
United States	Billings Clinic-Cody	Cody	Wyoming
United States	Kootenai Health - Coeur d'Alene	Coeur d'Alene	Idaho
United States	UCHealth Memorial Hospital Central	Colorado Springs	Colorado
United States	Ohio State University Comprehensive Cancer Center	Columbus	Ohio
United States	Bay Area Hospital	Coos Bay	Oregon
United States	Siteman Cancer Center at West County Hospital	Creve Coeur	Missouri
United States	Geisinger Medical Center	Danville	Pennsylvania
United States	UM Sylvester Comprehensive Cancer Center at Deerfield Beach	Deerfield Beach	Florida
United States	Colorado Blood Cancer Institute	Denver	Colorado
United States	Denver Health Medical Center	Denver	Colorado
United States	National Jewish Health-Main Campus	Denver	Colorado
United States	Presbyterian - Saint Lukes Medical Center - Health One	Denver	Colorado
United States	Rocky Mountain Cancer Centers-Midtown	Denver	Colorado
United States	Rocky Mountain Cancer Centers-Rose	Denver	Colorado
United States	SCL Health Saint Joseph Hospital	Denver	Colorado
United States	The Women's Imaging Center	Denver	Colorado
United States	Wayne State University/Karmanos Cancer Institute	Detroit	Michigan
United States	Cancer Center of Kansas - Dodge City	Dodge City	Kansas
United States	City of Hope Comprehensive Cancer Center	Duarte	California
United States	Duke University Medical Center	Durham	North Carolina
United States	Prisma Health Cancer Institute - Easley	Easley	South Carolina
United States	Marshfield Clinic Cancer Center at Sacred Heart	Eau Claire	Wisconsin
United States	Marshfield Medical Center-EC Cancer Center	Eau Claire	Wisconsin
United States	Swedish Cancer Institute-Edmonds	Edmonds	Washington
United States	Cancer Center of Kansas - El Dorado	El Dorado	Kansas
United States	Mountain Blue Cancer Care Center - Swedish	Englewood	Colorado
United States	Swedish Medical Center	Englewood	Colorado
United States	Providence Regional Cancer Partnership	Everett	Washington
United States	Fairbanks Memorial Hospital	Fairbanks	Alaska
United States	Farmington Health Center	Farmington	Utah
United States	Simonds-Sinon Regional Cancer Center	Fitchburg	Massachusetts
United States	Aurora Health Center-Fond du Lac	Fond Du Lac	Wisconsin
United States	Poudre Valley Hospital	Fort Collins	Colorado
United States	Cancer Center of Kansas - Fort Scott	Fort Scott	Kansas
United States	Vanderbilt-Ingram Cancer Center Cool Springs	Franklin	Tennessee
United States	Saint Luke's Cancer Institute - Fruitland	Fruitland	Idaho
United States	University of Florida Health Science Center - Gainesville	Gainesville	Florida
United States	Aurora Health Care Germantown Health Center	Germantown	Wisconsin
United States	National Jewish Health-Western Hematology Oncology	Golden	Colorado
United States	Aurora Cancer Care-Grafton	Grafton	Wisconsin
United States	Grand Valley Oncology	Grand Junction	Colorado
United States	Saint Mary's Hospital and Regional Medical Center	Grand Junction	Colorado
United States	Corewell Health Grand Rapids Hospitals - Butterworth Hospital	Grand Rapids	Michigan
United States	Trinity Health Grand Rapids Hospital	Grand Rapids	Michigan
United States	Benefis Sletten Cancer Institute	Great Falls	Montana
United States	Great Falls Clinic	Great Falls	Montana
United States	Banner North Colorado Medical Center	Greeley	Colorado
United States	Aurora BayCare Medical Center	Green Bay	Wisconsin
United States	Prisma Health Cancer Institute - Butternut	Greenville	South Carolina
United States	Prisma Health Cancer Institute - Eastside	Greenville	South Carolina
United States	Prisma Health Cancer Institute - Faris	Greenville	South Carolina
United States	Prisma Health Greenville Memorial Hospital	Greenville	South Carolina
United States	Saint Francis Cancer Center	Greenville	South Carolina
United States	Saint Francis Hospital	Greenville	South Carolina
United States	Prisma Health Cancer Institute - Greer	Greer	South Carolina
United States	Geisinger Medical Center-Cancer Center Hazleton	Hazleton	Pennsylvania
United States	Saint Peter's Community Hospital	Helena	Montana
United States	Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center	Houston	Texas
United States	Cancer Center of Kansas-Independence	Independence	Kansas
United States	Swedish Cancer Institute-Issaquah	Issaquah	Washington
United States	Ascension Borgess Cancer Center	Kalamazoo	Michigan
United States	Borgess Medical Center	Kalamazoo	Michigan
United States	Bronson Methodist Hospital	Kalamazoo	Michigan
United States	West Michigan Cancer Center	Kalamazoo	Michigan
United States	Kalispell Regional Medical Center	Kalispell	Montana
United States	University of Kansas Cancer Center	Kansas City	Kansas
United States	Kadlec Clinic Hematology and Oncology	Kennewick	Washington
United States	Aurora Cancer Care-Kenosha South	Kenosha	Wisconsin
United States	Cancer Center of Kansas-Kingman	Kingman	Kansas
United States	UC San Diego Moores Cancer Center	La Jolla	California
United States	Providence Regional Cancer System-Lacey	Lacey	Washington
United States	Marshfield Medical Center - Ladysmith	Ladysmith	Wisconsin
United States	Good Samaritan Medical Center	Lafayette	Colorado
United States	Lawrence Memorial Hospital	Lawrence	Kansas
United States	Dartmouth Hitchcock Medical Center/Dartmouth Cancer Center	Lebanon	New Hampshire
United States	Beebe Medical Center	Lewes	Delaware
United States	Geisinger Medical Oncology-Lewisburg	Lewisburg	Pennsylvania
United States	Lewistown Hospital	Lewistown	Pennsylvania
United States	Cancer Center of Kansas-Liberal	Liberal	Kansas
United States	Rocky Mountain Cancer Centers-Littleton	Littleton	Colorado
United States	Logan Regional Hospital	Logan	Utah
United States	Loma Linda University Medical Center	Loma Linda	California
United States	Rocky Mountain Cancer Centers-Sky Ridge	Lone Tree	Colorado
United States	PeaceHealth Saint John Medical Center	Longview	Washington
United States	Cedars Sinai Medical Center	Los Angeles	California
United States	The James Graham Brown Cancer Center at University of Louisville	Louisville	Kentucky
United States	Banner McKee Medical Center	Loveland	Colorado
United States	University of Wisconsin Carbone Cancer Center - University Hospital	Madison	Wisconsin
United States	Cancer Center of Kansas-Manhattan	Manhattan	Kansas
United States	Aurora Bay Area Medical Group-Marinette	Marinette	Wisconsin
United States	Marshfield Medical Center	Marshfield	Wisconsin
United States	Marshfield Medical Center-Marshfield	Marshfield	Wisconsin
United States	Loyola University Medical Center	Maywood	Illinois
United States	Cancer Center of Kansas - McPherson	McPherson	Kansas
United States	Baptist Memorial Hospital and Cancer Center-Memphis	Memphis	Tennessee
United States	Saint Luke's Cancer Institute - Meridian	Meridian	Idaho
United States	University of Miami Miller School of Medicine-Sylvester Cancer Center	Miami	Florida
United States	Aurora Cancer Care-Milwaukee	Milwaukee	Wisconsin
United States	Aurora Saint Luke's Medical Center	Milwaukee	Wisconsin
United States	Aurora Sinai Medical Center	Milwaukee	Wisconsin
United States	Medical College of Wisconsin	Milwaukee	Wisconsin
United States	University of Minnesota/Masonic Cancer Center	Minneapolis	Minnesota
United States	Marshfield Clinic-Minocqua Center	Minocqua	Wisconsin
United States	Community Medical Center	Missoula	Montana
United States	Saint Patrick Hospital - Community Hospital	Missoula	Montana
United States	Intermountain Medical Center	Murray	Utah
United States	Trinity Health Muskegon Hospital	Muskegon	Michigan
United States	Saint Alphonsus Cancer Care Center-Nampa	Nampa	Idaho
United States	Saint Luke's Cancer Institute - Nampa	Nampa	Idaho
United States	Vanderbilt Breast Center at One Hundred Oaks	Nashville	Tennessee
United States	Vanderbilt University/Ingram Cancer Center	Nashville	Tennessee
United States	Smilow Cancer Center/Yale-New Haven Hospital	New Haven	Connecticut
United States	Yale University	New Haven	Connecticut
United States	UC Comprehensive Cancer Center at Silver Cross	New Lenox	Illinois
United States	Ochsner Medical Center Jefferson	New Orleans	Louisiana
United States	Tulane University School of Medicine	New Orleans	Louisiana
United States	NYP/Weill Cornell Medical Center	New York	New York
United States	Christiana Care Health System-Christiana Hospital	Newark	Delaware
United States	Delaware Clinical and Laboratory Physicians PA	Newark	Delaware
United States	Helen F Graham Cancer Center	Newark	Delaware
United States	Medical Oncology Hematology Consultants PA	Newark	Delaware
United States	Providence Newberg Medical Center	Newberg	Oregon
United States	Cancer Center of Kansas - Newton	Newton	Kansas
United States	Corewell Health Lakeland Hospitals - Niles Hospital	Niles	Michigan
United States	Cancer and Hematology Centers of Western Michigan - Norton Shores	Norton Shores	Michigan
United States	McKay-Dee Hospital Center	Ogden	Utah
United States	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma
United States	Nebraska Medicine-Village Pointe	Omaha	Nebraska
United States	University of Nebraska Medical Center	Omaha	Nebraska
United States	Saint Alphonsus Cancer Care Center-Ontario	Ontario	Oregon
United States	UC Irvine Health/Chao Family Comprehensive Cancer Center	Orange	California
United States	Providence Willamette Falls Medical Center	Oregon City	Oregon
United States	Vince Lombardi Cancer Clinic - Oshkosh	Oshkosh	Wisconsin
United States	Upstate Cancer Center at Oswego	Oswego	New York
United States	Cancer Center of Kansas - Parsons	Parsons	Kansas
United States	Fox Chase Cancer Center	Philadelphia	Pennsylvania
United States	University of Pittsburgh Cancer Institute (UPCI)	Pittsburgh	Pennsylvania
United States	UM Sylvester Comprehensive Cancer Center at Plantation	Plantation	Florida
United States	Legacy Good Samaritan Hospital and Medical Center	Portland	Oregon
United States	Oregon Health and Science University	Portland	Oregon
United States	Providence Portland Medical Center	Portland	Oregon
United States	Providence Saint Vincent Medical Center	Portland	Oregon
United States	Kootenai Clinic Cancer Services - Post Falls	Post Falls	Idaho
United States	Geisinger Cancer Services-Pottsville	Pottsville	Pennsylvania
United States	Cancer Center of Kansas - Pratt	Pratt	Kansas
United States	Utah Valley Regional Medical Center	Provo	Utah
United States	Aurora Cancer Care-Racine	Racine	Wisconsin
United States	Corewell Health Reed City Hospital	Reed City	Michigan
United States	Beebe Health Campus	Rehoboth Beach	Delaware
United States	Marshfield Medical Center-Rice Lake	Rice Lake	Wisconsin
United States	Virginia Commonwealth University/Massey Cancer Center	Richmond	Virginia
United States	Riverton Hospital	Riverton	Utah
United States	Mayo Clinic in Rochester	Rochester	Minnesota
United States	University of Rochester	Rochester	New York
United States	University of California Davis Comprehensive Cancer Center	Sacramento	California
United States	Saint George Regional Medical Center	Saint George	Utah
United States	Corewell Health Lakeland Hospitals - Marie Yeager Cancer Center	Saint Joseph	Michigan
United States	Corewell Health Lakeland Hospitals - Saint Joseph Hospital	Saint Joseph	Michigan
United States	Siteman Cancer Center-South County	Saint Louis	Missouri
United States	SSM Health Saint Louis University Hospital	Saint Louis	Missouri
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	Cancer Center of Kansas - Salina	Salina	Kansas
United States	Huntsman Cancer Institute/University of Utah	Salt Lake City	Utah
United States	LDS Hospital	Salt Lake City	Utah
United States	Utah Cancer Specialists-Salt Lake City	Salt Lake City	Utah
United States	UCSF Medical Center-Parnassus	San Francisco	California
United States	Kootenai Clinic Cancer Services - Sandpoint	Sandpoint	Idaho
United States	Community Medical Center	Scranton	Pennsylvania
United States	TidalHealth Nanticoke / Allen Cancer Center	Seaford	Delaware
United States	FHCC South Lake Union	Seattle	Washington
United States	Fred Hutchinson Cancer Center	Seattle	Washington
United States	Kaiser Permanente Washington	Seattle	Washington
United States	Pacific Gynecology Specialists	Seattle	Washington
United States	Swedish Medical Center-Ballard Campus	Seattle	Washington
United States	Swedish Medical Center-Cherry Hill	Seattle	Washington
United States	Swedish Medical Center-First Hill	Seattle	Washington
United States	University of Washington Medical Center - Montlake	Seattle	Washington
United States	Geisinger Medical Oncology-Selinsgrove	Selinsgrove	Pennsylvania
United States	Prisma Health Cancer Institute - Seneca	Seneca	South Carolina
United States	Vince Lombardi Cancer Clinic-Sheboygan	Sheboygan	Wisconsin
United States	Providence Regional Cancer System-Shelton	Shelton	Washington
United States	LSU Health Sciences Center at Shreveport	Shreveport	Louisiana
United States	Avera Cancer Institute	Sioux Falls	South Dakota
United States	South Jordan Health Center	South Jordan	Utah
United States	MultiCare Deaconess Cancer and Blood Specialty Center - Downtown	Spokane	Washington
United States	MultiCare Deaconess Cancer and Blood Specialty Center - North	Spokane	Washington
United States	MultiCare Deaconess Cancer and Blood Specialty Center - Valley	Spokane Valley	Washington
United States	Geisinger Medical Group	State College	Pennsylvania
United States	Marshfield Medical Center-River Region at Stevens Point	Stevens Point	Wisconsin
United States	Aurora Medical Center in Summit	Summit	Wisconsin
United States	State University of New York Upstate Medical University	Syracuse	New York
United States	Moffitt Cancer Center	Tampa	Florida
United States	Munson Medical Center	Traverse City	Michigan
United States	Banner University Medical Center - Tucson	Tucson	Arizona
United States	University of Arizona Cancer Center-North Campus	Tucson	Arizona
United States	Saint Luke's Cancer Institute - Twin Falls	Twin Falls	Idaho
United States	Vince Lombardi Cancer Clinic-Two Rivers	Two Rivers	Wisconsin
United States	PeaceHealth Southwest Medical Center	Vancouver	Washington
United States	Providence Saint Mary Regional Cancer Center	Walla Walla	Washington
United States	Marshfield Clinic-Wausau Center	Wausau	Wisconsin
United States	Aurora Cancer Care-Milwaukee West	Wauwatosa	Wisconsin
United States	Cancer Center of Kansas - Wellington	Wellington	Kansas
United States	Aurora West Allis Medical Center	West Allis	Wisconsin
United States	University of Cincinnati Cancer Center-West Chester	West Chester	Ohio
United States	Marshfield Medical Center - Weston	Weston	Wisconsin
United States	University of Kansas Hospital-Westwood Cancer Center	Westwood	Kansas
United States	SCL Health Lutheran Medical Center	Wheat Ridge	Colorado
United States	Ascension Via Christi Hospitals Wichita	Wichita	Kansas
United States	Associates In Womens Health	Wichita	Kansas
United States	Cancer Center of Kansas - Wichita	Wichita	Kansas
United States	Cancer Center of Kansas-Wichita Medical Arts Tower	Wichita	Kansas
United States	Geisinger Wyoming Valley/Henry Cancer Center	Wilkes-Barre	Pennsylvania
United States	Christiana Care Health System-Wilmington Hospital	Wilmington	Delaware
United States	Cancer Center of Kansas - Winfield	Winfield	Kansas
United States	Wake Forest University Health Sciences	Winston-Salem	North Carolina
United States	Marshfield Clinic - Wisconsin Rapids Center	Wisconsin Rapids	Wisconsin
United States	UMass Memorial Medical Center - University Campus	Worcester	Massachusetts
United States	University of Michigan Health - West	Wyoming	Michigan
United States	Providence Regional Cancer System-Yelm	Yelm	Washington

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Countries where clinical trial is conducted

United States,  Saudi Arabia, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Fludeoxyglucose positron emission tomography (FDG-PET) imaging results	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.	Baseline
Other	GSTT1 null allele expression	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.	Baseline
Other	Single-nuclear polymorphisms (SNPs) in the BCNU metabolism or damage repair pathways	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.	Baseline
Other	BCR pathway mutations	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.	Baseline
Other	BCL2, MYC, and Ki67 expression in tissue samples by immunohistochemistry (IHC)	The expression of BCL2, MYC, and Ki67 will be analyzed to assess whether they affect clinical outcomes.	Baseline
Other	MYC translocations	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.	Baseline
Primary	24-month progression-free survival (PFS), defined as the proportion of patients who are alive and progression-free 2 years from randomization	Will be assessed using the Lugano classification.	Time between registration and disease progression or death, whichever comes first, assessed at 24 months
Secondary	Overall survival (OS)	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.	The time between randomization and death from any cause, assessed up to 5 years (60 months)
Secondary	Time to hematopoietic engraftment	Will be defined as platelet count greater than or equal to 20,000/uL following nadir.	First day of one week without platelet transfusion, assessed up to 5 years
Secondary	PFS	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.	Time between registration and disease progression or death, whichever comes first, assessed up to 5 years (60 months)
Secondary	Response rate using the Lugano classification	The metabolic response proportion following AutoHCT will be compared between the two arms using chi-squared test.	Up to 60 months
Secondary	Treatment-related mortality	Treatment-related mortality will be summarized using contingency tables.	Up to 60 months
Secondary	Incidence of hematologic toxicity of ibrutinib therapy	Hematologic toxicity will be summarized using contingency tables.	Up to 60 months
Secondary	Incidence of secondary malignancies	Incidence of secondary malignancies will be summarized using contingency tables.	Up to 60 months