AzTrials
AzTrials

AnemiaPhase 3NCT02048813

Ibrutinib and Rituximab Compared With Fludarabine Phosphate, Cyclophosphamide, and Rituximab in Treating Patients With Untreated Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

A Phase 3 study testing Cyclophosphamide, Fludarabine Phosphate and Ibrutinib in people with Anemia and Chronic Lymphocytic Leukemia, run by National Cancer Institute (NCI) at 781 sites in United States.

Active, not recruiting

Under way, not looking for participants. Everyone needed has enrolled. The study is still running.

Official record

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Trial summary

This phase III trial studies ibrutinib and rituximab to see how well they work compared to fludarabine phosphate, cyclophosphamide, and rituximab in treating patients with untreated chronic lymphocytic leukemia or small lymphocytic lymphoma. Read more about this study

Who is it for?
Ages 18 to 70 years
What is being tested?
Cyclophosphamide, Fludarabine Phosphate and Ibrutinib
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
529 participants
Where
781 sitesUnited States
Study dates
10 Mar 2014to 9 Oct 2026
Phase
Phase 3

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 70 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Diagnosis of CLL according to the National Cancer Institute (NCI)/Internal Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria or small lymphocytic lymphoma (SLL) according to the World Health Organization (WHO) criteria; this includes previous documentation of:
  • Biopsy-proven small lymphocytic lymphoma or
  • Diagnosis of CLL according to the NCI/IWCLL criteria as evidenced by all of the following:
  • Peripheral blood lymphocyte count of greater than 5 x 10^9/L
  • Immunophenotype consistent with CLL defined as:
  • The predominant population of lymphocytes share both B-cell antigens (cluster of differentiation [CD]19, CD20 [typically dim expression], or CD23) as well as CD5 in the absence of other pan-T-cell markers (CD3, CD2, etc)
Show all 65Show fewer
  • Clonality as evidenced by kappa or lambda light chain restriction (typically dim immunoglobulin expression)
  • Negative FISH analysis for t(11;14)(immunoglobulin heavy locus [IgH]/cyclin D1 [CCND1]) on peripheral blood or tissue biopsy (e.g. marrow aspirate) or negative immunohistochemical stains for cyclin D1 staining on involved tissue biopsy (e.g. marrow aspirate or lymph node biopsy)
  • No prior chemotherapy, Bruton's tyrosine kinase (BTK) inhibitor therapy, or monoclonal anti-body therapy for treatment of CLL or SLL
  • Has met at least one of the following indications for treatment:
  • Evidence of progressive marrow failure as manifested by the development of worsening anemia (hemoglobin [Hg] < 11 g/dl) and/or thrombocytopenia (platelets < 100 x 10^9/L)
  • Symptomatic or progressive lymphadenopathy, splenomegaly, or hepatomegaly
  • One or more of the following disease-related symptoms:
  • Weight loss >= 10% within the previous 6 months
  • Grade 2 or 3 fatigue attributed to CLL
  • Fevers > 100.5 Fahrenheit (F) for 2 weeks without evidence of infection
  • Clinically significant night sweats without evidence of infection
  • Progressive lymphocytosis (not due to the effects of corticosteroids) with an increase of > 50% over a two-month period or an anticipated doubling time of less than six months
  • Age ≥ 18 years and ≤ 70
  • ECOG performance status between 0-2
  • Life expectancy of >= 12 months
  • Ability to tolerate FCR based therapy
  • No deletion of 17p13 on cytogenetic analysis by FISH
  • Glomerular filtration rate (GFR) > 40 mL/minute as calculated by the Cockcroft-Gault formula (obtained =< 14 days prior to registration)
  • Total bilirubin =< 2.5 x upper limit of normal (ULN) (obtained =< 14 days prior to registration) unless due to Gilbert's disease; for those with a total bilirubin > 2.5 x ULN, a direct bilirubin should be performed and must be < 1.5 mg/dL for Gilbert's to be diagnosed
  • If value is higher due to hepatic involvement by CLL, patient is eligible
  • Serum glutamic oxaloacetic transaminase (SGOT) (aspartate transaminase [AST])/serum glutamate-pyruvate transaminase (SGPT) (alanine transaminase [ALT]) =< 3.0 x the institutional ULN (obtained =< 14 days prior to registration)
  • If value is higher due to hepatic involvement by CLL, patient is eligible
  • Prothrombin time (PT)/international normalized ratio (INR) < 1.5 ULN and partial thromboplastin time (PTT) (activated partial thromboplastin time [aPTT]) < 1.5 X ULN (obtained =< 14 days prior to registration)
  • If value is higher due to hepatic involvement by CLL, patient is eligible
  • No active hemolytic anemia requiring immunosuppressive therapy or other pharmacologic treatment; patients who have a positive Coombs test but no evidence of hemolysis are NOT excluded from participation
  • No current use of corticosteroids; EXCEPTION: low doses of steroids (< 10 mg of prednisone or equivalent dose of other steroid) used for treatment of non-hematologic medical condition (e.g. chronic adrenal insufficiency) is permitted
  • No previous use of corticosteroids for autoimmune complications that have developed since the initial diagnosis of CLL; prior use of corticosteroids for reasons other than treatment of autoimmune complications is allowed
  • No other active primary malignancy (other than non-melanomatous skin cancer or carcinoma in situ of the cervix) requiring treatment or limiting expected survival to =< 2 years; NOTE: if there is a history of prior malignancy, they must not be receiving other specific treatment (other than hormonal therapy for their cancer)
  • Able to adhere to the study visit schedule and other protocol requirements
  • No major surgery within the last 4 weeks (28 days) of first dose of study drug or minor surgery within 3 days of first dose of study drug
  • No radiation therapy =< 4 weeks prior to registration
  • Patients with human immunodeficiency virus (HIV) infection may be eligible provided they meet the following criteria:
  • CD4-positive cell count >= lower limit of institutional normal
  • HIV viral load < 10,000 copies HIV ribonucleic acid (RNA)/mL (if not on anti-HIV therapy) OR < 50 copies HIV RNA/mL (if on anti-HIV therapy)
  • No evidence of hepatitis B or C infection
  • No evidence of resistant strains of HIV
  • No history of acquired immune deficiency syndrome (AIDS)-defining condition
  • Patients must not have any of the following conditions:
  • Congestive heart failure or New York Heart Association Functional Classification III or IV congestive heart failure
  • History of myocardial infarction, unstable angina, or acute coronary syndrome within 6 months prior to registration
  • Recent infections requiring systemic treatment; need to have completed anti-biotic therapy > 14 days before the first dose of study drug
  • Cerebral vascular accident or intracranial bleed within the last 6 months
  • Infection with known chronic, active hepatitis C
  • 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)
  • Patients are not eligible if they require treatment with a strong cytochrome P450 (CYP) family 3, subfamily A (3A) inhibitor
  • Patients may not be on any other investigational agents
  • Patients may not have received warfarin or another vitamin K antagonist in the preceding 30 days
  • Women must not be pregnant or breast-feeding since this study involves an investigational agent whose genotoxic, mutagenic, and teratogenic effects on the developing fetus and newborn are unknown; female patients of childbearing potential must have a negative serum pregnancy test within 2 weeks prior to registration to rule out pregnancy; female patients who are of non-reproductive potential are those who are post-menopausal by history (i.e. no menses for >= 1 year); OR history of hysterectomy; OR history of bilateral tubal ligation; OR history of bilateral oophorectomy)
  • Women of childbearing potential and sexually active males must be strongly advised to use an accepted and effective method of contraception or to abstain from sexual intercourse for 90 days after the last dose of study drug
  • Patient must be able to swallow capsules and not have the following conditions:
  • Disease significantly affecting gastrointestinal function
  • Resection of the stomach or small bowel
  • Symptomatic inflammatory bowel disease
  • Ulcerative colitis
  • Partial or complete bowel obstruction
  • Patient must not be on any other systemic immunosuppressant therapy other than corticosteroids within 28 days of the first dose of study drug
  • Patient must not be vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug
  • Patient must not have any known bleeding disorders (e.g., von Willebrand's disease) or hemophilia
  • Patient must not have currently active, clinically significant hepatic impairment (>= moderate hepatic impairment according to the NCI/Child Pugh)

Who cannot join

None listed.

Trial locations and contacts

781 sites in 1 country.

300 sites in 1 country

United States300 sites

  • Providence Regional Cancer System-Aberdeen

    Aberdeen, Washington, 98520

  • Bixby Medical Center

    Adrian, Michigan, 49221

  • Hickman Cancer Center

    Adrian, Michigan, 49221

  • Cleveland Clinic Akron General

    Akron, Ohio, 44307

  • Phoebe Putney Memorial Hospital

    Albany, Georgia, 31701

  • New York Oncology Hematology PC - Albany Medical Center

    Albany, New York, 12208

  • University of New Mexico Cancer Center

    Albuquerque, New Mexico, 87106

  • Lehigh Valley Hospital-Cedar Crest

    Allentown, Pennsylvania, 18103

  • The Don and Sybil Harrington Cancer Center

    Amarillo, Texas, 79106

  • Mary Greeley Medical Center

    Ames, Iowa, 50010

  • McFarland Clinic - Ames

    Ames, Iowa, 50010

  • Community Hospital of Anaconda

    Anaconda, Montana, 59711

  • Cancer Care Center at Island Hospital

    Anacortes, Washington, 98221

  • Kaiser Permanente-Anaheim

    Anaheim, California, 92806

  • Anchorage Associates in Radiation Medicine

    Anchorage, Alaska, 98508

  • Anchorage Radiation Therapy Center

    Anchorage, Alaska, 99504

  • Alaska Breast Care and Surgery LLC

    Anchorage, Alaska, 99508

  • Alaska Oncology and Hematology LLC

    Anchorage, Alaska, 99508

  • Alaska Regional Hospital

    Anchorage, Alaska, 99508

  • Alaska Women's Cancer Care

    Anchorage, Alaska, 99508

  • Anchorage Oncology Centre

    Anchorage, Alaska, 99508

  • Katmai Oncology Group

    Anchorage, Alaska, 99508

  • Providence Alaska Medical Center

    Anchorage, Alaska, 99508

  • Ascension Saint Vincent Anderson

    Anderson, Indiana, 46016

  • Michigan Cancer Research Consortium NCORP

    Ann Arbor, Michigan, 48106

  • Trinity Health Saint Joseph Mercy Hospital Ann Arbor

    Ann Arbor, Michigan, 48106

  • Aspirus Cancer Care-Antigo-Volm Cancer Center

    Antigo, Wisconsin, 54409

  • Kaiser Permanente-Deer Valley Medical Center

    Antioch, California, 94531

  • PCR Oncology

    Arroyo Grande, California, 93420

  • Mission Hospital

    Asheville, North Carolina, 28801

  • AdventHealth Infusion Center Asheville

    Asheville, North Carolina, 28803

  • Messino Cancer Centers

    Asheville, North Carolina, 28806

  • Emory University Hospital/Winship Cancer Institute

    Atlanta, Georgia, 30322

  • Sutter Auburn Faith Hospital

    Auburn, California, 95602

  • Sutter Cancer Centers Radiation Oncology Services-Auburn

    Auburn, California, 95603

  • Hematology Oncology Associates of Central New York-Auburn

    Auburn, New York, 13021

  • MultiCare Auburn Medical Center

    Auburn, Washington, 98001

  • Harold Alfond Center for Cancer Care

    Augusta, Maine, 04330

  • Rocky Mountain Cancer Centers-Aurora

    Aurora, Colorado, 80012

  • The Medical Center of Aurora

    Aurora, Colorado, 80012

  • Rush-Copley Medical Center

    Aurora, Illinois, 60504

  • Virginia Mason Bainbridge Island Medical Center

    Bainbridge Island, Washington, 98110

  • Kaiser Permanente-Baldwin Park

    Baldwin Park, California, 91706

  • University of Maryland/Greenebaum Cancer Center

    Baltimore, Maryland, 21201

  • Saint Agnes Hospital

    Baltimore, Maryland, 21229

  • Eastern Maine Medical Center

    Bangor, Maine, 04401

  • CommonSpirit Saint Joseph Hospital - Bardstown

    Bardstown, Kentucky, 40004

  • Ochsner Health Center-Summa

    Baton Rouge, Louisiana, 70809

  • UHHS-Chagrin Highlands Medical Center

    Beachwood, Ohio, 44122

  • UPMC-Heritage Valley Health System Beaver

    Beaver, Pennsylvania, 15009

  • Overlake Medical Center

    Bellevue, Washington, 98004

  • Swedish Cancer Institute-Eastside Oncology Hematology

    Bellevue, Washington, 98005

  • Kaiser Permanente-Bellflower

    Bellflower, California, 90706

  • PeaceHealth Saint Joseph Medical Center

    Bellingham, Washington, 98225

  • Strecker Cancer Center-Belpre

    Belpre, Ohio, 45714

  • Sanford Joe Lueken Cancer Center

    Bemidji, Minnesota, 56601

  • Saint Charles Health System

    Bend, Oregon, 97701

  • Alta Bates Summit Medical Center-Herrick Campus

    Berkeley, California, 94704

  • Central Vermont Medical Center/National Life Cancer Treatment

    Berlin Corners, Vermont, 05602

  • Lehigh Valley Hospital - Muhlenberg

    Bethlehem, Pennsylvania, 18017

  • Beverly Hospital

    Beverly, Massachusetts, 01915

  • Billings Clinic Cancer Center

    Billings, Montana, 59101

  • Saint Vincent Healthcare

    Billings, Montana, 59101

  • Montana Cancer Consortium NCORP

    Billings, Montana, 59102

  • University of Alabama at Birmingham Cancer Center

    Birmingham, Alabama, 35233

  • Sanford Bismarck Medical Center

    Bismarck, North Dakota, 58501

  • OSF Saint Joseph Medical Center

    Bloomington, Illinois, 61701

  • Illinois CancerCare-Bloomington

    Bloomington, Illinois, 61704

  • Prisma Health Cancer Institute - Spartanburg

    Boiling Springs, South Carolina, 29316

  • Saint Alphonsus Cancer Care Center-Boise

    Boise, Idaho, 83706

  • Saint Luke's Cancer Institute - Boise

    Boise, Idaho, 83712

  • Central Care Cancer Center - Bolivar

    Bolivar, Missouri, 65613

  • Parkland Health Center-Bonne Terre

    Bonne Terre, Missouri, 63628

  • McFarland Clinic - Boone

    Boone, Iowa, 50036

  • Tufts Medical Center

    Boston, Massachusetts, 02111

  • Eastern Cooperative Oncology Group

    Boston, Massachusetts, 02215

  • Boulder Community Foothills Hospital

    Boulder, Colorado, 80303

  • Rocky Mountain Cancer Centers-Boulder

    Boulder, Colorado, 80304

  • Toledo Clinic Cancer Centers-Bowling Green

    Bowling Green, Ohio, 43402

  • Bozeman Health Deaconess Hospital

    Bozeman, Montana, 59715

  • Essentia Health Saint Joseph's Medical Center

    Brainerd, Minnesota, 56401

  • Cox Cancer Center Branson

    Branson, Missouri, 65616

  • Lafayette Family Cancer Center-EMMC

    Brewer, Maine, 04412

  • United Hospital Center

    Bridgeport, West Virginia, 26330

  • Bristol Regional Medical Center

    Bristol, Tennessee, 37620

  • Henry Ford Cancer Institute-Downriver

    Brownstown, Michigan, 48183

  • Bryn Mawr Hospital

    Bryn Mawr, Pennsylvania, 19010

  • Roswell Park Cancer Institute

    Buffalo, New York, 14263

  • Providence Saint Joseph Medical Center/Disney Family Cancer Center

    Burbank, California, 91505

  • Highline Medical Center-Main Campus

    Burien, Washington, 98166

  • Mills-Peninsula Medical Center

    Burlingame, California, 94010

  • Lahey Clinic

    Burlington, Massachusetts, 01805

  • University of Vermont Medical Center

    Burlington, Vermont, 05401

  • University of Vermont and State Agricultural College

    Burlington, Vermont, 05405

  • Aurora Cancer Care-Southern Lakes VLCC

    Burlington, Wisconsin, 53105

  • Fairview Ridges Hospital

    Burnsville, Minnesota, 55337

  • Saint James Community Hospital and Cancer Treatment Center

    Butte, Montana, 59701

  • Sutter Cancer Centers Radiation Oncology Services-Cameron Park

    Cameron Park, California, 95682

  • Hematology Oncology Associates of CNY at Camillus

    Camillus, New York, 13031

  • Illinois CancerCare-Canton

    Canton, Illinois, 61520

  • Mercy Cancer Center - Cape Girardeau

    Cape Girardeau, Missouri, 63703

  • Saint Francis Medical Center

    Cape Girardeau, Missouri, 63703

  • Memorial Hospital of Carbondale

    Carbondale, Illinois, 62902

  • Illinois CancerCare-Carthage

    Carthage, Illinois, 62321

  • Rocky Mountain Oncology

    Casper, Wyoming, 82609

  • Eden Hospital Medical Center

    Castro Valley, California, 94546

  • Dayton Physicians LLC-Miami Valley South

    Centerville, Ohio, 45459

  • Miami Valley Hospital South

    Centerville, Ohio, 45459

  • Centralia Oncology Clinic

    Centralia, Illinois, 62801

  • Providence Regional Cancer System-Centralia

    Centralia, Washington, 98531

  • Christiana Care Health System-Concord Health Center

    Chadds Ford, Pennsylvania, 19317

  • Cancer Center of Kansas - Chanute

    Chanute, Kansas, 66720

  • Geauga Hospital

    Chardon, Ohio, 44024

  • Memorial Hospital

    Chattanooga, Tennessee, 37404

  • Cheyenne Regional Medical Center-West

    Cheyenne, Wyoming, 82001

  • Northwestern University

    Chicago, Illinois, 60611

  • University of Chicago Comprehensive Cancer Center

    Chicago, Illinois, 60637

  • Adventist Health Cancer Care Center Chico

    Chico, California, 95973

  • Adena Regional Medical Center

    Chillicothe, Ohio, 45601

  • Marshfield Clinic-Chippewa Center

    Chippewa Falls, Wisconsin, 54729

  • Oncology Hematology Care Inc-Eden Park

    Cincinnati, Ohio, 45202

  • Oncology Hematology Care Inc-Mercy West

    Cincinnati, Ohio, 45211

  • University of Cincinnati Cancer Center-UC Medical Center

    Cincinnati, Ohio, 45219

  • Good Samaritan Hospital - Cincinnati

    Cincinnati, Ohio, 45220

  • Oncology Hematology Care Inc-Anderson

    Cincinnati, Ohio, 45230

  • Oncology Hematology Care Inc-Kenwood

    Cincinnati, Ohio, 45236

  • Bethesda North Hospital

    Cincinnati, Ohio, 45242

  • Oncology Hematology Care Inc-Blue Ash

    Cincinnati, Ohio, 45242

  • TriHealth Cancer Institute-Westside

    Cincinnati, Ohio, 45247

  • TriHealth Cancer Institute-Anderson

    Cincinnati, Ohio, 45255

  • Siteman Cancer Center at Saint Peters Hospital

    City of Saint Peters, Missouri, 63376

  • Clackamas Radiation Oncology Center

    Clackamas, Oregon, 97015

  • Providence Cancer Institute Clackamas Clinic

    Clackamas, Oregon, 97015

  • Case Western Reserve University

    Cleveland, Ohio, 44106

  • MetroHealth Medical Center

    Cleveland, Ohio, 44109

  • Sampson Radiation Oncology

    Clinton, North Carolina, 28328

  • Southeastern Medical Oncology Center-Clinton

    Clinton, North Carolina, 28328

  • Henry Ford Macomb Hospital-Clinton Township

    Clinton Township, Michigan, 48038

  • Mercy Cancer Center-West Lakes

    Clive, Iowa, 50325

  • UI Health Care Mission Cancer and Blood - West Des Moines Clinic

    Clive, Iowa, 50325

  • Big Horn Basin Cancer Center

    Cody, Wyoming, 82414

  • Billings Clinic-Cody

    Cody, Wyoming, 82414

  • Kootenai Health - Coeur d'Alene

    Coeur d'Alene, Idaho, 83814

  • Penrose-Saint Francis Healthcare

    Colorado Springs, Colorado, 80907

  • Rocky Mountain Cancer Centers-Penrose

    Colorado Springs, Colorado, 80907

  • John B Amos Cancer Center

    Columbus, Georgia, 31904

  • Mount Carmel East Hospital

    Columbus, Ohio, 43213

  • Columbus Oncology and Hematology Associates Inc

    Columbus, Ohio, 43214

  • Riverside Methodist Hospital

    Columbus, Ohio, 43214

  • Columbus NCI Community Oncology Research Program

    Columbus, Ohio, 43215

  • Grant Medical Center

    Columbus, Ohio, 43215

  • The Mark H Zangmeister Center

    Columbus, Ohio, 43219

  • Mount Carmel Health Center West

    Columbus, Ohio, 43222

  • Doctors Hospital

    Columbus, Ohio, 43228

  • John Muir Medical Center-Concord

    Concord, California, 94520

  • Mercy Hospital

    Coon Rapids, Minnesota, 55433

  • Bay Area Hospital

    Coos Bay, Oregon, 97420

  • Commonwealth Cancer Center-Corbin

    Corbin, Kentucky, 40701

  • Alegent Health Mercy Hospital

    Council Bluffs, Iowa, 51503

  • Greater Regional Medical Center

    Creston, Iowa, 50801

  • Oncology Hematology Care Inc-Crestview

    Crestview Hills, Kentucky, 41017

  • Siteman Cancer Center at West County Hospital

    Creve Coeur, Missouri, 63141

  • Parkland Memorial Hospital

    Dallas, Texas, 75235

  • UT Southwestern/Simmons Cancer Center-Dallas

    Dallas, Texas, 75390

  • Carle at The Riverfront

    Danville, Illinois, 61832

  • Geisinger Medical Center

    Danville, Pennsylvania, 17822

  • Danville Regional Medical Center

    Danville, Virginia, 24541

  • Sutter Davis Hospital

    Davis, California, 95616

  • Good Samaritan Hospital - Dayton

    Dayton, Ohio, 45406

  • Miami Valley Hospital

    Dayton, Ohio, 45409

  • Dayton Physician LLC - Englewood

    Dayton, Ohio, 45415

  • Miami Valley Hospital North

    Dayton, Ohio, 45415

  • Dayton Veterans Affairs Medical Center

    Dayton, Ohio, 45428

  • Dayton NCI Community Oncology Research Program

    Dayton, Ohio, 45459

  • Corewell Health Dearborn Hospital

    Dearborn, Michigan, 48124

  • Henry Ford Medical Center-Fairlane

    Dearborn, Michigan, 48126

  • Cancer Care Specialists of Illinois - Decatur

    Decatur, Illinois, 62526

  • Decatur Memorial Hospital

    Decatur, Illinois, 62526

  • Delaware Health Center-Grady Cancer Center

    Delaware, Ohio, 43015

  • Delaware Radiation Oncology

    Delaware, Ohio, 43015

  • Grady Memorial Hospital

    Delaware, Ohio, 43015

  • Denver Health Medical Center

    Denver, Colorado, 80204

  • Kaiser Permanente-Franklin

    Denver, Colorado, 80205

  • National Jewish Health-Main Campus

    Denver, Colorado, 80206

  • AdventHealth Porter

    Denver, Colorado, 80210

  • Colorado Blood Cancer Institute

    Denver, Colorado, 80218

  • Presbyterian - Saint Lukes Medical Center - Health One

    Denver, Colorado, 80218

  • Rocky Mountain Cancer Centers-Midtown

    Denver, Colorado, 80218

  • Saint Joseph Hospital - Cancer Centers of Colorado

    Denver, Colorado, 80218

  • Rocky Mountain Cancer Centers-Rose

    Denver, Colorado, 80220

  • Rose Medical Center

    Denver, Colorado, 80220

  • Western States Cancer Research NCORP

    Denver, Colorado, 80222

  • Smilow Cancer Hospital-Derby Care Center

    Derby, Connecticut, 06418

  • Mercy Medical Center - Des Moines

    Des Moines, Iowa, 50314

  • UI Health Care Mission Cancer and Blood - Laurel Clinic

    Des Moines, Iowa, 50314

  • Wayne State University/Karmanos Cancer Institute

    Detroit, Michigan, 48201

  • Henry Ford Hospital

    Detroit, Michigan, 48202

  • Henry Ford Health Saint John Hospital

    Detroit, Michigan, 48236

  • Cancer Center of Kansas - Dodge City

    Dodge City, Kansas, 67801

  • Wentworth-Douglass Hospital

    Dover, New Hampshire, 03820

  • Essentia Health Cancer Center

    Duluth, Minnesota, 55805

  • Essentia Health Saint Mary's Medical Center

    Duluth, Minnesota, 55805

  • Miller-Dwan Hospital

    Duluth, Minnesota, 55805

  • CommonSpirit Cancer Center Mercy

    Durango, Colorado, 81301

  • Mercy Medical Center

    Durango, Colorado, 81301

  • Prisma Health Cancer Institute - Easley

    Easley, South Carolina, 29640

  • Veterans Adminstration New Jersey Health Care System

    East Orange, New Jersey, 07018-1095

  • HSHS Sacred Heart Hospital

    Eau Claire, Wisconsin, 54701

  • Marshfield Clinic Cancer Center at Sacred Heart

    Eau Claire, Wisconsin, 54701

  • Fairview Southdale Hospital

    Edina, Minnesota, 55435

  • Swedish Cancer Institute-Edmonds

    Edmonds, Washington, 98026

  • Carle Physician Group-Effingham

    Effingham, Illinois, 62401

  • Crossroads Cancer Center

    Effingham, Illinois, 62401

  • Cancer Center of Kansas - El Dorado

    El Dorado, Kansas, 67042

  • Ascension Alexian Brothers - Elk Grove Village

    Elk Grove Village, Illinois, 60007

  • Mercy Cancer Center-Elyria

    Elyria, Ohio, 44035

  • Mountain Blue Cancer Care Center - Swedish

    Englewood, Colorado, 80113

  • Swedish Medical Center

    Englewood, Colorado, 80113

  • Saint Elizabeth Hospital

    Enumclaw, Washington, 98022

  • UPMC Hillman Cancer Center Erie

    Erie, Pennsylvania, 16505

  • OSF Saint Francis Hospital and Medical Group

    Escanaba, Michigan, 49829

  • Illinois CancerCare-Eureka

    Eureka, Illinois, 61530

  • NorthShore University HealthSystem-Evanston Hospital

    Evanston, Illinois, 60201

  • Providence Regional Cancer Partnership

    Everett, Washington, 98201

  • Fairbanks Memorial Hospital

    Fairbanks, Alaska, 99701

  • Smilow Cancer Hospital Care Center-Fairfield

    Fairfield, Connecticut, 06824

  • Oncology Hematology Care Inc-Healthplex

    Fairfield, Ohio, 45014

  • Essentia Health Cancer Center-South University Clinic

    Fargo, North Dakota, 58103

  • Sanford Broadway Medical Center

    Fargo, North Dakota, 58122

  • Sanford Roger Maris Cancer Center

    Fargo, North Dakota, 58122

  • Weisberg Cancer Treatment Center

    Farmington Hills, Michigan, 48334

  • Corewell Health Farmington Hills Hospital

    Farmington Hills, Michigan, 48336

  • Virginia Mason Federal Way Medical Center

    Federal Way, Washington, 98002

  • Saint Francis Hospital

    Federal Way, Washington, 98003

  • Lake Region Healthcare Corporation-Cancer Care

    Fergus Falls, Minnesota, 56537

  • Armes Family Cancer Center

    Findlay, Ohio, 45840

  • Blanchard Valley Hospital

    Findlay, Ohio, 45840

  • Orion Cancer Care

    Findlay, Ohio, 45840

  • Genesys Hurley Cancer Institute

    Flint, Michigan, 48503

  • Hurley Medical Center

    Flint, Michigan, 48503

  • Aurora Health Center-Fond du Lac

    Fond du Lac, Wisconsin, 54937

  • Kaiser Permanente-Fontana

    Fontana, California, 92335

  • McFarland Clinic - Trinity Cancer Center

    Fort Dodge, Iowa, 50501

  • Cancer Center of Kansas - Fort Scott

    Fort Scott, Kansas, 66701

  • Atrium Medical Center-Middletown Regional Hospital

    Franklin, Ohio, 45005-1066

  • Dayton Physicians LLC-Atrium

    Franklin, Ohio, 45005

  • Fredericksburg Oncology Inc

    Fredericksburg, Virginia, 22401

  • Hematology Oncology Associates of Fredericksburg Inc

    Fredericksburg, Virginia, 22408

  • Kaiser Permanente-Fremont

    Fremont, California, 94538

  • Kaiser Permanente-Fresno

    Fresno, California, 93720

  • Unity Hospital

    Fridley, Minnesota, 55432

  • Saint Luke's Cancer Institute - Fruitland

    Fruitland, Idaho, 83619

  • Gibbs Cancer Center-Gaffney

    Gaffney, South Carolina, 29341

  • Illinois CancerCare-Galesburg

    Galesburg, Illinois, 61401

  • Western Illinois Cancer Treatment Center

    Galesburg, Illinois, 61401

  • Northwestern Medicine Cancer Center Delnor

    Geneva, Illinois, 60134

  • Aurora Health Care Germantown Health Center

    Germantown, Wisconsin, 53022

  • Tacoma/Valley Radiation Oncology Centers-Gig Harbor

    Gig Harbor, Washington, 98332

  • MultiCare Gig Harbor Medical Park

    Gig Harbor, Washington, 98335

  • Glens Falls Hospital

    Glens Falls, New York, 12801

  • NorthShore University HealthSystem-Glenbrook Hospital

    Glenview, Illinois, 60026

  • Addison Gilbert Hospital

    Gloucester, Massachusetts, 01930

  • Mountain Blue Cancer Care Center

    Golden, Colorado, 80401

  • National Jewish Health-Western Hematology Oncology

    Golden, Colorado, 80401

  • Southeastern Medical Oncology Center-Goldsboro

    Goldsboro, North Carolina, 27534

  • Wayne Memorial Hospital

    Goldsboro, North Carolina, 27534

  • Wayne Radiation Oncology

    Goldsboro, North Carolina, 27534

  • Aurora Cancer Care-Grafton

    Grafton, Wisconsin, 53024

  • Nebraska Cancer Specialists/Oncology Hematology West PC

    Grand Island, Nebraska, 68803

  • Benefis Sletten Cancer Institute

    Great Falls, Montana, 59405

  • Great Falls Clinic

    Great Falls, Montana, 59405

  • Banner North Colorado Medical Center

    Greeley, Colorado, 80631

  • Green Bay Oncology at Saint Vincent Hospital

    Green Bay, Wisconsin, 54301-3526

  • Bellin Memorial Hospital

    Green Bay, Wisconsin, 54301

  • Saint Vincent Hospital Cancer Center Green Bay

    Green Bay, Wisconsin, 54301

  • Saint Vincent Hospital Cancer Center at Saint Mary's

    Green Bay, Wisconsin, 54303

  • Aurora BayCare Medical Center

    Green Bay, Wisconsin, 54311

  • Marin Cancer Care Inc

    Greenbrae, California, 94904

  • Marin General Hospital

    Greenbrae, California, 94904

  • UPMC Cancer Centers - Arnold Palmer Pavilion

    Greensburg, Pennsylvania, 15601

  • Dayton Physicians LLC-Wayne

    Greenville, Ohio, 45331

  • Wayne Hospital

    Greenville, Ohio, 45331

  • Greenville Health System Cancer Institute-Andrews

    Greenville, South Carolina, 29601

  • Saint Francis Hospital

    Greenville, South Carolina, 29601

  • Prisma Health Cancer Institute - Butternut

    Greenville, South Carolina, 29605

  • Prisma Health Cancer Institute - Faris

    Greenville, South Carolina, 29605

  • Prisma Health Greenville Memorial Hospital

    Greenville, South Carolina, 29605

  • Saint Francis Cancer Center

    Greenville, South Carolina, 29607

  • Prisma Health Cancer Institute - Eastside

    Greenville, South Carolina, 29615

  • Rocky Mountain Cancer Centers-Greenwood Village

    Greenwood Village, Colorado, 80111

  • Prisma Health Cancer Institute - Greer

    Greer, South Carolina, 29650

  • Gibbs Cancer Center-Pelham

    Greer, South Carolina, 29651

  • William Beaumont Hospital-Grosse Pointe

    Grosse Pointe, Michigan, 48230

  • Kaiser Permanente South Bay

    Harbor City, California, 90710

  • Smilow Cancer Hospital Care Center at Saint Francis

    Hartford, Connecticut, 06105

  • Geisinger Medical Center-Cancer Center Hazleton

    Hazleton, Pennsylvania, 18201

  • Saint Peter's Community Hospital

    Helena, Montana, 59601

  • Cancer and Blood Specialists-Henderson

    Henderson, Nevada, 89052

  • Comprehensive Cancer Centers of Nevada - Henderson

    Henderson, Nevada, 89052

  • Las Vegas Cancer Center-Henderson

    Henderson, Nevada, 89052

Other trials in United States

About this study

Official title: A Randomized Phase III Study of Ibrutinib (PCI-32765)-Based Therapy vs Standard Fludarabine, Cyclophosphamide, and Rituximab (FCR) Chemoimmunotherapy in Untreated Younger Patients With Chronic Lymphocytic Leukemia (CLL)

This phase III trial studies ibrutinib and rituximab to see how well they work compared to fludarabine phosphate, cyclophosphamide, and rituximab in treating patients with untreated chronic lymphocytic leukemia or small lymphocytic lymphoma. Ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Chemotherapy drugs, such as fludarabine phosphate and cyclophosphamide, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Rituximab is a monoclonal antibody. It binds to a protein called CD20, which is found on B cells (a type of white blood cell) and some types of cancer cells. This may help the immune system kill cancer cells. It is not yet known whether fludarabine phosphate, cyclophosphamide, and rituximab may work better than ibrutinib and rituximab in treating patients with untreated chronic lymphocytic leukemia or small lymphocytic lymphoma.

Read the detailed description

PRIMARY OBJECTIVE:

  1. To evaluate the ability of ibrutinib-based induction therapy to prolong progression free survival (PFS) compared to standard fludarabine phosphate, cyclophosphamide, and rituximab (FCR) chemoimmunotherapy for younger patients with chronic lymphocytic leukemia (CLL).

SECONDARY OBJECTIVES:

  1. Evaluate overall survival (OS) of patients based on treatment arm. II. Monitor and assess toxicity of treatment with ibrutinib-based induction relative to standard FCR chemotherapy.

III. To compare quality of life (QOL) in CLL patients during the first 6 months of treatment among patients receiving ibrutinib-based induction therapy relative to standard FCR chemoimmunotherapy.

IV. To compare QOL over the long-term in CLL patients receiving continuous therapy using ibrutinib to that of CLL patients who completed FCR therapy.

  1. Determine the effect of pretreatment clinical and biological characteristics (e.g. disease stage, immunoglobulin heavy chain variable region gene [IGHV] mutation status, fluorescent in situ hybridization [FISH]) on clinical outcomes (e.g. complete response, PFS) of the different arms.

VI. Determine if the minimal residual disease (MRD) status as assessed by flow cytometry at different time points during and after treatment is an effective surrogate marker for prolonged PFS and overall survival.

VII. Compare the genetic abnormalities and dynamics of intra-clonal architecture of CLL patients before and after treatment with chemoimmunotherapy (CIT) and non-CIT approaches and explore relationships with treatment resistance.

VIII. Explore the effects of FCR and ibrutinib-based therapy on T-cell immune function.

IX. Conduct confirmatory validation genotyping of single nucleotide polymorphisms (SNPs) associated with the efficacy and toxicity of fludarabine-based therapy as in a prior Eastern Cooperative Oncology Group (ECOG) genome-wide association study (GWAS) analysis in the E2997 trial.

  1. Evaluate the ability of prognostic model that incorporates clinical and biologic characters to predict a response to therapy and clinical outcome (PFS, OS).

XI. Evaluate signaling networks downstream of the B-cell receptor in patients receiving ibrutinib-based therapy.

XII. Collect relapse samples to study mechanisms of resistance to both FCR and ibrutinib-based therapy.

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

ARM A: Patients receive ibrutinib orally (PO) once daily (QD) on days 1-28. Beginning cycle 2, patients also receive rituximab intravenously (IV) over 4 hours on days 1 and 2 of cycle 2, and day 1 of cycles 3-7. Treatment repeats every 28 days for 7 cycles in the absence of unacceptable toxicity. In the absence of disease progression, patients may continue ibrutinib PO QD for a maximum of 10 years.

ARM B: Patients receive rituximab IV over 4 hours on days 1 and 2 of cycle 1, and day 1 of cycles 2-6. Patients also receive fludarabine phosphate IV over 30 minutes and cyclophosphamide IV over 30 minutes on days 1-3. Treatment repeats every 28 days for 6 cycles in the absence of unacceptable toxicity.

After completion of study treatment, patients are followed up for 10 years.

Being tested
Cyclophosphamide, Fludarabine Phosphate, Ibrutinib, Laboratory Biomarker Analysis, Pharmacogenomic Study
Medical subject headings
Anemia, Leukemia, Lymphocytic, Chronic, B-Cell

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • CyclophosphamideDrug

    Also called (-)-Cyclophosphamide, 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate, Asta B 518, B 518

    Given IV

  • Fludarabine PhosphateDrug

    Also called 2-F-ara-AMP, 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-, Beneflur, Fludara

    Given IV

  • IbrutinibDrug

    Also called BTK Inhibitor PCI-32765, CRA 032765, CRA-032765, CRA032765

    Given PO

  • Laboratory Biomarker AnalysisOther

    Correlative studies

  • Pharmacogenomic StudyOther

    Also called PHARMACOGENOMIC

    Correlative studies

  • Quality-of-Life AssessmentOther

    Also called Quality of Life Assessment

    Ancillary studies

  • RituximabBiological

    Also called ABP 798, ABP-798, ABP798, BI 695500

    Given IV

Study groups in NCT02048813
Study groupRoleWhat they receive
Arm A (ibrutinib, rituximab)ExperimentalPatients receive ibrutinib PO QD on days 1-28. Beginning cycle 2, patients also receive rituximab IV over 4 hours on days 1 and 2 of cycle 2, and day 1 of cycles 3-7. Treatment repeats every 28 days for 7 cycles in the absence of unacceptable toxicity. In the absence of disease progression, patients may continue ibrutinib PO QD for a maximum of 10 years.
Receives: Drug: Ibrutinib; Other: Laboratory Biomarker Analysis; Other: Pharmacogenomic Study; Other: Quality-of-Life Assessment; Biological: Rituximab
Arm B (rituximab, fludarabine phosphate, cyclophosphamide)Active comparatorPatients receive rituximab IV over 4 hours on days 1 and 2 of cycle 1, and day 1 of cycles 2-6. Patients also receive fludarabine phosphate IV over 30 minutes and cyclophosphamide IV over 30 minutes on days 1-3. Treatment repeats every 28 days for 6 cycles in the absence of unacceptable toxicity.
Receives: Drug: Cyclophosphamide; Drug: Fludarabine Phosphate; Other: Laboratory Biomarker Analysis; Other: Pharmacogenomic Study; Other: Quality-of-Life Assessment; Biological: Rituximab

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Progression-free Survival (PFS) Rate at 3 Years

    PFS was defined as the time from randomization to CLL progression or death, whichever occurred first. Progression is characterized by any of the following:

    • ≥ 50% increase from nadir since start of treatment (tx) in the sum of the products of at least 2 lymph nodes on 2 consecutive examinations 2 weeks apart
    • ≥ 50% increase from nadir since start of tx in the size of liver and/or spleen
    • ≥ 50% increase in the absolute number of circulating lymphocytes not due to tumor flare reaction. The absolute lymphocyte count must be ≥ 5x10^9/L to qualify as disease progression.
    • Transformation to a more aggressive histology (e.g. Richter's syndrome or prolymphocytic leukemia with > 55% prolymphocytes). For patients who achieve a complete response or nodular partial response, progression is defined as recurrence of circulating leukemia cell clone in the peripheral blood and an absolute lymphocyte count > 5x10^9/L and/or recurrence of palpable lymphadenopathy > 1.5 cm by physical exam.

    Measured: Assessed every 3 months until progression up to 4 years and 8 months

Secondary outcomes (5)

  1. Overall Survival (OS) Rate at 3 Years

    Overall survival was defined as time from randomization to death from any cause or date last known alive. Overall survival rate at 3 years was estimated using the method of Kaplan-Meier.

    Measured: Assessed every 3 months until progression; after progression, assessed every 3 months for first 2 years, every 6 months for years 3-5, up to 4 years and 8 months

  2. The Functional Assessment of Cancer Therapy - Leukemia (FACT-Leu) Trial Outcome Index (TOI) Score at 6 Months

    The Functional Assessment of Cancer Therapy - Leukemia (FACT-Leu) Trial Outcome Index (TOI) is comprised of the physical well-being (PWB) and functional well-being (FWB) components of the FACT-General (FACT-G) and the leukemia subscale. The FACT-Leu TOI contains a total of 31 items, with scores ranging from 0 to 124. The higher the score, the better the quality of life (QOL).

    Measured: Assessed at 6 months

  3. The Functional Assessment of Cancer Therapy - Leukemia (FACT-Leu) Trial Outcome Index (TOI) Score at 12 Months

    The Functional Assessment of Cancer Therapy - Leukemia (FACT-Leu) Trial Outcome Index (TOI) is comprised of the physical well-being (PWB) and functional well-being (FWB) components of the FACT-General (FACT-G) and the leukemia subscale. The FACT-Leu TOI contains a total of 31 items, with scores ranging from 0 to 124. The higher the score, the better the quality of life (QOL).

    Measured: Assessed at 12 months

  4. The Association Between Baseline Rai Stage and Complete Response (CR) Rate

    Patients are classified as stage 0-IV according to the Rai system and categorized into one of the three risk groups:

    Low risk - Stage 0 Intermediate risk - Stage I or II High risk - Stage III or IV

    CR requires all of the following for at least 2 months:

    • Absence of lymphadenopathy by physical examination on 2 occasions at least 4 weeks apart and appropriate radiographic techniques. For patients whose only measurable disease at the time of enrollment is on CT scan, a CT scan is required and all lymph nodes must be ≤ 1.5 cm before classifying the patient a CR.
    • Absence of hepatomegaly or splenomegaly by physical examination
    • Absence of constitutional symptoms due to disease
    • Normal complete blood count
    • One marrow aspirate and biopsy should be performed 52 weeks after Day 1 of cycle 1 among patients with clinical and laboratory evidence of a CR to document a CR. The marrow sample must be at least normocellular with < 30% of nucleated cells being lymphocytes.

    Measured: Assessed at baseline, every 3 months for the first 2 years, and every 6 months for years 3-5

  5. Progression-free Survival (PFS) by Measurable Residual Disease (MDR) Status at 2 Years

    PFS was defined as time from randomization to progression or death. Progression is characterized by any of the following:

    • ≥ 50% increase from nadir since start of treatment (tx) in the sum of the products of ≥ 2 lymph nodes on 2 consecutive exams 2 weeks apart
    • ≥ 50% increase from nadir since start of tx in the size of liver and/or spleen
    • ≥ 50% increase in the absolute number of circulating lymphocytes not due to tumor flare reaction. The absolute lymphocyte count must be ≥ 5x10^9/L to qualify as progression.
    • Transformation to a more aggressive histology. For patients with a complete response or nodular partial response, progression is defined as recurrence of circulating leukemia cell clone in the peripheral blood and an absolute lymphocyte count > 5x10^9/L and/or recurrence of palpable lymphadenopathy >1.5 cm by physical exam.

    MRD status was evaluated at 2 years and samples with <=20 monotypic events or an MRD level of <10^-4 were classified as undetectable MRD.

    Measured: Assessed every 3 months until progression up to 5 years

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted29 Jan 2014 (estimated)
  2. Study start10 Mar 2014
  3. Primary completion24 Oct 2018
  4. Study completion9 Oct 2026 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
529 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02048813
Sponsor's protocol ID
NCI-2014-00118
Other IDs
NCI-2014-00118, E1912, ECOG-E1912, E1912, E1912, R01CA193541, U10CA021115, U10CA180820
Status last verified
Apr 2026
First submitted
27 Jan 2014
Last updated
28 Aug 2026
Data monitoring committee
No

Publications

  • O'Connell NS, Zhao F, Lee JW, Ip EH, Peipert JD, Graham N, Smith ML, Gareen IF, Carlos RC, Obeng-Gyasi S, Sparano JA, Shanafelt TD, Thomas ML, Cella D, Wagner LI, Gray R. Importance of Low- and Moderate-Grade Adverse Events in Patients' Treatment Experience and Treatment Discontinuation: An Analysis of the E1912 Trial. J Clin Oncol. 2024 Jan 20;42(3):266-272. doi: 10.1200/JCO.23.00377. Epub 2023 Oct 6.

    PubMed 37801678

  • Shanafelt TD, Wang XV, Hanson CA, Paietta EM, O'Brien S, Barrientos J, Jelinek DF, Braggio E, Leis JF, Zhang CC, Coutre SE, Barr PM, Cashen AF, Mato AR, Singh AK, Mullane MP, Little RF, Erba H, Stone RM, Litzow M, Tallman M, Kay NE. Long-term outcomes for ibrutinib-rituximab and chemoimmunotherapy in CLL: updated results of the E1912 trial. Blood. 2022 Jul 14;140(2):112-120. doi: 10.1182/blood.2021014960.

    PubMed 35427411

  • Allan JN, Shanafelt T, Wiestner A, Moreno C, O'Brien SM, Li J, Krigsfeld G, Dean JP, Ahn IE. Long-term efficacy of first-line ibrutinib treatment for chronic lymphocytic leukaemia in patients with TP53 aberrations: a pooled analysis from four clinical trials. Br J Haematol. 2022 Feb;196(4):947-953. doi: 10.1111/bjh.17984. Epub 2021 Dec 5.

    PubMed 34865212

  • List AF, Sun Z, Verma A, Bennett JM, Komrokji RS, McGraw K, Maciejewski J, Altman JK, Cheema PS, Claxton DF, Luger SM, Mattison RJ, Wassenaar TR, Artz AS, Schiffer CA, Litzow MR, Tallman MS. Lenalidomide-Epoetin Alfa Versus Lenalidomide Monotherapy in Myelodysplastic Syndromes Refractory to Recombinant Erythropoietin. J Clin Oncol. 2021 Mar 20;39(9):1001-1009. doi: 10.1200/JCO.20.01691. Epub 2021 Jan 13.

    PubMed 33439748

  • Shanafelt TD, Wang XV, Kay NE, Hanson CA, O'Brien S, Barrientos J, Jelinek DF, Braggio E, Leis JF, Zhang CC, Coutre SE, Barr PM, Cashen AF, Mato AR, Singh AK, Mullane MP, Little RF, Erba H, Stone RM, Litzow M, Tallman M. Ibrutinib-Rituximab or Chemoimmunotherapy for Chronic Lymphocytic Leukemia. N Engl J Med. 2019 Aug 1;381(5):432-443. doi: 10.1056/NEJMoa1817073.

    PubMed 31365801

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