iFCR: A Phase II Study of Ibrutinib Plus FCR in Previously Untreated, Younger Patients With Chronic Lymphocytic Leukemia

Sponsor
Dana-Farber Cancer Institute (Other)
Overall Status
Active, not recruiting
CT.gov ID
NCT02251548
Collaborator
Pharmacyclics LLC. (Industry), The Leukemia and Lymphoma Society (Other), Blood Cancer Research Partnership (Other)
85
Enrollment
9
Locations
1
Arm
123
Anticipated Duration (Months)
9.4
Patients Per Site
0.1
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This research study is evaluating a new drug called ibrutinib in combination with the standard drugs fludarabine, cyclophosphamide, and rituximab (FCR) as a possible treatment for Chronic Lymphocytic Leukemia (CLL).

Detailed Description

Ibrutinib is a type of drug called a kinase inhibitor. It is believed to block a protein called Bruton's tyrosine kinase (BTK) that helps CLL cells live and grow. By blocking this, it is possible that the study drug will kill cancer cells or stop them from growing. Ibrutinib has been FDA approved for the treatment of CLL patients who have received at least one prior treatment; however, the FDA has not yet approved ibrutinib as the first treatment for previously untreated CLL. Therefore, ibrutinib is still considered to be study drug, which means it is still being studied.

Fludarabine, cyclophosphamide, and rituximab (FCR) are intravenous chemotherapy and antibody drugs that together are a standard chemotherapy regimen used for younger patients with CLL. Although FCR is highly effective, it does not typically lead to cure.

In this research study, the investigators are combining a new treatment for CLL, ibrutinib, with a standard chemotherapy regimen for CLL, FCR, to determine whether this combination (iFCR) is safe and effective for patients with previously untreated CLL.

Study Design

Study Type:
Interventional
Actual Enrollment :
85 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Phase II Study of Ibrutinib in Combination With Fludarabine, Cyclophosphamide, and Rituximab (iFCR) in Previously Untreated, Younger Patients With Chronic Lymphocytic Leukemia
Actual Study Start Date :
Oct 1, 2014
Actual Primary Completion Date :
Jan 1, 2019
Anticipated Study Completion Date :
Jan 1, 2025

Arms and Interventions

ArmIntervention/Treatment
Experimental: Ibrutinib

- Ibrutinib- Oral, daily during each cycle fludarabine-administered at standard dosing for up to 6 cycles cyclophosphamide-administered at standard dosing for up to 6 cycles rituximab-administered at standard dosing for up to 6 cycles

Drug: Ibrutinib
Oral BTK inhibitor
Other Names:
  • Imbruvica™
  • Drug: Fludarabine
    IV purine analogue chemotherapy agent
    Other Names:
  • Fludara
  • Drug: Cyclophosphamide
    IV alkylator chemotherapy agent
    Other Names:
  • Cytoxan®
  • Neosar®
  • Drug: Rituximab
    IV anti-CD20 monoclonal antibody
    Other Names:
  • Rituxan®
  • Outcome Measures

    Primary Outcome Measures

    1. Part I: Participants Who Achieve a Minimal Residual Disease (MRD) Negative Complete Response (CR) in the Bone Marrow at 2 Months Post FCR [2 months after completing combination therapy]

      To assess the number of participants who achieve an MRD negative complete response at the 2 months post last dose of FCR timepoint by 2008 IW-CLL criteria ( Hallek et. al). Participants will have a bone marrow biopsy procedure 2 months after completing combination therapy (Ibrutinib+ FCR) in tandem with a chest, neck, abdomen and pelvic PET CT scan. A central read of the PET CT scan will confirm a radiographic complete response, and the bone marrow pathology and morphology assessments will confirm morphological CR in the bone marrow, while MRD testing will be done by four-color flow cytometry on the bone marrow aspirate with a detection level of 10-4.

    2. Part II: Participants Who Achieve a Minimal Residual Disease (MRD) Negative Complete Response (CR) in the Bone Marrow at 2 Years Post Discontinuation of Ibrutinib After Having Achieved MRD Negative CR at the 2 Months Post FCR Timepoint [2 years post discontinuation of ibrutinib after 24 months of ibrutinib maintenance]

      Participants will have bone marrow biopsies in tandem with a chest, neck, abdomen and pelvic PET CT scan as clinically indicated after discontinuation of treatment. A central read of the PET CT scan will confirm the radiographic response, and the bone marrow pathology and morphology assessments will confirm morphological response in the bone marrow, while MRD testing will be done by four-color flow cytometry on the bone marrow aspirate with a detection level of 10-4. Response and progression will be evaluated in this study using the 2008 IW-CLL criteria for CLL (Hallek et al., 2008).

    Secondary Outcome Measures

    1. Overall Response Rate [Response assessed after Cycle 3, 2 months post FCR, at 1 year and 2 years post FCR, yearly therafter for those not having achieved an MRD negative CR, and as clinically indicated]

      Participants will have bone marrow biopsies in tandem with a chest, neck, abdomen and pelvic PET CT scan at baseline, end of cycle 3, 2 months post FCR, 1 year post FCR for those not having reached a radiographic CR, 2 years post FCR, and as clinically indicated thereafter. A central read of the PET CT scan will confirm a radiographic response, and the bone marrow pathology and morphology assessments will confirm morphological response in the bone marrow, while MRD testing will be done by four-color flow cytometry on the bone marrow aspirate with a detection level of 10-4. Response and progression will be evaluated in this study using the 2008 IW-CLL criteria for CLL (Hallek et al., 2008). Overall response rate will include PR,CRi and CR

    2. Rate of Complete Response [Response assessed after Cycle 3, 2 months post FCR, at 1 year and 2 years post FCR, yearly therafter for those not having achieved a radiographic CR, and as clinically indicated therafter]

      Participants will have bone marrow biopsies in tandem with a chest, neck, abdomen and pelvic PET CT scan at baseline, end of cycle 3, 2 months post FCR, 1 year post FCR for those not having reached a radiographic CR, 2 years post FCR, and as clinically indicated thereafter. A central read of the PET CT scan will confirm a radiographic response, and the bone marrow pathology and morphology assessments will confirm morphological response in the bone marrow, while MRD testing will be done by four-color flow cytometry on the bone marrow aspirate with a detection level of 10-4. Response and progression will be evaluated in this study using the 2008 IW-CLL criteria for CLL (Hallek et al., 2008).

    3. Rate of Partial Response [Response assessed after Cycle 3, 2 months post FCR, at 1 year and 2 years post FCR, yearly therafter for those not having achieved an MRD negative CR, and as clinically indicated]

      Participants will have bone marrow biopsies in tandem with a chest, neck, abdomen and pelvic PET CT scan at baseline, end of cycle 3, 2 months post FCR, 1 year post FCR for those not having reached a radiographic CR, 2 years post FCR, and as clinically indicated thereafter. A central read of the PET CT scan will confirm a radiographic response, and the bone marrow pathology and morphology assessments will confirm morphological response in the bone marrow, while MRD testing will be done by four-color flow cytometry on the bone marrow aspirate with a detection level of 10-4. Response and progression will be evaluated in this study using the 2008 IW-CLL criteria for CLL (Hallek et al., 2008).

    4. Rate of Progression Free of Survival [From date of study entry until the date of first documented progression or date of death from any cause, whichever came first]

      Progression free survival is defined as the time from study entry to the earliest documentation of disease progression as defined by 2008 IW-CLL criteria for CLL (Hallek et al., 2008). Participants will be followed for disease progression and/or survival after discontinuation of treatment every 3 months until subsequent therapy, withdrawal, lost to follow up, or death.

    5. Rate of Overall Survival [From date of starting study treatment until the date of death from any cause]

      Overall survival is defined as the time from study entry to death or date last known alive. Participants will be followed for survival after discontinuation of treatment every 3 months until subsequent therapy, withdrawal, or death.

    6. Rate of MRD Negative CR After 3 Cycles of iFCR [After 3 cycles of iFCR for each patient completing 3 cycles; on average, after 12 weeks of treatment during which 1 bone marrow biopsy is performed and MRD is tested]

      To determine the rate of minimal residual disease negative complete response (MRD negative CR) in the bone marrow after 3 cycles of ibrutinib + FCR. Participants will have a bone marrow biopsy procedure after completing 3 cycles in tandem with a chest, neck, abdomen and pelvic PET CT scan. A central read of the PET CT scan will confirm a radiographic complete response, and the bone marrow pathology and morphology assessments will confirm morphological CR in the bone marrow, while MRD testing will be done by four-color flow cytometry on the bone marrow aspirate with a detection level of 10-4. Response and progression will be evaluated in this study using the 2008 IW-CLL criteria for CLL (Hallek et al., 2008)

    7. Rate of MRD Negative CR After 1 Year of Ibrutinib+ FCR [After 12 months (1 year) from the start of therapy]

      To determine the rate of minimal residual disease negative complete response (MRD negative CR) in the bone marrow at 12 months from start of therapy, participants will have a bone marrow biopsy procedure at the 1 year timepoint after completing combination therapy (ibrutinib + FCR) in tandem with a chest, neck, abdomen and pelvic PET CT scan. A central read of the PET CT scan will confirm a radiographic complete response, and the bone marrow pathology and morphology assessments will confirm morphological CR in the bone marrow, while MRD testing will be done by four-color flow cytometry on the bone marrow aspirate with a detection level of 10-4. Response and progression will be evaluated in this study using the 2008 IW-CLL criteria for CLL (Hallek et al., 2008)

    8. Rate of MRD Negative CR After 2 Years of Ibrutinib Maintenance [2 years (24 months) from start of therapy]

      To determine the rate of minimal residual disease negative complete response (MRD negative CR) in the bone marrow at 24 months post last cycle of FCR, participants will have a bone marrow biopsy procedure 24 months after completing combination therapy (ibrutinib + FCR) in tandem with a chest, neck, abdomen and pelvic PET CT scan. A central read of the PET CT scan will confirm a radiographic complete response, and the bone marrow pathology and morphology assessments will confirm morphological CR in the bone marrow, while MRD testing will be done by four-color flow cytometry on the bone marrow aspirate with a detection level of 10-4. Response and progression will be evaluated in this study using the 2008 IW-CLL criteria for CLL (Hallek et al., 2008)

    9. Number of Participants Who Convert From Bone Marrow MRD Negative PR to Bone Marrow MRD Negative CR After 1 Year of Ibrutinib Maintenance [12 months ( 1year) after starting therapy]

      To determine the rate of minimal residual disease negative complete response (MRD negative CR) in the bone marrow at 12 months from start of therapy, participants will have a bone marrow biopsy procedure at the 1 year timepoint after completing combination therapy (ibrutinib + FCR) in tandem with a chest, neck, abdomen and pelvic PET CT scan. A central read of the PET CT scan will confirm a radiographic complete response, and the bone marrow pathology and morphology assessments will confirm morphological CR in the bone marrow, while MRD testing will be done by four-color flow cytometry on the bone marrow aspirate with a detection level of 10-4. Response and progression will be evaluated in this study using the 2008 IW-CLL criteria for CLL (Hallek et al., 2008)

    10. Number of Participants Who Convert From Bone Marrow MRD Negative PR to Bone Marrow MRD Negative CR After 2 Years on Treatment [2 years (24 months) from start of therapy]

      MRD testing will be done by four-color flow cytometry on the bone marrow aspirate with a detection level of 10-4. Response and progression will be evaluated in this study using the 2008 IW-CLL criteria for CLL (Hallek et al., 2008)- Bone marrow biopsies will be performed at baseline, after cycle 3, 2 months post FCR, at 1 year and 2 years of ibrutinib maintenance, and as clinically indicated thereafter- Participants will have a bone marrow biopsy procedure 24 months after completing combination therapy (Ibrutinib+ FCR) in tandem with a chest, neck, abdomen and pelvic PET CT scan. A central read of the PET CT scan will confirm a radiographic complete response, and the bone marrow pathology and morphology assessments will confirm morphological CR in the bone marrow, while MRD testing will be done by four-color flow cytometry on the bone marrow aspirate with a detection level of 10-4.

    11. Time to Bone Marrow MRD Negativity [From date of starting study treatment until achievement of MRD negativity in the bone marrow]

      MRD testing will be done by four-color flow cytometry on the bone marrow aspirate with a detection level of 10-4. Response and progression will be evaluated in this study using the 2008 IW-CLL criteria for CLL (Hallek et al., 2008)- Bone marrow biopsies will be performed at baseline, after cycle 3, 2 months post FCR, at 1 year and 2 years of ibrutinib maintenance, and as clinically indicated thereafter

    12. Participants Who Convert From Bone Marrow MRD Negativity to MRD Positivity in Participants Who Discontinue Ibrutinib [From date of starting study treatment until achievement of MRD negativity in the bone marrow to conversion to MRD positivity]

      .MRD testing will be done by four-color flow cytometry on the bone marrow aspirate with a detection level of 10-4. Response and progression will be evaluated in this study using the 2008 IW-CLL criteria for CLL (Hallek et al., 2008)- Bone marrow biopsies will be performed at baseline, after cycle 3, 2 months post FCR, at 1 year and 2 years of ibrutinib maintenance, and as clinically indicated thereafter

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years to 65 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:
    • Must have a confirmed diagnosis of chronic lymphocytic leukemia or small lymphocytic lymphoma. as per IW-CLL 2008 criteria. Patients must also require therapy for that diagnosis, based on meeting at least one of the following criteria:

    • evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia (hemoglobin <11.0 g/L) and/or thrombocytopenia (platelets <100 x 10^9/L)

    • massive (≥ 6 cm below the left costal margin), progressive, or symptomatic splenomegaly

    • massive nodes (at least 10 cm longest diameter), progressive, or symptomatic lymphadenopathy

    • progressive lymphocytosis with an increase of more than 50% over a 2-month period or LDT of <6 months. Lymphocyte doubling time may be obtained by linear regression extrapolation of absolute lymphocyte counts obtained at intervals of 2 weeks over an observation period of 2 to 3 months. In subjects with initial blood lymphocyte counts of <30 x 10^9/L, LDT should not be used as a single parameter to define indication for treatment. In addition, factors contributing to lymphocytosis or lymphadenopathy other than CLL (eg, infections) should be excluded

    • autoimmune anemia and/or thrombocytopenia that is poorly responsive to corticosteroids or other standard therapy

    • documented constitutional symptoms, defined as 1 or more of the following disease-related symptoms or signs:

    • unintentional weight loss >10% within 6 months prior to screening

    • significant fatigue (inability to work or perform usual activities)

    • fevers >100.5° F or 38.0° C for 2 or more weeks prior to screening without evidence of infection

    • night sweats for more than 1 month prior to screening without evidence of infection

    • No prior CLL-directed therapy that was instituted due to patient previously meeting IW-CLL 2008 criteria for treatment

    • Age greater than or equal to 18 years and less than or equal to 65. Because CLL is extremely rare in persons <18 years of age, children are excluded from this study. Because iFCR is an aggressive therapy that is likely to be less well-tolerated even in fit elderly subjects, persons > 65 years of age are excluded

    • ECOG performance status ≤ 1

    • Adequate hematologic function independent of growth factor support for at least 7 days prior to screening and randomization, with the exception of pegylated G-CSF (pegfilgrastim) and darbepoetin which cannot be administered within 14 days of screening.

    • Patients must meet the following hematologic criteria at screening:

    • Absolute neutrophil count ≥ 750 cells/mm3 (0.75 x 109/L).

    • Platelet count ≥ 50,000 cells/mm3 (50 x 109/L).

    • Hemoglobin ≥ 8 g/L - Adequate hepatic and renal function defined as:

    • Serum aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3.0 x upper limit of normal (ULN)

    • Bilirubin ≤ 1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin)

    • Adequate renal function defined by serum creatinine >1.5 x ULN

    • PT/INR <1.5 x ULN and PTT (aPTT) <1.5 x ULN.

    • The effects of ibrutinib on the developing human fetus are unknown. For this reason and because similar agents are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation.

    Exclusion Criteria:
    • Concurrent Conditions:

    • History of other malignancies, except:

    • Malignancy treated with curative intent and with no known active disease present for ≥ 3 years before the first dose of study drug and felt to be at low risk for recurrence by treating physician.

    • Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease.

    • Adequately treated carcinoma in situ without evidence of disease.

    • Concurrent systemic immunosuppressant therapy (eg, cyclosporine A, tacrolimus, etc., or chronic administration of >20 mg/day of prednisone) within 28 days of the first dose of study drug.

    • Vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug.

    • Recent infection requiring systemic treatment that was completed ≤ 14 days before the first dose of study drug.

    • Known bleeding disorders (eg, von Willebrand's disease) or hemophilia.

    • History of stroke or intracranial hemorrhage within 6 months prior to enrollment.

    • Known history of human immunodeficiency virus (HIV) or active with hepatitis C virus (HCV) or hepatitis B virus (HBV). Patients who are positive for hepatitis B core antibody or hepatitis B surface antigen must have a negative polymerase chain reaction (PCR) result before enrollment. Those who are PCR positive will be excluded.

    • Any uncontrolled active systemic infection.

    • Major surgery within 4 weeks of first dose of study drug.

    • Any life-threatening illness, medical condition, or organ system dysfunction that, in the investigator's opinion, could compromise the subject's safety or put the study outcomes at undue risk.

    • Currently active, clinically significant cardiovascular disease, such as uncontrolled arrhythmia or Class 3 or 4 congestive heart failure as defined by the New York Heart Association Functional Classification; or a history of myocardial infarction, unstable angina, or acute coronary syndrome within 6 months prior to randomization.

    • Unable to swallow capsules or malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel, symptomatic inflammatory bowel disease or ulcerative colitis, or partial or complete bowel obstruction.

    • Lactating or pregnant.

    • Patients receiving any other study agents

    • Patients with known CNS involvement

    • Baseline QTcF >480 ms. NOTE: This criterion does not apply to patients with a left bundle branch block.

    • Patients who require warfarin or other vitamin K antagonists for anticoagulation (other anticoagulants are allowed after consultation with the Principal Investigator).

    • Concurrent administration of medications or foods that are strong inhibitors or inducers of CYP3A

    • Patients with ongoing use of prophylactic antibiotics are eligible as long as there is no evidence of active infection and the antibiotic is not included on the list of prohibited medications

    • Significant co-morbid condition or disease which in the judgment of the Principal Investigator would place the patient at undue risk or interfere with the study

    • Unable to receive prophylactic treatment for pneumocystis

    • Patients with del(17p) confirmed by FISH in ≥20% of cells or on stimulated karyotype3.2.24 Patients with del(17p) confirmed by FISH in ≥20% of cells or on stimulated karyotype

    • Patients with unmutated IGHV who also have a complex karyotype on a stimulated karyotype

    Contacts and Locations

    Locations

    SiteCityStateCountryPostal Code
    1University of Miami Sylvester Comprehensive Cancer CenterCoral GablesFloridaUnited States33146
    2University of Miami Sylvester Comprehensive Cancer CenterDeerfield BeachFloridaUnited States33442
    3Unversity of Miami Sylvester Comprehensve Cancer CenterMiamiFloridaUnited States33136
    4University of Kansas Cancer CenterWestwoodKansasUnited States66205
    5Massachusetts General HospitalBostonMassachusettsUnited States02114
    6Beth Israel Deaconess Medical CenterBostonMassachusettsUnited States02215
    7Dana Farber Cancer InstituteBostonMassachusettsUnited States02215
    8West Michigan Cancer CenterKalamazooMichiganUnited States49007
    9Duke University Medical CenterDurhamNorth CarolinaUnited States27710

    Sponsors and Collaborators

    • Dana-Farber Cancer Institute
    • Pharmacyclics LLC.
    • The Leukemia and Lymphoma Society
    • Blood Cancer Research Partnership

    Investigators

    • Principal Investigator: Matthew Davids, MD, Dana-Farber Cancer Institute

    Study Documents (Full-Text)

    More Information

    Publications

    None provided.
    Responsible Party:
    Matthew S. Davids, MD, Principal Investigator, Dana-Farber Cancer Institute
    ClinicalTrials.gov Identifier:
    NCT02251548
    Other Study ID Numbers:
    • 14-296
    First Posted:
    Sep 29, 2014
    Last Update Posted:
    Mar 21, 2022
    Last Verified:
    Mar 1, 2022
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    Keywords provided by Matthew S. Davids, MD, Principal Investigator, Dana-Farber Cancer Institute
    Additional relevant MeSH terms:

    Study Results

    Participant Flow

    Recruitment DetailsThe study opened to enrollment on 10/3/2014 and closed to enrollment on 4/24/2018. 58 participants were enrolled at Dana-Farber, 9 at Massachusetts General Hospital, 3 at Beth Israel Deaconess Medical Center, 9 at Duke University, 1 at University of Kansas, 3 at West Michigan Cancer Center, and 2 at University of Miami for a total of 85 enrolled.
    Pre-assignment Detail
    Arm/Group TitleFCR +420mg Ibrutinib Daily
    Arm/Group DescriptionPatients received oral agent ibrutinib daily on days 1-28 of a 28 day cycle, except for Cycle 1, which lasts 35 with a 7 day ibrutinib run in, then will continue daily dosing.Fludarabine, cyclophosphamide, rituximab (FCR) will be given standard dosing intravenously (IV) Days 1-3 during week 1 of a cycle for up to 6 cycles, with dose reductions permitted. Patients will receive ibrutinib monotherapy indefinitely unless they are found to be minimal residual disease(MRD) negative in the bone marrow at the 24 months of ibrutinib maintenance timepoint, at which point they will discontinue ibrutinib to undergo active disease monitoring. If during active monitoring they develop MRD positivity in the blood, they may resume ibrutinib monotherapy. Patients are treated until progression without clinical benefit, toxicity, or withdrawal of consent by the patient, or closure of the trial by the Overall PI or regulatory authorities
    Period Title: Overall Study
    STARTED85
    COMPLETED0
    NOT COMPLETED85

    Baseline Characteristics

    Arm/Group TitleFCR+ 420 mg Ibrutinib Daily
    Arm/Group DescriptionPatients received oral agent ibrutinib daily on days 1-28 of a 28 day cycle, except for Cycle 1, which lasts 35 with a 7 day ibrutinib run in, then will continue daily dosing.Fludarabine, cyclophosphamide, rituximab (FCR) will be given standard dosing intravenously (IV) Days 1-3 during week 1 of a cycle for up to 6 cycles, with dose reductions permitted. Patients will receive ibrutinib monotherapy indefinitely unless they are found to be minimal residual disease(MRD) negative in the bone marrow at the 24 months of ibrutinib maintenance timepoint, at which point they will discontinue ibrutinib to undergo active disease monitoring. If during active monitoring they develop MRD positivity in the blood, they may resume ibrutinib monotherapy. Patients are treated until progression without clinical benefit, toxicity, or withdrawal of consent by the patient, or closure of the trial by the Overall PI or regulatory authorities
    Overall Participants85
    Age (Count of Participants)
    <=18 years
    0
    0%
    Between 18 and 65 years
    85
    100%
    >=65 years
    0
    0%
    Age (years) [Median (Full Range) ]
    Median (Full Range) [years]
    55
    Sex: Female, Male (Count of Participants)
    Female
    30
    35.3%
    Male
    55
    64.7%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    3
    3.5%
    Not Hispanic or Latino
    81
    95.3%
    Unknown or Not Reported
    1
    1.2%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    Asian
    2
    2.4%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    Black or African American
    0
    0%
    White
    82
    96.5%
    More than one race
    0
    0%
    Unknown or Not Reported
    1
    1.2%
    Region of Enrollment (Count of Participants)
    United States
    85
    100%

    Outcome Measures

    1. Primary Outcome
    TitlePart I: Participants Who Achieve a Minimal Residual Disease (MRD) Negative Complete Response (CR) in the Bone Marrow at 2 Months Post FCR
    DescriptionTo assess the number of participants who achieve an MRD negative complete response at the 2 months post last dose of FCR timepoint by 2008 IW-CLL criteria ( Hallek et. al). Participants will have a bone marrow biopsy procedure 2 months after completing combination therapy (Ibrutinib+ FCR) in tandem with a chest, neck, abdomen and pelvic PET CT scan. A central read of the PET CT scan will confirm a radiographic complete response, and the bone marrow pathology and morphology assessments will confirm morphological CR in the bone marrow, while MRD testing will be done by four-color flow cytometry on the bone marrow aspirate with a detection level of 10-4.
    Time Frame2 months after completing combination therapy

    Outcome Measure Data

    Analysis Population Description
    No prior CLL-directed therapy that was instituted due to patient previously meeting IWCLL 2008 criteria for treatment- Age greater than or equal to 18 years and less than or equal to 65 and must require therapy by standard IW-CLL 2008 criteria with adequate renal, hepatic, and hematologic function
    Arm/Group TitleFCR+ 420mg Ibrutinib Daily
    Arm/Group DescriptionPatients received oral agent ibrutinib daily on days 1-28 of a 28 day cycle, except for Cycle 1, which lasts 35 with a 7 day ibrutinib run in, then will continue daily dosing.Fludarabine, cyclophosphamide, rituximab (FCR) will be given standard dosing intravenously (IV) Days 1-3 during week 1 of a cycle for up to 6 cycles, with dose reductions permitted. Patients will receive ibrutinib monotherapy indefinitely unless they are found to be minimal residual disease(MRD) negative in the bone marrow at the 24 months of ibrutinib maintenance timepoint, at which point they will discontinue ibrutinib to undergo active disease monitoring. If during active monitoring they develop MRD positivity in the blood, they may resume ibrutinib monotherapy. Patients are treated until progression without clinical benefit, toxicity, or withdrawal of consent by the patient, or closure of the trial by the Overall PI or regulatory authorities
    Measure Participants85
    Count of Participants [Participants]
    28
    32.9%
    2. Primary Outcome
    TitlePart II: Participants Who Achieve a Minimal Residual Disease (MRD) Negative Complete Response (CR) in the Bone Marrow at 2 Years Post Discontinuation of Ibrutinib After Having Achieved MRD Negative CR at the 2 Months Post FCR Timepoint
    DescriptionParticipants will have bone marrow biopsies in tandem with a chest, neck, abdomen and pelvic PET CT scan as clinically indicated after discontinuation of treatment. A central read of the PET CT scan will confirm the radiographic response, and the bone marrow pathology and morphology assessments will confirm morphological response in the bone marrow, while MRD testing will be done by four-color flow cytometry on the bone marrow aspirate with a detection level of 10-4. Response and progression will be evaluated in this study using the 2008 IW-CLL criteria for CLL (Hallek et al., 2008).
    Time Frame2 years post discontinuation of ibrutinib after 24 months of ibrutinib maintenance

    Outcome Measure Data

    Analysis Population Description
    All participants have not yet reached this timepoint therefore we have not analyzed or published this endpoint a the time of this submission
    Arm/Group TitleFCR+ 420mg Ibrutinib Daily
    Arm/Group DescriptionPatients received oral agent ibrutinib daily on days 1-28 of a 28 day cycle, except for Cycle 1, which lasts 35 with a 7 day ibrutinib run in, then will continue daily dosing.Fludarabine, cyclophosphamide, rituximab (FCR) will be given standard dosing intravenously (IV) Days 1-3 during week 1 of a cycle for up to 6 cycles, with dose reductions permitted. Patients will receive ibrutinib monotherapy indefinitely unless they are found to be minimal residual disease(MRD) negative in the bone marrow at the 24 months of ibrutinib maintenance timepoint, at which point they will discontinue ibrutinib to undergo active disease monitoring. If during active monitoring they develop MRD positivity in the blood, they may resume ibrutinib monotherapy. Patients are treated until progression without clinical benefit, toxicity, or withdrawal of consent by the patient, or closure of the trial by the Overall PI or regulatory authorities
    Measure Participants0
    3. Secondary Outcome
    TitleOverall Response Rate
    DescriptionParticipants will have bone marrow biopsies in tandem with a chest, neck, abdomen and pelvic PET CT scan at baseline, end of cycle 3, 2 months post FCR, 1 year post FCR for those not having reached a radiographic CR, 2 years post FCR, and as clinically indicated thereafter. A central read of the PET CT scan will confirm a radiographic response, and the bone marrow pathology and morphology assessments will confirm morphological response in the bone marrow, while MRD testing will be done by four-color flow cytometry on the bone marrow aspirate with a detection level of 10-4. Response and progression will be evaluated in this study using the 2008 IW-CLL criteria for CLL (Hallek et al., 2008). Overall response rate will include PR,CRi and CR
    Time FrameResponse assessed after Cycle 3, 2 months post FCR, at 1 year and 2 years post FCR, yearly therafter for those not having achieved an MRD negative CR, and as clinically indicated

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    4. Secondary Outcome
    TitleRate of Complete Response
    DescriptionParticipants will have bone marrow biopsies in tandem with a chest, neck, abdomen and pelvic PET CT scan at baseline, end of cycle 3, 2 months post FCR, 1 year post FCR for those not having reached a radiographic CR, 2 years post FCR, and as clinically indicated thereafter. A central read of the PET CT scan will confirm a radiographic response, and the bone marrow pathology and morphology assessments will confirm morphological response in the bone marrow, while MRD testing will be done by four-color flow cytometry on the bone marrow aspirate with a detection level of 10-4. Response and progression will be evaluated in this study using the 2008 IW-CLL criteria for CLL (Hallek et al., 2008).
    Time FrameResponse assessed after Cycle 3, 2 months post FCR, at 1 year and 2 years post FCR, yearly therafter for those not having achieved a radiographic CR, and as clinically indicated therafter

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    5. Secondary Outcome
    TitleRate of Partial Response
    DescriptionParticipants will have bone marrow biopsies in tandem with a chest, neck, abdomen and pelvic PET CT scan at baseline, end of cycle 3, 2 months post FCR, 1 year post FCR for those not having reached a radiographic CR, 2 years post FCR, and as clinically indicated thereafter. A central read of the PET CT scan will confirm a radiographic response, and the bone marrow pathology and morphology assessments will confirm morphological response in the bone marrow, while MRD testing will be done by four-color flow cytometry on the bone marrow aspirate with a detection level of 10-4. Response and progression will be evaluated in this study using the 2008 IW-CLL criteria for CLL (Hallek et al., 2008).
    Time FrameResponse assessed after Cycle 3, 2 months post FCR, at 1 year and 2 years post FCR, yearly therafter for those not having achieved an MRD negative CR, and as clinically indicated

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    6. Secondary Outcome
    TitleRate of Progression Free of Survival
    DescriptionProgression free survival is defined as the time from study entry to the earliest documentation of disease progression as defined by 2008 IW-CLL criteria for CLL (Hallek et al., 2008). Participants will be followed for disease progression and/or survival after discontinuation of treatment every 3 months until subsequent therapy, withdrawal, lost to follow up, or death.
    Time FrameFrom date of study entry until the date of first documented progression or date of death from any cause, whichever came first

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    7. Secondary Outcome
    TitleRate of Overall Survival
    DescriptionOverall survival is defined as the time from study entry to death or date last known alive. Participants will be followed for survival after discontinuation of treatment every 3 months until subsequent therapy, withdrawal, or death.
    Time FrameFrom date of starting study treatment until the date of death from any cause

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    8. Secondary Outcome
    TitleRate of MRD Negative CR After 3 Cycles of iFCR
    DescriptionTo determine the rate of minimal residual disease negative complete response (MRD negative CR) in the bone marrow after 3 cycles of ibrutinib + FCR. Participants will have a bone marrow biopsy procedure after completing 3 cycles in tandem with a chest, neck, abdomen and pelvic PET CT scan. A central read of the PET CT scan will confirm a radiographic complete response, and the bone marrow pathology and morphology assessments will confirm morphological CR in the bone marrow, while MRD testing will be done by four-color flow cytometry on the bone marrow aspirate with a detection level of 10-4. Response and progression will be evaluated in this study using the 2008 IW-CLL criteria for CLL (Hallek et al., 2008)
    Time FrameAfter 3 cycles of iFCR for each patient completing 3 cycles; on average, after 12 weeks of treatment during which 1 bone marrow biopsy is performed and MRD is tested

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group TitleFCR +420mg Ibrutinib Daily
    Arm/Group DescriptionPatients received oral agent ipilimumab daily on days 1-28 of a 28 day cycle, except for Cycle 1, which lasts 35 with a 7 day ipilimumab run in, then will continue daily dosing.Fludarabine, cyclophosphamide, rituximab (FCR) will be given standard dosing intravenously (IV) Days 1-3 during week 1 of a cycle for up to 6 cycles, with dose reductions permitted. Patients will receive ibrutinib monotherapy indefinitely unless they are found to be minimal residual disease(MRD) negative in the bone marrow at the 24 months of ibrutinib maintenance timepoint, at which point they will discontinue ibrutinib to undergo active disease monitoring. If during active monitoring they develop MRD positivity in the blood, they may resume ibrutinib monotherapy. Patients are treated until progression without clinical benefit, toxicity, or withdrawal of consent by the patient, or closure of the trial by the Overall PI or regulatory authorities
    Measure Participants85
    Count of Participants [Participants]
    9
    10.6%
    9. Secondary Outcome
    TitleRate of MRD Negative CR After 1 Year of Ibrutinib+ FCR
    DescriptionTo determine the rate of minimal residual disease negative complete response (MRD negative CR) in the bone marrow at 12 months from start of therapy, participants will have a bone marrow biopsy procedure at the 1 year timepoint after completing combination therapy (ibrutinib + FCR) in tandem with a chest, neck, abdomen and pelvic PET CT scan. A central read of the PET CT scan will confirm a radiographic complete response, and the bone marrow pathology and morphology assessments will confirm morphological CR in the bone marrow, while MRD testing will be done by four-color flow cytometry on the bone marrow aspirate with a detection level of 10-4. Response and progression will be evaluated in this study using the 2008 IW-CLL criteria for CLL (Hallek et al., 2008)
    Time FrameAfter 12 months (1 year) from the start of therapy

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    10. Secondary Outcome
    TitleRate of MRD Negative CR After 2 Years of Ibrutinib Maintenance
    DescriptionTo determine the rate of minimal residual disease negative complete response (MRD negative CR) in the bone marrow at 24 months post last cycle of FCR, participants will have a bone marrow biopsy procedure 24 months after completing combination therapy (ibrutinib + FCR) in tandem with a chest, neck, abdomen and pelvic PET CT scan. A central read of the PET CT scan will confirm a radiographic complete response, and the bone marrow pathology and morphology assessments will confirm morphological CR in the bone marrow, while MRD testing will be done by four-color flow cytometry on the bone marrow aspirate with a detection level of 10-4. Response and progression will be evaluated in this study using the 2008 IW-CLL criteria for CLL (Hallek et al., 2008)
    Time Frame2 years (24 months) from start of therapy

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    11. Secondary Outcome
    TitleNumber of Participants Who Convert From Bone Marrow MRD Negative PR to Bone Marrow MRD Negative CR After 1 Year of Ibrutinib Maintenance
    DescriptionTo determine the rate of minimal residual disease negative complete response (MRD negative CR) in the bone marrow at 12 months from start of therapy, participants will have a bone marrow biopsy procedure at the 1 year timepoint after completing combination therapy (ibrutinib + FCR) in tandem with a chest, neck, abdomen and pelvic PET CT scan. A central read of the PET CT scan will confirm a radiographic complete response, and the bone marrow pathology and morphology assessments will confirm morphological CR in the bone marrow, while MRD testing will be done by four-color flow cytometry on the bone marrow aspirate with a detection level of 10-4. Response and progression will be evaluated in this study using the 2008 IW-CLL criteria for CLL (Hallek et al., 2008)
    Time Frame12 months ( 1year) after starting therapy

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    12. Secondary Outcome
    TitleNumber of Participants Who Convert From Bone Marrow MRD Negative PR to Bone Marrow MRD Negative CR After 2 Years on Treatment
    DescriptionMRD testing will be done by four-color flow cytometry on the bone marrow aspirate with a detection level of 10-4. Response and progression will be evaluated in this study using the 2008 IW-CLL criteria for CLL (Hallek et al., 2008)- Bone marrow biopsies will be performed at baseline, after cycle 3, 2 months post FCR, at 1 year and 2 years of ibrutinib maintenance, and as clinically indicated thereafter- Participants will have a bone marrow biopsy procedure 24 months after completing combination therapy (Ibrutinib+ FCR) in tandem with a chest, neck, abdomen and pelvic PET CT scan. A central read of the PET CT scan will confirm a radiographic complete response, and the bone marrow pathology and morphology assessments will confirm morphological CR in the bone marrow, while MRD testing will be done by four-color flow cytometry on the bone marrow aspirate with a detection level of 10-4.
    Time Frame2 years (24 months) from start of therapy

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    13. Secondary Outcome
    TitleTime to Bone Marrow MRD Negativity
    DescriptionMRD testing will be done by four-color flow cytometry on the bone marrow aspirate with a detection level of 10-4. Response and progression will be evaluated in this study using the 2008 IW-CLL criteria for CLL (Hallek et al., 2008)- Bone marrow biopsies will be performed at baseline, after cycle 3, 2 months post FCR, at 1 year and 2 years of ibrutinib maintenance, and as clinically indicated thereafter
    Time FrameFrom date of starting study treatment until achievement of MRD negativity in the bone marrow

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    14. Secondary Outcome
    TitleParticipants Who Convert From Bone Marrow MRD Negativity to MRD Positivity in Participants Who Discontinue Ibrutinib
    Description.MRD testing will be done by four-color flow cytometry on the bone marrow aspirate with a detection level of 10-4. Response and progression will be evaluated in this study using the 2008 IW-CLL criteria for CLL (Hallek et al., 2008)- Bone marrow biopsies will be performed at baseline, after cycle 3, 2 months post FCR, at 1 year and 2 years of ibrutinib maintenance, and as clinically indicated thereafter
    Time FrameFrom date of starting study treatment until achievement of MRD negativity in the bone marrow to conversion to MRD positivity

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description

    Adverse Events

    Time FrameAdverse events are assessed from the time the participants sign informed consent, and then are assessed by the study team at minimum every week during cycle 1, and day 1 of every cycle thereafter during combination, then every three cycles thereafter while in maintenance for the duration of their time on active treatment through study completion, an average of 3 years. Intra-cycle communication occurs throughout the treatment phase of the trial by electronic medical record secure email.
    Adverse Event Reporting Description Maximum grade toxicity by type-Serious AEs were defined as per DFCI criteria: Any grade 2, 3, or 4 unexpected and treatment related event, and all and 5 events regardless of attribution to study treatment , and includes events deemed medically important by overall PI. Other AEs were defined as events with the attribution of at least possibly related to the study treatment that did not meet the SAE criteria. CTCAE 4.0 was used in investigator assessment and lab value review.
    Arm/Group TitleFCR+Ibrutinib 420mg Daily
    Arm/Group DescriptionPatients received oral agent ipilimumab daily on days 1-28 of a 28 day cycle, except for Cycle 1, which lasts 35 with a 7 day ipilimumab run in, then will continue daily dosing. Fludarabine, cyclophosphamide, rituximab (FCR) will be given standard dosing intravenously (IV) Days 1-3 during week 1 of a cycle for up to 6 cycles, with dose reductions permitted. Patients will receive ibrutinib monotherapy indefinitely unless they are found to be minimal residual disease(MRD) negative in the bone marrow at the 24 months of ibrutinib maintenance timepoint, at which point they will discontinue ibrutinib to undergo active disease monitoring. If during active monitoring they develop MRD positivity in the blood, they may resume ibrutinib monotherapy. Patients are treated until progression without clinical benefit, toxicity, or withdrawal of consent by the patient, or closure of the trial by the Overall PI or regulatory authorities
    All Cause Mortality
    FCR+Ibrutinib 420mg Daily
    Affected / at Risk (%)# Events
    Total1/85 (1.2%)
    Serious Adverse Events
    FCR+Ibrutinib 420mg Daily
    Affected / at Risk (%)# Events
    Total24/85 (28.2%)
    Cardiac disorders
    Non-Cardiac Chest Pain1/85 (1.2%) 1
    Atrial Fibrillation1/85 (1.2%) 1
    Gastrointestinal disorders
    Pneumatosis1/85 (1.2%) 1
    Diarrhea1/85 (1.2%) 1
    General disorders
    Sudden Death1/85 (1.2%) 1
    Hepatobiliary disorders
    Cholecystitis1/85 (1.2%) 1
    Immune system disorders
    Hemophagocytic lymphohistiocytosis1/85 (1.2%) 1
    Infections and infestations
    Appendicitis1/85 (1.2%) 1
    Anaplasmosis1/85 (1.2%) 1
    Pneumocystis Jivrocii Pneumonia3/85 (3.5%) 3
    Respiratory Syncytial Virus1/85 (1.2%) 1
    Appendiceal Mucocele1/85 (1.2%) 1
    Sepsis2/85 (2.4%) 2
    Febrile Neutropenia1/85 (1.2%) 1
    Cellulitis1/85 (1.2%) 1
    Investigations
    Aspartate Aminotransferase Increased1/85 (1.2%) 1
    Lipase Increased1/85 (1.2%) 1
    Alanine Amintransferase Increased3/85 (3.5%) 3
    Metabolism and nutrition disorders
    Hypoglycemia1/85 (1.2%) 1
    Musculoskeletal and connective tissue disorders
    Spondylosis1/85 (1.2%) 1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Secondary Malignancy- Myelodysplastic Syndrome1/85 (1.2%) 1
    Psychiatric disorders
    Depression1/85 (1.2%) 1
    Other (Not Including Serious) Adverse Events
    FCR+Ibrutinib 420mg Daily
    Affected / at Risk (%)# Events
    Total85/85 (100%)
    Blood and lymphatic system disorders
    Leukocytosis18/85 (21.2%)
    Febrile neutropenia8/85 (9.4%)
    Cardiac disorders
    Palpitations12/85 (14.1%)
    Atrial fibrillation5/85 (5.9%)
    Gastrointestinal disorders
    Vomiting18/85 (21.2%)
    Gastroesophageal reflux disease15/85 (17.6%)
    Dyspepsia10/85 (11.8%)
    Abdominal pain8/85 (9.4%)
    Gastrointestinal disorders - Other, specify7/85 (8.2%)
    Dry mouth5/85 (5.9%)
    Mucositis oral5/85 (5.9%)
    General disorders
    Fever17/85 (20%)
    Edema limbs12/85 (14.1%)
    Pain9/85 (10.6%)
    Chills7/85 (8.2%)
    Infusion related reaction5/85 (5.9%)
    Localized edema5/85 (5.9%)
    Infections and infestations
    Upper respiratory infection18/85 (21.2%)
    Lung infection9/85 (10.6%)
    Sinusitis6/85 (7.1%)
    Investigations
    Aspartate aminotransferase increased25/85 (29.4%)
    Lymphocyte count increased20/85 (23.5%)
    Alanine aminotransferase increased17/85 (20%)
    Blood bilirubin increased16/85 (18.8%)
    Alkaline phosphatase increased10/85 (11.8%)
    Creatinine increased9/85 (10.6%)
    Investigations - Other, specify5/85 (5.9%)
    Metabolism and nutrition disorders
    Hyponatremia23/85 (27.1%)
    Hyperkalemia17/85 (20%)
    Hypokalemia15/85 (17.6%)
    Hypophosphatemia14/85 (16.5%)
    Hypoglycemia13/85 (15.3%)
    Hypomagnesemia13/85 (15.3%)
    Hypoalbuminemia9/85 (10.6%)
    Anorexia8/85 (9.4%)
    Hypernatremia5/85 (5.9%)
    Metabolism and nutrition disorders - Other, specify5/85 (5.9%)
    Musculoskeletal and connective tissue disorders
    Pain in extremity23/85 (27.1%)
    Myalgia20/85 (23.5%)
    Back pain13/85 (15.3%)
    Bone pain11/85 (12.9%)
    Musculoskeletal and connective tissue disorder - Other, specify9/85 (10.6%)
    Flank pain5/85 (5.9%)
    Neck pain5/85 (5.9%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specify7/85 (8.2%)
    Nervous system disorders
    Headache21/85 (24.7%)
    Dizziness12/85 (14.1%)
    Peripheral sensory neuropathy6/85 (7.1%)
    Psychiatric disorders
    Insomnia17/85 (20%)
    Anxiety12/85 (14.1%)
    Depression5/85 (5.9%)
    Respiratory, thoracic and mediastinal disorders
    Nasal congestion15/85 (17.6%)
    Dyspnea8/85 (9.4%)
    Epistaxis6/85 (7.1%)
    Sore throat6/85 (7.1%)
    Allergic rhinitis5/85 (5.9%)
    Skin and subcutaneous tissue disorders
    Rash acneiform26/85 (30.6%)
    Skin/subcutaneous tissue disorders; Other, specify21/85 (24.7%)
    Dry skin13/85 (15.3%)
    Rash maculo-papular11/85 (12.9%)
    Pruritus10/85 (11.8%)
    Hyperhidrosis5/85 (5.9%)
    Vascular disorders
    Hot flashes6/85 (7.1%)
    Hypertension6/85 (7.1%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    All Principal Investigators ARE employed by the organization sponsoring the study.

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/TitleMatthew Davids, MD
    OrganizationDana-Farber Cancer Institute
    Phone617-632-6331
    Emailmatthew_davids@dfci.harvard.edu
    Responsible Party:
    Matthew S. Davids, MD, Principal Investigator, Dana-Farber Cancer Institute
    ClinicalTrials.gov Identifier:
    NCT02251548
    Other Study ID Numbers:
    • 14-296
    First Posted:
    Sep 29, 2014
    Last Update Posted:
    Mar 21, 2022
    Last Verified:
    Mar 1, 2022