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)
• Enrollment: 85
• Locations: 9
• Arm: 1
• Anticipated Duration (Months): 123
• Patients Per Site: 9.4
• Patients Per Site Per Month: 0.1

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).

Condition or Disease	Intervention/Treatment	Phase
Chronic Lymphocytic Leukemia; Leukemia	Drug: Ibrutinib; Drug: Fludarabine; Drug: Cyclophosphamide; Drug: Rituximab	Phase 2

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

Arm	Intervention/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

	Site	City	State	Country	Postal Code
1	University of Miami Sylvester Comprehensive Cancer Center	Coral Gables	Florida	United States	33146
2	University of Miami Sylvester Comprehensive Cancer Center	Deerfield Beach	Florida	United States	33442
3	Unversity of Miami Sylvester Comprehensve Cancer Center	Miami	Florida	United States	33136
4	University of Kansas Cancer Center	Westwood	Kansas	United States	66205
5	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
6	Beth Israel Deaconess Medical Center	Boston	Massachusetts	United States	02215
7	Dana Farber Cancer Institute	Boston	Massachusetts	United States	02215
8	West Michigan Cancer Center	Kalamazoo	Michigan	United States	49007
9	Duke University Medical Center	Durham	North Carolina	United States	27710

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)

• Study Protocol and Statistical Analysis Plan - Jul 11, 2017

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: Chronic lymphocytic leukemia; Leukemia
• Additional relevant MeSH terms: Leukemia; Leukemia, Lymphoid; Leukemia, Lymphocytic, Chronic, B-Cell; Cyclophosphamide; Rituximab; Fludarabine

Study Results

Participant Flow

Recruitment Details	The 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.

Arm/Group Title	FCR +420mg Ibrutinib Daily
Arm/Group Description	Patients 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
STARTED	85
COMPLETED	0
NOT COMPLETED	85

Baseline Characteristics

Arm/Group Title	FCR+ 420 mg Ibrutinib Daily
Arm/Group Description	Patients 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 Participants	85
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

Title	Part I: Participants Who Achieve a Minimal Residual Disease (MRD) Negative Complete Response (CR) in the Bone Marrow at 2 Months Post FCR
Description	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.
Time Frame	2 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 Title	FCR+ 420mg Ibrutinib Daily
Arm/Group Description	Patients 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 Participants	85
Count of Participants [Participants]	28 32.9%

2. Primary Outcome

Title	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
Description	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).
Time Frame	2 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 Title	FCR+ 420mg Ibrutinib Daily
Arm/Group Description	Patients 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 Participants	0

3. Secondary Outcome

Title	Overall Response Rate
Description	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
Time Frame	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

4. Secondary Outcome

Title	Rate of Complete Response
Description	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).
Time Frame	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

5. Secondary Outcome

Title	Rate of Partial Response
Description	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).
Time Frame	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

6. Secondary Outcome

Title	Rate of Progression Free of Survival
Description	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.
Time Frame	From 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

Title	Rate of Overall Survival
Description	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.
Time Frame	From 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

Title	Rate of MRD Negative CR After 3 Cycles of iFCR
Description	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)
Time Frame	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	FCR +420mg Ibrutinib Daily
Arm/Group Description	Patients 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 Participants	85
Count of Participants [Participants]	9 10.6%

9. Secondary Outcome

Title	Rate of MRD Negative CR After 1 Year of Ibrutinib+ FCR
Description	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)
Time Frame	After 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

Title	Rate of MRD Negative CR After 2 Years of Ibrutinib Maintenance
Description	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)
Time Frame	2 years (24 months) from start of therapy

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

11. Secondary Outcome

Title	Number of Participants Who Convert From Bone Marrow MRD Negative PR to Bone Marrow MRD Negative CR After 1 Year of Ibrutinib Maintenance
Description	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)
Time Frame	12 months ( 1year) after starting therapy

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

12. Secondary Outcome

Title	Number of Participants Who Convert From Bone Marrow MRD Negative PR to Bone Marrow MRD Negative CR After 2 Years on Treatment
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- 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 Frame	2 years (24 months) from start of therapy

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

13. Secondary Outcome

Title	Time to Bone Marrow MRD Negativity
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 Frame	From 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

Title	Participants 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 Frame	From 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 Frame	Adverse 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 Title	FCR+Ibrutinib 420mg Daily
Arm/Group Description	Patients 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
Total	1/85 (1.2%)
Serious Adverse Events
	FCR+Ibrutinib 420mg Daily
	Affected / at Risk (%)	# Events
Total	24/85 (28.2%)
Cardiac disorders
Non-Cardiac Chest Pain	1/85 (1.2%)	1
Atrial Fibrillation	1/85 (1.2%)	1
Gastrointestinal disorders
Pneumatosis	1/85 (1.2%)	1
Diarrhea	1/85 (1.2%)	1
General disorders
Sudden Death	1/85 (1.2%)	1
Hepatobiliary disorders
Cholecystitis	1/85 (1.2%)	1
Immune system disorders
Hemophagocytic lymphohistiocytosis	1/85 (1.2%)	1
Infections and infestations
Appendicitis	1/85 (1.2%)	1
Anaplasmosis	1/85 (1.2%)	1
Pneumocystis Jivrocii Pneumonia	3/85 (3.5%)	3
Respiratory Syncytial Virus	1/85 (1.2%)	1
Appendiceal Mucocele	1/85 (1.2%)	1
Sepsis	2/85 (2.4%)	2
Febrile Neutropenia	1/85 (1.2%)	1
Cellulitis	1/85 (1.2%)	1
Investigations
Aspartate Aminotransferase Increased	1/85 (1.2%)	1
Lipase Increased	1/85 (1.2%)	1
Alanine Amintransferase Increased	3/85 (3.5%)	3
Metabolism and nutrition disorders
Hypoglycemia	1/85 (1.2%)	1
Musculoskeletal and connective tissue disorders
Spondylosis	1/85 (1.2%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Secondary Malignancy- Myelodysplastic Syndrome	1/85 (1.2%)	1
Psychiatric disorders
Depression	1/85 (1.2%)	1
Other (Not Including Serious) Adverse Events
	FCR+Ibrutinib 420mg Daily
	Affected / at Risk (%)	# Events
Total	85/85 (100%)
Blood and lymphatic system disorders
Leukocytosis	18/85 (21.2%)
Febrile neutropenia	8/85 (9.4%)
Cardiac disorders
Palpitations	12/85 (14.1%)
Atrial fibrillation	5/85 (5.9%)
Gastrointestinal disorders
Vomiting	18/85 (21.2%)
Gastroesophageal reflux disease	15/85 (17.6%)
Dyspepsia	10/85 (11.8%)
Abdominal pain	8/85 (9.4%)
Gastrointestinal disorders - Other, specify	7/85 (8.2%)
Dry mouth	5/85 (5.9%)
Mucositis oral	5/85 (5.9%)
General disorders
Fever	17/85 (20%)
Edema limbs	12/85 (14.1%)
Pain	9/85 (10.6%)
Chills	7/85 (8.2%)
Infusion related reaction	5/85 (5.9%)
Localized edema	5/85 (5.9%)
Infections and infestations
Upper respiratory infection	18/85 (21.2%)
Lung infection	9/85 (10.6%)
Sinusitis	6/85 (7.1%)
Investigations
Aspartate aminotransferase increased	25/85 (29.4%)
Lymphocyte count increased	20/85 (23.5%)
Alanine aminotransferase increased	17/85 (20%)
Blood bilirubin increased	16/85 (18.8%)
Alkaline phosphatase increased	10/85 (11.8%)
Creatinine increased	9/85 (10.6%)
Investigations - Other, specify	5/85 (5.9%)
Metabolism and nutrition disorders
Hyponatremia	23/85 (27.1%)
Hyperkalemia	17/85 (20%)
Hypokalemia	15/85 (17.6%)
Hypophosphatemia	14/85 (16.5%)
Hypoglycemia	13/85 (15.3%)
Hypomagnesemia	13/85 (15.3%)
Hypoalbuminemia	9/85 (10.6%)
Anorexia	8/85 (9.4%)
Hypernatremia	5/85 (5.9%)
Metabolism and nutrition disorders - Other, specify	5/85 (5.9%)
Musculoskeletal and connective tissue disorders
Pain in extremity	23/85 (27.1%)
Myalgia	20/85 (23.5%)
Back pain	13/85 (15.3%)
Bone pain	11/85 (12.9%)
Musculoskeletal and connective tissue disorder - Other, specify	9/85 (10.6%)
Flank pain	5/85 (5.9%)
Neck pain	5/85 (5.9%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specify	7/85 (8.2%)
Nervous system disorders
Headache	21/85 (24.7%)
Dizziness	12/85 (14.1%)
Peripheral sensory neuropathy	6/85 (7.1%)
Psychiatric disorders
Insomnia	17/85 (20%)
Anxiety	12/85 (14.1%)
Depression	5/85 (5.9%)
Respiratory, thoracic and mediastinal disorders
Nasal congestion	15/85 (17.6%)
Dyspnea	8/85 (9.4%)
Epistaxis	6/85 (7.1%)
Sore throat	6/85 (7.1%)
Allergic rhinitis	5/85 (5.9%)
Skin and subcutaneous tissue disorders
Rash acneiform	26/85 (30.6%)
Skin/subcutaneous tissue disorders; Other, specify	21/85 (24.7%)
Dry skin	13/85 (15.3%)
Rash maculo-papular	11/85 (12.9%)
Pruritus	10/85 (11.8%)
Hyperhidrosis	5/85 (5.9%)
Vascular disorders
Hot flashes	6/85 (7.1%)
Hypertension	6/85 (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.