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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02251548
Recruitment Status : Active, not recruiting
First Posted : September 29, 2014
Results First Posted : May 15, 2020
Last Update Posted : May 15, 2020
Sponsor:
Collaborators:
Pharmacyclics LLC.
The Leukemia and Lymphoma Society
Blood Cancer Research Partnership
Information provided by (Responsible Party):
Matthew S. Davids, MD, Dana-Farber Cancer Institute

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.

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Study Type : Interventional  (Clinical Trial)
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 : October 2014
Actual Primary Completion Date : January 2019
Estimated Study Completion Date : January 2022


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 Name: Imbruvica™

Drug: Fludarabine
IV purine analogue chemotherapy agent
Other Name: Fludara

Drug: Cyclophosphamide
IV alkylator chemotherapy agent
Other Names:
  • Cytoxan®
  • Neosar®

Drug: Rituximab
IV anti-CD20 monoclonal antibody
Other Name: Rituxan®




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 [ Time Frame: 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 [ Time Frame: 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 [ 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 ]
    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 [ 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 ]
    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 [ 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 ]
    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 [ Time Frame: 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 [ Time Frame: 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 [ 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 ]
    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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02251548


Locations
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United States, Florida
University of Miami Sylvester Comprehensive Cancer Center
Coral Gables, Florida, United States, 33146
University of Miami Sylvester Comprehensive Cancer Center
Deerfield Beach, Florida, United States, 33442
Unversity of Miami Sylvester Comprehensve Cancer Center
Miami, Florida, United States, 33136
United States, Kansas
University of Kansas Cancer Center
Westwood, Kansas, United States, 66205
United States, Massachusetts
Massachusetts General Hospital
Boston, Massachusetts, United States, 02114
Beth Israel Deaconess Medical Center
Boston, Massachusetts, United States, 02215
Dana Farber Cancer Institute
Boston, Massachusetts, United States, 02215
United States, Michigan
West Michigan Cancer Center
Kalamazoo, Michigan, United States, 49007
United States, North Carolina
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
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Principal Investigator: Matthew Davids, MD Dana-Farber Cancer Institute
  Study Documents (Full-Text)

Documents provided by Matthew S. Davids, MD, Dana-Farber Cancer Institute:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Matthew S. Davids, MD, Principal Investigator, Dana-Farber Cancer Institute
ClinicalTrials.gov Identifier: NCT02251548    
Other Study ID Numbers: 14-296
First Posted: September 29, 2014    Key Record Dates
Results First Posted: May 15, 2020
Last Update Posted: May 15, 2020
Last Verified: May 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Keywords provided by Matthew S. Davids, MD, Dana-Farber Cancer Institute:
Chronic lymphocytic leukemia
Leukemia
Additional relevant MeSH terms:
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Fludarabine
Leukemia
Leukemia, Lymphoid
Leukemia, Lymphocytic, Chronic, B-Cell
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Leukemia, B-Cell
Cyclophosphamide
Rituximab
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antineoplastic Agents, Immunological