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. Identifier: NCT02251548
Recruitment Status : Active, not recruiting
First Posted : September 29, 2014
Last Update Posted : May 7, 2018
Pharmacyclics LLC.
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.

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 85 participants
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
Study Start Date : October 2014
Estimated 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. Rate of MRD Negative Complete Response [ Time Frame: 2 months after completing combination therapy ]
    Clopper-Pearson binomial method

Secondary Outcome Measures :
  1. Rate of MRD-negative CR [ Time Frame: after 3 cycles of iFCR, 1 year, 2 years ]
  2. Percentage of Overall Response Rate [ Time Frame: 2 months after completing combination therapy ]
    2008 IW-CLL criteria

  3. Percentage of Complete Response Rate [ Time Frame: 2 months after completing combination therapy ]
    2008 IW-CLL criteria

  4. Percentage Rate of Partial Response [ Time Frame: 2 months after completing combination therapy ]
    2008 IW-CLL criteria

  5. Rate of Progression Free of Survival [ Time Frame: From date of starting study treatment until the date of first documented progression or date of death from any cause, whichever came first ]
    2008 IW-CLL criteria

  6. Rate of Overall Survival [ Time Frame: From date of starting study treatment until the date of death from any cause ]
    2008 IW-CLL criteria

  7. Time to MRD-negativity [ Time Frame: After 3 cycles of iFCR, 1 year, 2 year ]
    To determine the time to MRD-negativity for patients who achieve MRD-negativity

  8. Number of Participants with Serious and Non-Serious Adverse Events [ Time Frame: From date of starting study treatment until 30 days after completing study treatment, or in the case of ongoing SAEs until the date of resolution of the SAE ]
  9. Association of established CLL prognostic factors including FISH cytogenetics, IGHV mutation status, and TP53 mutation with clinical response [ Time Frame: 2 months after completing combination therapy ]

Information from the National Library of Medicine

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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

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 identifier (NCT number): NCT02251548

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

Responsible Party: Matthew S. Davids, MD, Principal Investigator, Dana-Farber Cancer Institute Identifier: NCT02251548     History of Changes
Other Study ID Numbers: 14-296
First Posted: September 29, 2014    Key Record Dates
Last Update Posted: May 7, 2018
Last Verified: May 2018
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

Additional relevant MeSH terms:
Fludarabine phosphate
Leukemia, Lymphoid
Leukemia, Lymphocytic, Chronic, B-Cell
Neoplasms by Histologic Type
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Leukemia, B-Cell
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antimetabolites, Antineoplastic