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

NCT02251548 | Active Not Recruiting Phase 2 Results DMC

• 1 other identifier: 14-296
• Study Type: interventional
• Target: 85
• Locations: 1 country
• Sites: 9

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).

Conditions

Chronic Lymphocytic Leukemia; Leukemia

Keywords

Chronic lymphocytic leukemia; Leukemia

Outcome Measures

Primary Outcomes (2)

• Part I: Participants Who Achieve a Minimal Residual Disease (MRD) Negative Complete Response (CR) in the Bone Marrow at 2 Months Post FCR

  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 months after completing combination therapy

• 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

  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).

  2 years post discontinuation of ibrutinib after 24 months of ibrutinib maintenance

Secondary Outcomes (11)

• Overall Response Rate

  Response evaluated at 2 months post iFCR. Treatment up to 6 cycles (28 days each).

• Complete Response Rate (CRR)

  Response evaluated at 2 months post iFCR. Treatment up to 6 cycles (28 days each).

• Partial Response Rate (PRR)

  Response evaluated at 2 months post iFCR. Treatment up to 6 cycles (28 days each).

• Median Progression-Free Survival (PFS)

  Disease will be evaluated through imaging cycle 3-6 day 1, and In long-term follow-up, after removal or until participant withdrawal, death, or removal from study. Median follow-up is: 63.24 months (range: 6.83-95.8).

• Median Overall Survival (OS)

  Median follow-up is: 63.24 months (range: 6.83-95.8).

Study Arms (1)

Ibrutinib

EXPERIMENTAL

\- 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; Drug: Fludarabine; Drug: Cyclophosphamide; Drug: Rituximab

Interventions

Ibrutinib DRUG

Oral BTK inhibitor

Also known as: Imbruvica™

Ibrutinib

Fludarabine DRUG

IV purine analogue chemotherapy agent

Also known as: Fludara

Ibrutinib

Cyclophosphamide DRUG

IV alkylator chemotherapy agent

Also known as: Cytoxan®, Neosar®

Ibrutinib

Rituximab DRUG

IV anti-CD20 monoclonal antibody

Also known as: Rituxan®

Ibrutinib

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

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

Study Sites (9)

University of Miami Sylvester Comprehensive Cancer Center

Coral Gables, Florida, 33146, United States

Location

University of Miami Sylvester Comprehensive Cancer Center

Deerfield Beach, Florida, 33442, United States

Location

Unversity of Miami Sylvester Comprehensve Cancer Center

Miami, Florida, 33136, United States

Location

University of Kansas Cancer Center

Westwood, Kansas, 66205, United States

Location

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

Beth Israel Deaconess Medical Center

Boston, Massachusetts, 02215, United States

Location

Dana Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

West Michigan Cancer Center

Kalamazoo, Michigan, 49007, United States

Location

Duke University Medical Center

Durham, North Carolina, 27710, United States

Location

Related Publications (2)

• Ahn IE, Brander DM, Ren Y, Zhou Y, Tyekucheva S, Walker HA, Black R, Montegaard J, Alencar A, Shune L, Omaira M, Jacobson CA, Armand P, Ng SY, Crombie J, Fisher DC, LaCasce AS, Arnason J, Hochberg EP, Takvorian RW, Abramson JS, Brown JR, Davids MS. Five-year follow-up of a phase 2 study of ibrutinib plus fludarabine, cyclophosphamide, and rituximab as initial therapy in CLL. Blood Adv. 2024 Feb 27;8(4):832-841. doi: 10.1182/bloodadvances.2023011574.

  PMID: 38163317 DERIVED

• Davids MS, Brander DM, Kim HT, Tyekucheva S, Bsat J, Savell A, Hellman JM, Bazemore J, Francoeur K, Alencar A, Shune L, Omaira M, Jacobson CA, Armand P, Ng S, Crombie J, LaCasce AS, Arnason J, Hochberg EP, Takvorian RW, Abramson JS, Fisher DC, Brown JR; Blood Cancer Research Partnership of the Leukemia & Lymphoma Society. Ibrutinib plus fludarabine, cyclophosphamide, and rituximab as initial treatment for younger patients with chronic lymphocytic leukaemia: a single-arm, multicentre, phase 2 trial. Lancet Haematol. 2019 Aug;6(8):e419-e428. doi: 10.1016/S2352-3026(19)30104-8. Epub 2019 Jun 14.

  PMID: 31208944 DERIVED

MeSH Terms

Conditions

Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia

Interventions

ibrutinib; fludarabine; fludarabine phosphate; Cyclophosphamide; Rituximab

Condition Hierarchy (Ancestors)

Leukemia, B-Cell; Leukemia, Lymphoid; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Results Point of Contact

• Title: Matthew Davids, MD
• Organization: Dana-Farber Cancer Institute

matthew_davids@dfci.harvard.edu

617-632-6331

Study Officials

• Matthew Davids, MD

  Dana-Farber Cancer Institute

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: September 23, 2014
• First Posted: September 29, 2014
• Study Start: October 1, 2014
• Primary Completion: January 1, 2025
• Study Completion (Estimated): January 1, 2027
• Last Updated: October 24, 2025
• Results First Posted: May 15, 2020

Record last verified: 2025-09

Data Sharing

• IPD Sharing: Will not share

Locations

US (9)