Study Title:

A Randomized Phase III Study of Ibrutinib (PCI-32765)-Based Therapy vs Standard Fludarabine, Cyclophosphamide, and Rituximab (FCR) Chemoimmunotherapy in Untreated Younger Patients With Chronic Lymphocytic Leukemia (CLL) Identifier:


National Cancer Institute


Cancer Trials Support Unit, National Cancer Institute

Participating Centers:

More than 600 sites in the United States

Accrual Goal:


Study Design:

This is a phase III randomized trial, with a two-to-one randomization to the ibrutinib arm (arm A) of 346 patients and to the FCR control arm (arm B) of 173 patients.

Inclusion criteria include a diagnosis of CLL according to the National Cancer Institute or International Workshop on CLL criteria, no prior chemotherapy or antibody therapy for CLL or for small lymphocytic lymphoma, at least one criterion for initiation of treatment, ages 18 through 70 years, ECOG performance status 0 to 2, life expectancy of 12 months or longer, no deletion of 17p13 by fluorescence in-situ hybridization (FISH), and adequate renal and hepatic function. The acceptable criteria for initiation of treatment include anemia, thrombocytopenia, symptomatic or progressive lymphadenopathy or hepatosplenomegaly, weight loss, moderate fatigue, fever, and night sweats. Exclusion criteria include active hemolytic anemia, corticosteroids ≥ 10 mg prednisone daily, active prior malignancy with certain exceptions, major surgery or radiation therapy within four weeks, active hepatitis, pregnancy, cardiac disease, or a cerebrovascular accident. Treatment on arm A consists of oral ibrutinib with IV rituximab for seven cycles, then continuous oral ibrutinib until disease progression; arm B consists of six cycles of fludarabine and cyclophosphamide IV daily for three days and rituximab on day 1 of each cycle except split dosing on days 1 and 2 for cycle 1.

The primary objective of the trial is to assess the ability of ibrutinib-based induction therapy to prolong progression-free survival (PFS) as compared with FCR, the standard chemoimmunotherapy regimen. Secondary objectives include evaluation of overall survival (OS), relative toxicity, quality of life (both short and long term), correlation of pretreatment characteristics with outcomes, longitudinal evaluation of minimal residual disease (MRD), genetic examination and monitoring of clonal evolution, examination of T-cell function, and signaling networks downstream of the B-cell receptor. A prognostic model that incorporates clinical and biologic characteristics will be used to predict PFS and OS. Laboratory specimens will be collected for biomarker and diagnostic analysis, and relapse specimens will be collected to analyze for mechanisms of resistance.


FCR has exhibited a high response rate – 95 percent overall with a 72 percent complete response (CR) – and an excellent duration of response with median time to progression of 80 months, especially for patients who achieve a CR without MRD, for whom the median time to progression is 89 months.1  In two meta analyses of upfront regimens for CLL, FCR has been the leader in terms of PFS and/or OS.2,3  However, FCR is an intensive regimen, with a high rate of serious adverse events, such as cytopenias and infections. In particular, FCR can be difficult for older patients,4  and as 70 is the average age at diagnosis of CLL, the regimen is perceived as too toxic for many individuals. Moreover, prolonged cytopenias (19% lasting > three months),1  and therapy-related myelodysplastic syndrome/acute myeloid leukemia are ever-present concerns.5 

Ibrutinib, a Bruton tyrosine kinase inhibitor, has been a successful therapy for several B-cell malignancies, and it has received U.S. Food and Drug Administration approval for mantle cell lymphoma with at least one prior treatment, CLL with at least one prior treatment, upfront CLL with del17p, and Waldenström macroglobulinemia. These approvals have been in rapid succession between November 2013 and January 2015, with impressive results even as a single agent. There are ongoing trials in follicular lymphoma, central nervous system lymphoma, multiple myeloma, diffuse large B-cell lymphoma, and other cancers, as well as combination trials for many indications. The combination of ibrutinib and rituximab has been studied in phase II trials in CLL.6  There have also been reports that ibrutinib interferes with the response of CLL cells to rituximab in laboratory studies,7,8  which may have implications for the efficacy of the combination in the clinic.


FCR has remained the standard intensive treatment for CLL for a decade, but IR will certainly be a formidable opponent in the randomized study. It remains to be seen whether there will be similar rates of failure and development of resistance and whether there will be different rates of PFS and OS. Moreover, the trial includes laboratory correlative studies that will likely reveal clinical features and, possibly, biomarkers or molecular signatures associated with response to the two regimens.


Tam CS, O'Brien S, Wierda W, et al.
Long-term results of the fludarabine, cyclophosphamide, and rituximab regimen as initial therapy of chronic lymphocytic leukemia.
Messori A, Fadda V, Maratea D, et al.
First-line treatments for chronic lymphocytic leukaemia: interpreting efficacy data by network meta-analysis.
Ann Hematol.
2015 [Epub ahead of print].
Ladyzynski P, Molik M, Foltynski P, et al.
A network meta-analysis of progression free survival and overall survival in first-line treatment of chronic lymphocytic leukemia.
Cancer Treat Rev.
Shah N, Tam C, Seymour JF, et al.
How applicable is fludarabine, cyclophosphamide and rituximab to the elderly?
Leuk Lymphoma.
2014;1-12 [Epub ahead of print].
Benjamini O, Jain P, Trinh L, et al.
Second cancers in patients with chronic lymphocytic leukemia who received frontline fludarabine, cyclophosphamide and rituximab therapy: distribution and clinical outcomes .
Leuk Lymphoma.
2014 [Epub ahead of print].
Burger JA, Keating MJ, Wierda WG, et al.
Safety and activity of ibrutinib plus rituximab for patients with high-risk chronic lymphocytic leukaemia: a single-arm, phase 2 study.
Lancet Oncol.
Da Roit F, Engelberts PJ, Taylor RP, et al.
Ibrutinib interferes with the cell-mediated anti-tumor activities of therapeutic CD20 antibodies: implications for combination therapy.
Borge M, Almejún MB, Podaza E, et al.
Ibrutinib impairs the phagocytosis of rituximab-coated leukemic cells from chronic lymphocytic leukemia patients by human macrophages.
2015 [Epub ahead of print].

Competing Interests

Dr. Becker is a member of the Southwest Oncology Group, and her institution will be participating in the trial.