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A Randomized, Multicenter, Open-label, Phase 3 Study of the Bruton's Tyrosine Kinase Inhibitor PCI-32765 Versus Chlorambucil in Patients 65 Years or Older With Treatment-naive Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma (RESONATE™-2)

Phase 3
65 Years
Open (Enrolling)
Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma

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Trial Information

A Randomized, Multicenter, Open-label, Phase 3 Study of the Bruton's Tyrosine Kinase Inhibitor PCI-32765 Versus Chlorambucil in Patients 65 Years or Older With Treatment-naive Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma (RESONATE™-2)

Study design: This is a randomized, multicenter, open-label, Phase 3 study designed to
compare the safety and efficacy of PCI-32765 versus chlorambucil in treatment-naive patients
65 years or older who have CLL or SLL.

Eligible patients will be randomized in a 1:1 ratio to Treatment Arm A or B:

- Treatment Arm A: Oral chlorambucil 0.5 mg/kg on Days 1 and 15 of each 28-day cycle;
the dose can be increased, if well tolerated, in increments of 0.1 mg/kg on Day 1 of
each cycle to a maximum of 0.8 mg/kg; patients receive a minimum of 3 and a maximum of
12 cycles, in the absence of progressive disease or unacceptable toxicity

- Treatment Arm B: Oral PCI-32765 420 mg/day Randomization will be stratified on Eastern
Cooperative Oncology Group (ECOG) performance status (0,1 versus 2); presence of
advanced Rai stage (yes/no), advanced being defined as Stages 3-4; and geographic
region: US versus non-US.

Inclusion Criteria:

1. Males or females of 65 years of age or greater. Patients between the ages of 65 and
70 years of age must have 1 or more of the following comorbidities that may preclude
the use of frontline chemo-immunotherapy with fludarabine, cyclophosphamide, or

- creatinine clearance < 70 mL/min using the Cockcroft-Gault equation

- platelet count < 100,000/μL or hemoglobin < 10 g/dL

- clinically apparent autoimmune cytopenia (autoimmune hemolytic anemia or immune

- ECOG performance score = 1 or 2

2. Diagnosis of CLL/SLL that meets IWCLL diagnostic criteria (Hallek 2008)

3. Active disease meeting at least 1 of the following IWCLL criteria (Hallek 2008) for
requiring treatment:

- Evidence of progressive marrow failure as manifested by the development of, or
worsening of, anemia and/or thrombocytopenia Massive, progressive, or
symptomatic splenomegaly

- Massive nodes or progressive or symptomatic lymphadenopathy

- Progressive lymphocytosis

- Autoimmune hemolytic anemia and/or immune thrombocytopenia that is poorly
responsive to corticosteroids or standard therapy

- Constitutional symptoms

4. Measurable nodal disease by computed tomography (CT)

5. ECOG performance status of 0-2

6. Life expectancy > 4 months from randomization

7. Adequate hematologic function, defined as absolute neutrophil count (ANC) ≥ 1,000/μL
(independent of growth factor support for at least 7 days prior to screening) and
platelet count ≥ 50,000/μL (independent of transfusion and growth factor support for
at least 7 days prior to screening)

8. Adequate hepatic function, defined as serum aspartate transaminase (AST) and alanine
transaminase (ALT) < 2.5 x upper limit of normal (ULN), and total bilirubin ≤ 1.5 x

9. Adequate renal function, defined as estimated creatinine clearance ≥ 30 mL/min using
the Cockcroft-Gault equation

10. Willingness to receive all outpatient treatment, all laboratory monitoring, and all
radiological evaluations at the institution that administers study drug for the
entire study

11. Willingness of male patients, if sexually active with a female of childbearing
potential, to use an effective barrier method of contraception during the study and
for 3 months following the last dose of study drug

12. Ability to provide written informed consent and to understand and comply with the
requirements of the study

Exclusion Criteria:

1. Known involvement of the central nervous system by lymphoma or leukemia

2. History or current evidence of Richter's transformation or prolymphocytic leukemia

3. Documentation of deletion of the short arm of chromosome 17: del(17p13.1) in more
than 20% of cells examined on any pretreatment fluorescence in situ hybridization
(FISH) or cytogenetic evaluation

4. Uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenic purpura

5. Any previous treatment (chemotherapy, radiotherapy, and/or monoclonal antibodies)
intended specifically to treat CLL/SLL

6. Received any immunotherapy, vaccine, or investigational drug within 4 weeks prior to

7. Corticosteroid use within 1 week prior to first dose of study drug, with the
exception of inhaled, topical, or other local administrations. Patients requiring
systemic steroids at daily doses > 20 mg prednisone (or corticosteroid equivalent,
see Appendix N), or those who are administered steroids for leukemia control or white
blood cell (WBC)-count-lowering are excluded.

8. Major surgery within 4 weeks prior to randomization

9. History of prior malignancy, with the exception of the following:

- malignancy treated with curative intent and with no evidence of active disease
present for more than 3 years prior to screening and felt to be at low risk for
recurrence by treating physician

- adequately treated nonmelanomatous skin cancer or lentigo maligna melanoma
without current evidence of disease

- adequately treated cervical carcinoma in situ without current evidence of

10. Currently active, clinically significant cardiovascular disease or a history of
myocardial infarction within 6 months prior to randomization

11. Inability to swallow capsules or tablets, or disease significantly affecting
gastrointestinal function

12. Uncontrolled active systemic fungal, bacterial, viral, or other infection or
requirement for intravenous (IV) antibiotics

13. Known history of infection with human immunodeficiency virus (HIV)

14. Serologic status reflecting active hepatitis B or C infection

15. History of stroke or intracranial hemorrhage within 6 months prior to enrollment

16. Current life-threatening illness, medical condition, or organ-system dysfunction that
could compromise patient safety or put the study at risk

17. Requirement for anticoagulation with warfarin

18. Requirement for treatment with a strong CYP3A4/5 and/or CYP2D6 inhibitor

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

The primary endpoint of this study is PFS as assessed by IRC review according to IWCLL 2008 criteria with modification for treatment-related lymphocytosis

Outcome Description:

Assessment of response should include physical examination, radiographic imaging, and evaluation of blood and marrow (if applicable). Patients who withdraw from the study or are considered lost to follow-up without prior documentation of disease progression will be censored on the date of the last adequate disease assessment. Patients who start new anticancer therapy before documentation of disease progression will be censored on the date of the last adequate disease assessment that is on or before the start date of the new anticancer therapy. For patients without an adequate post-baseline disease assessment, PFS will be censored on the date of randomization. Patients who have 2 or more consecutive missing disease assessments immediately before PD or death will be censored for analysis of PFS at the time of last adequate disease assessment. The adequate disease assessment is defined as physical examination and CBC, or CBC and CT scan.

Outcome Time Frame:

All enrolled patients have completed at least 12 months of treatment and/or follow-up and either (a) 81 progression or death events have been observed or (b) 15 months have elapsed after the last patient is randomized, whichever occurs first.

Safety Issue:


Principal Investigator

Alvina Chu, MD

Investigator Role:

Study Director

Investigator Affiliation:



United States: Food and Drug Administration

Study ID:




Start Date:

January 2013

Completion Date:

February 2016

Related Keywords:

  • Chronic Lymphocytic Leukemia
  • Small Lymphocytic Lymphoma
  • CLL, SLL
  • Leukemia
  • Leukemia, Lymphocytic, Chronic, B-Cell
  • Leukemia, Lymphoid
  • Lymphoma



University of MichiganAnn Arbor, Michigan  48109-0624
MD Anderson Cancer CenterHouston, Texas  77030-4096
City of Hope National Medical CenterLos Angeles, California  91010
Stanford Cancer CenterStanford, California  94305-5824
University of RochesterRochester, New York  14642
Washington UniversitySt. Louis, Missouri  63110
UPMC Cancer PavillionPittsburgh, Pennsylvania  15232
Peachtree Hematology Oncology ConsultantsAtlanta, Georgia  30309
UCSD Medical Center Thorton HospitalLa Jolla, California  92307
University of Chicago - Oncology DeptChicago, Illinois  60637
Norton Cancer Institute - PavilionLouisville, Kentucky  40202
U Mass Memorial University CampusWorcester, Massachusetts  01655
410 Lakeville RoadNew Hyde Park, New York  11040
Southeastern MedicalGoldsboro, North Carolina  27534
South Texas Research Alliance LLCLaredo, Texas  78041
Oncology of San AntonioSan Antonio, Texas  78240