Clinical trial NCT01292135: Safety and Tolerability Study of PCI-32765 Combined With Fludarabine/Cyclophosphamide/Rituximab (FCR) and Bendamustine/Rituximab (BR) in Chronic Lymphocytic Leukemia (CLL)
Official title: A Phase 1b, Multicenter, Open-label, Parallel-group Safety Study of a Bruton's Tyrosine Kinase (Btk) Inhibitor, PCI 32765, in Combination With Chemotherapy in Subjects With Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: B-cell Chronic Lymphocytic Leukemia
Small Lymphocytic Lymphoma
Keywords: Lymphoma, B-Cell
Leukemia, Lymphoid
Leukemia, B-Cell
Bruton's Tyrosine Kinase
Lead sponsor: Pharmacyclics LLC.
Sponsor class: INDUSTRY
First posted: 2011-02-09
Enrollment: 33
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to establish the safety of orally administered PCI-32765 in combination with fludarabine/cyclophosphamide/rituximab (FCR) and bendamustine/rituximab (BR) in patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma(SLL).

Detailed description: This is a Phase 1b, open-label, parallel-group, nonrandomized, multicenter study of PCI 32765 420 mg once daily oral (PO) administration in combination with 2 different chemotherapy regimens in subjects with relapsed/refractory chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL).

Eligibility criteria: Inclusion Criteria:

1. Histologically confirmed CLL or SLL and satisfying at least 1 of the following criteria for requiring treatment:

   * Progressive splenomegaly and/or lymphadenopathy identified by physical examination or radiographic studies
   * Anemia (\<11 g/dL) or thrombocytopenia (\<100,000/μL) due to bone marrow involvement
   * Presence of unintentional weight loss \> 10% over the preceding 6 months
   * NCI CTCAE Grade 2 or 3 fatigue
   * Fevers \> 100.5° or night sweats for \> 2 weeks without evidence of infection
   * Progressive lymphocytosis with an increase of \> 50% over a 2 month period or an anticipated doubling time of \< 6 months
2. 1 to 3 prior treatment regimens for CLL/SLL
3. ECOG performance status of ≤ 1
4. ≥ 18 years of age
5. Willing and able to participate in all required evaluations and procedures in this study protocol including swallowing capsules without difficulty
6. Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information (in accordance with national and local subject privacy regulations)

Exclusion Criteria:

1. Any chemotherapy, therapeutic antineoplastic antibodies (not including radio- or toxin immunoconjugates), radiation therapy, or experimental antineoplastic therapy within 4 weeks of first dose of study drug
2. Radio- or toxin-conjugated antibody therapy within 10 weeks of first dose of study drug
3. Concomitant use of medicines known to cause QT prolongation or torsades de pointes
4. Transformed lymphoma or Richter's transformation Any life-threatening illness, medical condition or organ system dysfunction which, in the investigator's opinion, could compromise the subject's safety, interfere with the absorption or metabolism of PCI-32765 PO, or put the study outcomes at undue risk
5. Any of the following laboratory abnormalities: oAbsolute neutrophil count (ANC) \< 1000 cells/mm3 (1.0 x 109/L) oPlatelet count \< 50,000/mm3 (50 x 109/L) oSerum aspartate transaminase (AST/SGOT) or alanine transaminase (ALT/SGPT) ≥ 3.0 x upper limit of normal (ULN) oCreatinine \> 2.0 x ULN or creatinine clearance \< 40 mL/min

Primary outcomes:
measure: Incidence of Prolonged Hematologic Toxicity Started in Cycle 1
timeFrame: From First day of dose to 30 days after last dose of any study medication. Participants were followed with a median follow-up time of 15.8 months.
Secondary outcomes:
measure: Incidence of Adverse Events Requiring Dose Delay or Discontinuation of Ibrutinib
timeFrame: From First day of dose to 30 days after last dose of any study medication. Participants were followed with a median follow-up time of 15.8 months.
measure: Overall Incidence of Grade ≥3 Adverse Events (AEs) Per NCI CTCAE V4.0
timeFrame: From First day of dose to 30 days after last dose of any study medication. Participants were followed with a median follow-up time of 15.8 months.
measure: Overall Incidence of Serious Adverse Events (SAEs)
timeFrame: From First day of dose to 30 days after last dose of any study medication. Participants were followed with a median follow-up time of 15.8 months.
measure: Overall Response Rate (Complete Response [CR] + Complete Response With Incomplete Marrow Recovery [CRi] + Nodular Partial Response [nPR] + Partial Response [PR])
timeFrame: From first response assessment to last response assessment. Participants were followed with a median follow-up time of 15.8 months.
measure: Sustained Hematologic Improvement in Subjects With Neutropenia, Anemia, or Thrombocytopenia at Baseline
timeFrame: From first response assessment to last response assessment. Participants were followed with a median follow-up time of 15.8 months.
measure: Progression Free Survival Rate at 12 Months
timeFrame: From first dose of any study medication to 12 months after first dose to progressive disease or death or the last clinical assessment before receiving new anticancer therapy or loss to follow-up, whichever occured the earliest.
Other outcomes:
Locations:
city: Boston
country: United States
facility: Dana Farber Cancer Center
state: Massachusetts
city: New Hyde Park
country: United States
facility: CLL Research and Treatment Program
state: New York
city: New York
country: United States
facility: Weill Medical College of Cornell University
state: New York
city: Rochester
country: United States
facility: University of Rochester
state: New York
city: Nashville
country: United States
facility: Sarah Cannon Research Institute
state: Tennessee
city: Houston
country: United States
facility: MD Anderson
state: Texas
Study officials:
affiliation: Pharmacyclics LLC.
name: Thorsten Graef, MD
role: STUDY_DIRECTOR
References:
citation: Brown JR, Barrientos JC, Barr PM, Flinn IW, Burger JA, Tran A, Clow F, James DF, Graef T, Friedberg JW, Rai K, O'Brien S. The Bruton tyrosine kinase inhibitor ibrutinib with chemoimmunotherapy in patients with chronic lymphocytic leukemia. Blood. 2015 May 7;125(19):2915-22. doi: 10.1182/blood-2014-09-585869. Epub 2015 Mar 9.