642. CLL: THERAPY, EXCLUDING TRANSPLANTATION: POSTER I |
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`NOVEMBER 15, 2013
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`Phase 1 Study Of Single Agent CC-292, a Highly Selective
`Bruton's Tyrosine Kinase (BTK) Inhibitor, In Relapsed/
`Refractory Chronic Lymphocytic Leukemia (CLL)
`
`Jennifer R. Brown, MD, PhD,1 Wael A. Harb, MD,2 Brian T. Hill, MD, PhD,3 Janice Gabrilove, MD,4
`Jeff P. Sharman, MD,5 Marshall T. Schreeder, MD, MPH,*,6 Paul M. Barr, MD,7 James
`M. Foran, MD,8 Thomas P. Miller, MD,9 Jan A. Burger, MD, PhD,10 Kevin R. Kelly, MD, PhD,11
`Daruka Mahadevan, MD, PhD,12 Shuo Ma, MD, PhD,13 Evelyn Barnett,*,14
`Jeffrey Marine,*,14
`Pilar Nava-Parada,*,14 Ada Azaryan,*,15 Jay Mei, MD,14 Thomas J. Kipps, MD, PhD16
`1Dana-Farber Cancer Institute, Boston, MA, USA,
`2Horizon Oncology Center, Lafayette, IN, USA,
`3Department of Hematologic Oncology and Blood Disorders,
`Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA,
`4Mount Sinai School of Medicine, New York, NY, USA,
`5Willamette Valley Cancer Institute and Research Center/US Oncology Research, Eugene, OR, USA,
`6Clearview Cancer Institute, Huntsville, AL, USA,
`7Hematology/Oncology, University of Rochester Medical Center, Rochester, NY, USA,
`8Hematology and Oncology, Mayo Clinic, Jacksonville, FL, USA,
`9University of Arizona Cancer Center, Tucson, AZ, USA,
`10Department of Leukemia, MD Anderson Cancer Center, Houston, TX, USA,
`11University of Texas Health Science Center at San Antonio,
`CTRC Institute for Drug Development, San Antonio, TX, USA,
`12The West Clinic, University of Tennessee Health Sciences Center, ACORN Research, LLC, Memphis, TN, USA,
`13Robert H. Lurie Comprehensive Cancer Center, Feinberg
`School of Medicine, Northwestern University, Chicago, IL, USA,
`14Celgene Corporation, Summit, NJ, USA,
`15Celgene Corporation, Berkeley Heights, NJ, USA,
`16University of California, San Diego, Moores Cancer Center, La Jolla, CA, USA
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`Blood (2013) 122 (21) : 1630.
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`http://doi.org/10.1182/blood.V122.21.1630.1630
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`Abstract
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`Introduction
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`CC-292, an oral, highly selective, small-molecule irreversible-inhibitor of Btk is under investigation for the
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`treatment of CLL and other B-cell malignancies. This phase 1 trial investigated the safety, dose limiting
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`toxicities (DLT), and clinical activity of CC-292 monotherapy in subjects with relapsed or refractory (R/
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`R) CLL or non-Hodgkin's lymphoma. This interim analysis focused on the safety and clinical activity in
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`subjects with CLL and small cell lymphocytic leukemia (SLL).
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`Methods
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`Eligible subjects with R/R (≥ 1 prior therapy) CLL/SLL were treated with monotherapy CC-292 in a dose-
`escalation study with doses ranging from 125 mg to 1000 mg QD and BID dose levels of 375 mg and 500
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`mg. As a maximum tolerated dose was not established, CLL patients have been enrolled in an early dose
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`expansion cohort of 750 mg QD and preliminary recommended phase 2 dose expansion cohort at 500
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`mg BID. All subjects received continuous dosing in 28-day cycles until progressive disease or intolerable
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`toxicity. Clinical activity was investigator assessed per the 2008 iwCLL criteria.
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`Results
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`83 subjects with R/R CLL/SLL have been enrolled as of June 30, 2013. Baseline characteristics include
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`median age of 67 years (34-89), 52% Rai stage 3/4 disease, median 3 prior therapies (1-12), and 34%
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`refractory to last treatment. Poor-risk factors were present in 67% of subjects, including del11q (22%),
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`del17p (24%), and unmutated IgVH (54%). 67% of subjects remain on study. Subjects have received
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`a median of 6 treatment cycles (0.2-21.6). The most frequent grade 3/4 adverse events (AEs) included
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`neutropenia (21%), thrombocytopenia (15%), pneumonia (10%), and anemia (8%). Rates of febrile
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`neutropenia were low (4%). The most common treatment-emergent AEs (≥ 10% of subjects) were
`diarrhea (59.7%), fatigue (37.5%), neutropenia (26.4%), thrombocytopenia (26.4%), nausea (26.4%),
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`pyrexia (22.2%), headache (19.4%), cough (19.4%), upper respiratory infection (16.7%), peripheral
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`edema (15.3%), abdominal pain (15.3%), dizziness (13.9%), muscle spasms (13.9%), contusion
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`(13.9%), anemia (12.5%), pneumonia (12.5%), sinusitis (12.5%), and urinary tract infection (11.1%).
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`One CLL patient at the 500 mg BID dose level has experienced a drug-related adverse event of grade
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`4 thrombocytopenia during Cycle 1 that was assessed as a DLT. The number of patients discontinuing
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`study treatment due to AEs was low (2.4%). Results are summarized for efficacy-evaluable patients
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`treated at the 4 dose levels where at least a partial response (PR) was achieved (750 mg, 1000 mg,
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`375 mg bid and 500 mg bid) (n = 55). During cycle 1, 89% experienced a ≥ 25% increase in absolute
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`lymphocyte count (ALC), which usually resolved with continued treatment. The table below details the
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`best responses achieved to date. In subjects with del11q, del17p, unmutated IgVH, and no high-risk
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`genomic factors, the PR rate was 42% (5/12), 25% (3/12), 44% (7/16), and 47% (7/15), respectively.
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`Importantly, nodal responses were induced in the majority of subjects receiving BID dosing (375 mg:
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`67%; 500 mg: 62%) with an overall PR rate of 40%. When achieved, nodal responses were typically
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`observed by cycle 2 and were sustained with continued treatment. Although the sample size is small,
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`subjects treated at 375 mg or 500 mg BID showed continued lymph node size reduction over time from
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`cycle 2 (mean reduction of 42% and 45%, respectively) to cycle 7 (mean reduction of 60% and 71%,
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`respectively).
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`Conclusion
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`CC-292 is well tolerated as an oral daily therapy. Single-agent therapy with CC-292 is sufficient to
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`achieve high nodal and partial response rates in relapsed/refractory CLL subjects, including those with
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`high-risk genomic features. These results support continued development of CC-292 for the treatment of
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`patients with CLL/SLL.
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`Dose Level
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`Evaluable
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`Total
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`(mg)
`
`(n)
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`Responders
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`Nodal
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`Response
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`PR
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`w/
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`increased
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`ALC
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`750 mg QD
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`29
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`16 (55%)
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`9 (31%)
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`7 (24%)
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`1000 mg
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`QD
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`375 mg BID
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`7
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`6
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`500 mg BID
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`13
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`4 (57%)
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`4 (57%)
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`4 (67%)
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`8 (62%)
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`4 (67%)
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`5 (38%)
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`0
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`0
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`3 (23%)
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`*Per investigator assessment via imaging.
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`Disclosures:
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`Median
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`Time on
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`Study
`
`(cycles)
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`11.2
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`9.9
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`10.6
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`2.9
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`Median
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`Follow-up
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`(Months)
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`12.7
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`10.4
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`10.6
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`2.9
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`Brown: Pharmacyclics: Consultancy; Genentech: Consultancy; Celgene: Consultancy, Research
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`Funding; Emergent: Consultancy; Onyx: Consultancy; Sanofi Aventis: Consultancy; Vertex: Consultancy;
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`Novartis: Consultancy; Genzyme: Research Funding. Off Label Use: The abstract shows scientific
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`information on CC292 which is an investigational product developed by Celgene. This investigational
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`product is not approved by any health authority for any indication. Harb: Celgene: Research Funding.
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`Hill: Celgene: Honoraria, Research Funding. Sharman: Celgene: Consultancy, Research Funding;
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`Genentech: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Pharmacyclics:
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`Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Cylene
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`Pharmaceuticals: Consultancy, Research Funding; Avila Pharmaceuticals: Consultancy, Research
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`Funding. Barr: Celgene: Consultancy. Foran: Celgene: Research Funding. Burger: Pharmalytics:
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`Research Funding; Gilead: Research Funding. Mahadevan: Novartis: Speakers Bureau; Millennium:
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`Speakers Bureau. Ma: Genentech: Consultancy; Abbvie: Consultancy. Barnett: Celgene: Employment,
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`Equity Ownership. Marine: Celgene: Employment, Equity Ownership. Nava-Parada: Celgene:
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`Employment, Equity Ownership. Azaryan: Celgene: Employment, Equity Ownership. Mei: Celgene:
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`Employment, Equity Ownership. Kipps: Celgene: Membership on an entity's Board of Directors or
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`advisory committees, Research Funding.
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`Author notes
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`* Asterisk with author names denotes non-ASH members.
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`© 2013 by the American Society of Hematology
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