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3849 An Expanded Multicenter Phase I/II Study of CYT387, a JAK- 1/2 Inhibitor for the Treatment of MyelofibrosisClinically Relevant Abstract

Program: Oral and Poster Abstracts
Session: 634. Myeloproliferative Syndromes: Poster III
Monday, December 12, 2011, 6:00 PM-8:00 PM
Hall GH (San Diego Convention Center)

Animesh Pardanani, MBBS, PhD1, Jason Gotlib, M.D., M.S.2*, Vikas Gupta, MD, FRCP, FRCPath3, Andrew W Roberts, MBBS, PhD4,5, Martha Wadleigh, MD6*, Shireen Sirhan, MD, FRCP7, Mark R. Litzow, MD8, William J Hogan, MBBCh9, Kebede Begna, MD1, Gregg Smith, PhD, MBA10*, Linda M Bavisotto, MD11*, Mark Kowalski, MD, PhD10* and Ayalew Tefferi, MD1

1Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN
2Divisions of Hematology and Oncology and Stanford Cancer Center, Stanford University School of Medicine, Stanford, CA
3Medical Oncology & Hematology, Princess Margaret Hospital, Toronto, ON, Canada
4Clinical Haematology &BMT, Royal Melbourne Hospital, Parkville, Australia
5Walter & Eliza Hall Institute, Parkville, Australia
6Dept. of Medical Oncology, Dana Farber Cancer Institute, Boston, MA
7Jewish General Hospital, Montreal, QC, Canada
8Hematology, Mayo Clinic, Rochester, MN
9Division of Hematology, Mayo Clinic, Rochester, MN
10YM Biosciences Inc., Mississauga, ON, Canada
11Porta Clinica, Seattle, WA

 

Background: CYT387 is a potent JAK-1/2 inhibitor. The maximum tolerated dose (MTD) and preliminary safety and efficacy of once daily dosing of CYT387 were determined in a single center Phase I/II study. Previously reported results from the first 60 subjects enrolled in this study determined a MTD of 300 mg QD and demonstrated improvements in splenomegaly and constitutional symptoms as well as in RBC transfusion requirements.  The study was expanded into a multicenter study with planned accrual of 165 subjects at 6 study sites and a twice daily dosing arm was added. The preliminary safety and efficacy results from this expanded multicenter study will be presented.

Methods: Subjects with high or intermediate-risk primary myelofibrosis (PMF) and post-polycythemia vera (post-PV) or post-essential thrombocythemia (ET) myelofibrosis were enrolled. In the core expansion study, oral CYT387 was administered either once daily at 150 mg or 300 mg or twice daily at 150 mg for 9 months. Patients who maintained at least stable disease were permitted to continue CYT387 treatment beyond 9 months in an extension phase of the study. Responses were assessed by International Working Group (IWG) Criteria.

Results: At present, 163 subjects have been enrolled across the 6 study sites. The diagnoses of enrolled subjects include 64% PMF, 14% post-ET MF and 22% post-PV MF; 67% of the patients were JAK2V617F positive. Starting doses of CYT387 in the dose escalation, confirmation and expansion phases of the study are shown in Table 1.

Table 1. CYT387 Starting Dose by Cohort

Dose

100mg QD

150 mg QD

200mg QD

300mg QD

400mg QD

150mg BID

Total

n (%)

3 (1.8)

52 (31.9)

3 (1.8)

60 (36.8)

6 (3.7)

39 (23.9)

163 (100)

The median duration (range) of treatment was 6.6 months (0.25 to 20.4 months). Patient characteristics were as follows: median age 68 years, 58% male, 87% were spleen evaluable at baseline per IWG criteria (median spleen length was 18 cm by palpation). Sixty three percent (63%) of subjects were anemia evaluable at baseline per IWG criteria; 46% were transfusion dependent. Previous JAK inhibitor and IMiD therapy was reported for 11% and 8% of enrolled subjects, respectively. Reductions in spleen size, improvements in constitutional symptoms and the achievement of transfusion independence were observed in subjects in the expanded multicenter study.

CYT387 was well tolerated. Based on currently available data, 73% of subjects reported treatment-related adverse events, with the majority reported as Grade 1. The most common Grade 3-4 treatment related adverse events included thrombocytopenia (16%), and hyperlipasemia (3%). New onset treatment-related Grade 3-4 anemia remains rare (<1%). Grade 1 toxicities included peripheral sensory neuropathy whose incidence and natural history is currently being studied. Twenty-five of 163 subjects (15%) have discontinued from the 9 month core study giving a retention rate of 85%.

Conclusions:  When examined in an expanded, multicenter study, CYT387 continues to show substantial clinical activity in myelofibrosis, with improvements in splenomegaly, constitutional symptoms and anemia. It appears to be well tolerated when administered in either a once or twice daily dosing regimen. CYT387 continues to demonstrate an ability to induce durable anemia responses in a subset of subjects. Detailed analyses of safety and efficacy will be available at the time of the meeting.

Disclosures: Pardanani: Sanofi-Aventis: Clinical trial support to institution from sponsor; Bristol Myers Squibb: Clinical trial support to institution from sponsor; TargeGen: Clinical trial support to institution from sponsor; Incyte: Clinical trial support to institution from sponsor; YM Biosciences: Clinical trial support to institution from sponsor; Celgene: Clinical trial support to institution from sponsor; Novartis: Clinical trial support to institution from sponsor; TargeGen: Research Funding; Cytopia: Research Funding. Off Label Use: Clinical trial data. Gupta: Incyte: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees. Smith: YM Biosciences: Employment, Equity Ownership. Bavisotto: YM Biosciences: Consultancy. Kowalski: YM Biosciences: Employment, Equity Ownership.

*signifies non-member of ASH