Safety and Efficacy Study of CYT387 in Primary Myelofibrosis (PMF) or Post-polycythemia Vera (PV) or Post-essential Thrombocythemia (ET)

The myeloproliferative neoplasms (MPN), most notably polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) are a diverse but inter-related suite of clonal disorders of pluripotent hematopoietic stem cells (Tefferi et al., 2008). The MPN share a range of biological, pathological, and clinical features including the relative overproduction of one or more cells of myeloid origin, growth factor independent colony formation in vitro, marrow hypercellularity, extramedullary hematopoiesis, splenomegaly and hepatomegaly, and thrombotic and/or hemorrhagic diatheses (Tefferi et al., 2005).

This is an open-label, non-randomized, dose-escalation study, to be conducted in two phases: a single-centre dose-escalation phase with supernumerary patient addition (Part 1), to determine the safety and tolerability of CYT387, and to identify a therapeutic dose for the confirmation portion of the study; and a multiple-centre dose-confirmation phase (Part 2), which will be a cohort expansion at or below the maximum tolerated dose (MTD) of CYT387.

In Part 1 of the study, patients will be assigned to dose levels in successive cohorts starting with a dose in the first cohort of 100 mg/day, administered orally as a single daily dose (ie QD: at least 20 and no more than 28 hours apart, preferably in a fasted state at least one hour before and two hours after a meal). Dose-escalation will proceed initially with a 1.5-fold increment however, based on toxicity and efficacy information at a specific dose level, the dose escalation increment may be reduced to a 1.25-fold escalation at the discretion of the investigator. At any dose level, if one patient experiences a Grade 2 toxicity or higher, the dose-escalation may only proceed with 1.25-fold increments.

The MTD is defined as the highest dose level at which > 2 of 6 subjects develop first cycle DLT. New dose levels may begin accrual only if all subjects at the current dose level have been observed for a minimum of 28 days from the first day of treatment. The recommended Phase II dose will be the MTD unless significant clinical activity (efficacy) is seen below the MTD. With the exception of the first cohort, dose levels may be decreased from the intended dose levels for the next cohort, if Grade 2 or greater toxicities are observed.

Twenty (20) patients will be assigned to receive CYT387 at 150 mg twice daily (BID) with doses approximately 10-12 hours apart to determine the comparative safety, tolerability and preliminary activity of CYT387 administered twice-daily. Initially, a maximum of 6 (six) patients will be enrolled for safety assessment. If none of the six patients experiences a first-cycle DLT, then the remaining 14 patients may be enrolled following approval by the Data Safety Monitoring Board (DSMB).

In the multi-centre portion of the study (Part 2), sixty (60) additional patients will be dosed at either 150 mg or 300 mg once daily (QD). Subjects will be evaluated weekly for the first cycle, every 2 weeks for cycle 2, and at the end of each subsequent cycle for up to 9 cycles of CYT387 treatment. If, after 6 months of therapy an individual patient has not experienced a drug-related serious adverse event (SAE), the investigator may, with the written concurrence of the independent safety monitor, elect to have that patient's monthly safety assessment performed by a registered medical practitioner remote to the investigational centre. Subjects will return for a follow-up visit 30 days after completion of the last dose of study drug. Subjects who achieve at least stable disease or better and tolerate the drug well may be allowed to continue to receive CYT387 beyond the planned 9 cycles under the extension protocol CCL09101E.