A Phase I/II, Open-Label, Dose-Escalation Study Evaluating the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Orally-Administered CYT387 in Primary Myelofibrosis or Post-Polycythemia Vera or Post-Essential Thrombocythemia Myelofibrosis.
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.
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Safety and tolerability, dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of orally-administered CYT387 in patients with PMF or post-ET/PV MF.
Ongoing throughout therapy up until 30 days after last dose of CYT387
Ayalew Tefferi, MD
United States: Food and Drug Administration
|Mayo Clinic||Rochester, Minnesota 55905|
|Dana-Farber Cancer Institute||Boston, Massachusetts 02115|
|Stanford Cancer Center||Stanford, California 94305-5824|