Phase 1 Study of Terameprocol (EM-1421) a Survivin and Cyclin-Dependent Kinase-1 (Cdc2) Inhibitor, in Patients With Leukemia
The dose of Terameprocol (EM-1421) will be escalated in successive cohorts of 3 patients.
Patients will be entered sequentially on each dose level. If none of the first 3 patients
at a dose level experience first cycle drug related dose-limiting toxicity (DLT), new
patients may be entered at the next higher dose level. If 1 of 3 patients experience first
cycle DLT, up to 3 more patients are started at that same dose level. If 2 or more
experience first cycle DLT, no further patients are started at that dose. The MTD is the
highest dose level in which <2 patients of 6 develop a first cycle DLT. New dose levels may
begin accrual only if all patients at the current dose level have been observed for a
minimum of 3 weeks after the last infusion of Terameprocol (EM-1421). The recommended phase
2 dose (RP2D) will be the MTD unless significant clinical activity is seen below the MTD.
During the observation period of 3 weeks, additional accrual to a previously assessed lower
dose level, with no documented DLTs, will be allowed with sponsor approval.
Patients will be treated three times a week, with at least one day in between infusions, for
two weeks followed by one week of rest. The dose for new cohorts will be escalated from
1000, to 1500 and 2200 mg or de-escalated to 500 mg if 1000 mg exceeds the MTD. The
principal investigator will consult with the sponsor to determine the appropriate dose level
for a new patient. At the MTD, up to 10 additional patients may be accrued in that dose
cohort to further define the toxicities and response of the agent. If the initial dose
level exceeds the MTD, a fallback dose level of 500 mg will be implemented.
Patients are allowed to be treated with subsequent cycles of Terameprocol (EM-1421) until
disease progression or until severe toxicities occur and side effects do not outweigh the
benefit of study drug administration in the assessment of the treating physician.
Intrapatient dose escalation Intrapatient dose escalation by one dose level may be
permitted, but only if at least 3 patients in the next higher dose level have been treated
and have been followed for 21 days without experiencing DLT. Decisions for intrapatient dose
escalation will be made jointly by the Study Sponsor, treating physician and Principal
Terameprocol (EM-1421) as a single agent given intravenously over 6 hours three times a week
for two weeks followed by one week rest (two weeks on, one week off)in the following dose
cohorts starting with 1000 mg dose cohort.
Dose Level -1: 500 mg
Dose Level 1: 1000 mg
Dose Level 2: 1500 mg
Dose Level 3: 2200 mg
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Safety, maximum tolerated dose (MTD) and dose limiting toxicity (DLT) of Terameprocol (EM-1421) given as intravenous infusion three times a week in patients with leukemia
Adverse events and toxicity will be assessed prior to each cycle of treatment and at times when clinically indicated.
Neil Frazer, MB, ChB
United States: Food and Drug Administration
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