Phase I Dose Escalation Study of Gemcitabine and 24 Hour Infusion of ON 01910.Na in Patients With Advanced or Metastatic Solid Tumors
The order of infusion will be gemcitabine first, immediately followed by ON 01910.Na (with
the only exception being the first infusion for those patients undergoing PK sampling; where
the ON 01910.Na infusion will be given first on this occasion). The dose of gemcitabine
will be fixed at 1000 mg/m2 i.v. as a 30 minutes infusion on days 1, 8, and 15 every 28
days. As of Amendment 2, the starting dose of ON 01910.Na is 250 mg/m2 as a 24 hour
intravenous (i.v.) infusion on days 1, 8 and 15 of a 28-day course. The dose of ON 01910.Na
will be escalated in increments in successive cohorts (dose level (DL) 1 = 250 mg/m2, DL 2 =
650 mg/m2, DL 3 = 1050 mg/m2, DL 4= 1350 mg/m2) of new patients. A course is defined as 4
weeks in length. Toxicity will be graded according to the National Cancer Institute Common
Terminology Criteria for Adverse Events (NCI CTCAE v3.0). A minimum of three new patients
will be treated at each dose level with a minimum of a 1 week stagger between the dosing of
the first and remaining patients in each new dose cohort. In exceptional circumstances
(e.g. where there is one slot available in a cohort and two eligible patients have been
screened), the Sponsor may allow four patients to enter a cohort (or seven patients to enter
an expanded cohort). A DL -1A (ON 01910.Na = 125 mg/m2) is set in case dose de-escalation
is required with the starting dose due to ON 01910.Na-related toxicity. A DL -1A
gemcitabine = 750 mg/m2 and DL - 1B at 500 mg/m2 are set in case dose de-escalation is
required with the starting and subsequent doses due to gemcitabine-related toxicity. If DLT
is not observed in the first three patients, then the dose of ON 01910.Na will be increased
to the next level. If DLT occurs in any of the first three new patients in the first
course, at least three additional new patients will be treated. If no further DLT is
encountered, dose escalation will proceed. Alternately, if DLT is noted in one or more of
three additional patients, dose escalation will be terminated and the MTD will be defined as
the highest dose level at which none of the first three patients or no more than one of six
patients experienced DLT in course 1. All patients receiving doses exceeding the confirmed
MTD will have their dose reduced to the MTD; even if apparently tolerating their current
dose. Intra-patient dose escalation of ON 01910.Na will be permitted. There will be no
limit to the number of courses that could be administered to a patient who is both
tolerating and benefiting from therapy.
Escalation to the next dose level will occur only after the third evaluable patient (or
sixth, if an expanded cohort), on the previous dose level has been observed for 4 weeks.
Dose escalation decisions will be made by a Cohort Review Committee (CRC). Intra-patient
dose escalation of ON 01910.Na will be allowed after the third evaluable patient on the next
dose level has been observed for 4 weeks with acceptable tolerability.
Once the MTD has been defined, an expanded cohort of 9 to 12 additional patients (depending
if 3 or 6 patients were enrolled on the previous cohort) will be enrolled at the MTD dose
level in order to further define the safety and tolerability of this regimen, and
characterize the pharmacokinetics of ON 01910.Na alone and after gemcitabine, and perform a
tumor biomarker study.
Interventional
Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Adverse Events and Laboratory Parameters
Incidence of adverse signs and/or symptoms (adverse events and laboratory parameters)
Throughout study
Yes
Sridhar Mani, MD
Principal Investigator
Albert Einstein College of Medicine of Yeshiva University
United States: Food and Drug Administration
Onconova 04-10
NCT01165905
January 2010
July 2011
Name | Location |
---|---|
Department of Medicine, University of California San Francisco | San Francisco, California 94143 |
Albert Einstein Cancer Center/Montefiore Medical Center | Bronx, New York 10461 |