Phase I Dose Escalation Study of Gemcitabine and ON 01910.Na in Patients With Advanced or Metastatic Solid Tumors
The order of infusion on Days 1, 8, and 15 will be gemcitabine first, immediately followed
by ON 01910.Na. 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. The starting dose of ON 01910.Na is 600 mg/m2
as a 2 hour intravenous (i.v.) infusion on days 1, 4, 8, 11, 15 and 18 of a 28-day course.
The dose of ON 01910.Na will be escalated in increments in successive cohorts (dose level
(DL) 1 = 600 mg/m2, DL 2 = 1200 mg/m2, DL 3 = 1800 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 = 400 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 (see Section 4.2 for definitions of DLT). 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.
A patient will be considered evaluable for the purposes of the dose escalation decision if
the patient completes the first course of therapy without missing more than 1 dose of ON
01910.Na for reasons unrelated to toxicity, or if the patient is withdrawn due to a DLT.
Non-evaluable patients will be replaced. 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 (ie, MTD has not been exceeded per criteria above).
Once the MTD has been defined, an expanded cohort of 20 to 23 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.
Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Incidence of adverse events, including laboratory parameters, as assessed by NCI CTCAE v3.0.
Start of treatment to 30 days after end of treatment.
Antonio Jimeno, MD, PhD
University of Colorado at Denver Health and Sciences Center
United States: Food and Drug Administration
|Roswell Park Cancer Institute||Buffalo, New York 14263|
|University of Colorado Cancer Center||Denver, Colorado 80262|