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Phase I Dose Escalation Study of Gemcitabine and ON 01910.Na in Patients With Advanced or Metastatic Solid Tumors

Phase 1
18 Years
Not Enrolling
Malignant Neoplasmas, Solid Tumors

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Trial Information

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.

Inclusion Criteria:

- Patients with histologically confirmed solid malignancy for which standard curative
or palliative measures do not exist or are no longer effective; or patients with a
clinical rationale for a gemcitabine-based therapy.

- The last radiotherapy/chemotherapy dose must have been given ≥4 weeks prior to study
drug initiation; with any acute or chronic adverse events of prior radiotherapy or
chemotherapy having resolved to
- Patients must have a life expectancy of at least 12 weeks and an ECOG performance
status of <1.

- Patients must be >18 years of age.

- Patients must have evaluable disease, either with informative tumor markers, or with
measurable disease on imaging, by RECIST (Response Evaluation Criteria in Solid
Tumors) criteria (Appendix II).

- Patients must have adequate liver and renal function as defined by serum creatinine
no greater than 2.0 times the institution's upper normal limits (or a 24 hour
creatinine clearance of >50 ml/min) and total bilirubin level no greater than 2.0
times the institution's upper normal limits and transaminase levels no higher than
3.0 times the institution's upper normal limits. (Note that patients with primary
liver cancer or hepatic metastases may have a total bilirubin value of up to 1.5
mg/dl and transaminase levels of up to 5.0 times the limit of normal).

- Patients must have adequate bone marrow function as defined by a granulocyte count of
>1,500/mm3, platelet count of >100,000/mm3, and hemoglobin >9 g/dl.

- Patients at the expanded phase at the MTD must be willing and able to undergo blood
sampling for pharmacokinetic studies in Course 1.

- For patients in the expanded phase at the MTD, tumor amenable to a single tumor
biopsy, and willingness to undergo a baseline tumor biopsy.

- Patients must sign an informed consent form indicating that they are aware of the
investigational nature of this study and in keeping with the policies of the

Exclusion Criteria:

Patients will be excluded if:

- They have evidence of active heart disease including myocardial infarction within the
previous 3 months; symptomatic coronary insufficiency or heart block; uncontrolled
congestive heart failure; moderate or severe pulmonary dysfunction.

- They have an active infectious process.

- They have active central nervous system metastases.

- They have received prior radiotherapy administered to more than 30% of marrow-bearing
bone mass.

- They have ascites requiring active medical management including paracentesis more
than twice a month or hyponatremia (defined as serum sodium value of <134 Meq/L).

- Women who are pregnant or lactating.

- Male patients with female sexual partners who are unwilling to follow the strict
contraception requirements described in this protocol (see Section 5.4).

- Patients who have had major surgery without full recovery or major surgery within 3
weeks of ON 01910.Na treatment start.

Type of Study:


Study Design:

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Adverse events

Outcome Description:

Incidence of adverse events, including laboratory parameters, as assessed by NCI CTCAE v3.0.

Outcome Time Frame:

Start of treatment to 30 days after end of treatment.

Safety Issue:


Principal Investigator

Antonio Jimeno, MD, PhD

Investigator Role:

Study Chair

Investigator Affiliation:

University of Colorado at Denver Health and Sciences Center


United States: Food and Drug Administration

Study ID:




Start Date:

January 2009

Completion Date:

September 2011

Related Keywords:

  • Malignant Neoplasmas
  • Solid Tumors
  • gemcitabine hydrochloride
  • Gemzar
  • ON 01910.Na
  • Neoplasms



Roswell Park Cancer InstituteBuffalo, New York  14263
University of Colorado Cancer CenterDenver, Colorado  80262