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Phase I Dose Escalation Study of Gemcitabine and 24 Hour Infusion of ON 01910.Na in Patients With Advanced or Metastatic Solid Tumors


Phase 1
18 Years
N/A
Not Enrolling
Both
Solid Tumor

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Trial Information

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.


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 (Appendix I).

- 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 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
institution.

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.

- Patients will be excluded if they have an active infectious process.

- Patients will be excluded if they have active central nervous system metastases.

- Patients will be excluded if they have received prior radiotherapy administered to
more than 30% of marrow-bearing bone mass.

- Patients will be excluded if they have ascites requiring active medical management
including paracentesis for more than twice a month or hyponatremia (defined as serum
sodium value of <134 Meq/L).

- Patients will be excluded if they are women who are pregnant or lactating.

- Patients will be excluded if they are male patients with female sexual partners who
are unwilling to follow the strict contraception requirements described in this
protocol.

- Patients will be excluded if they have had major surgery without full recovery or
major surgery within 3 weeks of ON 01910.Na treatment start.

Type of Study:

Interventional

Study Design:

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

Outcome Measure:

Adverse Events and Laboratory Parameters

Outcome Description:

Incidence of adverse signs and/or symptoms (adverse events and laboratory parameters)

Outcome Time Frame:

Throughout study

Safety Issue:

Yes

Principal Investigator

Sridhar Mani, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Albert Einstein College of Medicine of Yeshiva University

Authority:

United States: Food and Drug Administration

Study ID:

Onconova 04-10

NCT ID:

NCT01165905

Start Date:

January 2010

Completion Date:

July 2011

Related Keywords:

  • Solid Tumor
  • cancer
  • solid malignancy
  • tumor
  • malignant neoplasm
  • histologically confirmed solid malignancy
  • Neoplasms

Name

Location

Department of Medicine, University of California San FranciscoSan Francisco, California  94143
Albert Einstein Cancer Center/Montefiore Medical CenterBronx, New York  10461