Safety of 24-hour Infusion of ON 01910.Na in Combination With Gemcitabine in Advanced Solid Tumors

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Onconova Therapeutics, Inc.
ClinicalTrials.gov Identifier:
NCT01165905
First received: July 18, 2010
Last updated: December 29, 2011
Last verified: December 2011
  Purpose

Treatment of cancer is often more effective when two or more drugs are used together. For example, when gemcitabine, an approved drug, and ON 01910.Na, a new investigational anti-cancer drug, are used together to treat cancer cells in laboratory animals, there is more inhibition of the growth of the cancer cells compared to either drug used by itself. These results offer promise that gemcitabine and ON 01910.Na could be used to treat cancer in patients. However, before studies that seek to find out if gemcitabine and ON 01910.Na is an effective combination in patients can be done, doctors must first know what is largest, safe dose of ON 01910.Na that can be used in combination with gemcitabine and what is the best regimen to use. This study is designed to answer that question.


Condition Intervention Phase
Solid Tumor
Drug: ON 01910.Na
Drug: Gemcitabine
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase I Dose Escalation Study of Gemcitabine and 24 Hour Infusion of ON 01910.Na in Patients With Advanced or Metastatic Solid Tumors

Resource links provided by NLM:


Further study details as provided by Onconova Therapeutics, Inc.:

Primary Outcome Measures:
  • Adverse Events and Laboratory Parameters [ Time Frame: Throughout study ] [ Designated as safety issue: Yes ]
    Incidence of adverse signs and/or symptoms (adverse events and laboratory parameters)


Secondary Outcome Measures:
  • Pharmacokinetics [ Time Frame: MTD confirmation phase of study ] [ Designated as safety issue: No ]
    The derived plasma pharmacokinetic parameters of ON 01910.Na administered alone and with gemcitabine at the MTD will also be investigated: Cmax, tmax, terminal half-life, AUC0-last, AUC0-inf., CL, and Vss.


Enrollment: 10
Study Start Date: January 2010
Study Completion Date: July 2011
Primary Completion Date: July 2011 (Final data collection date for primary outcome measure)
Intervention Details:
    Drug: ON 01910.Na
    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.
    Other Name: rigosertib sodium
    Drug: Gemcitabine
    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.
    Other Names:
    • Gemzar
    • gemcitabine HCl
    • 2´-deoxy-2´,2´-difluorocytidine monohydrochloride (-isomer)
    • gemcitabine for injection, USP
    • nucleoside metabolic inhibitor
Detailed Description:

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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 <Grade 2 as determined by CTCAE v3.0 (Appendix IV).
  • 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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01165905

Locations
United States, California
Department of Medicine, University of California San Francisco
San Francisco, California, United States, 94143
United States, New York
Albert Einstein Cancer Center/Montefiore Medical Center
Bronx, New York, United States, 10461
Sponsors and Collaborators
Onconova Therapeutics, Inc.
Investigators
Principal Investigator: Sridhar Mani, MD Albert Einstein College of Medicine of Yeshiva University
Principal Investigator: Pamela N. Munster, MD Department of Medicine, University of California San Francisco
  More Information

No publications provided

Responsible Party: Onconova Therapeutics, Inc.
ClinicalTrials.gov Identifier: NCT01165905     History of Changes
Other Study ID Numbers: Onconova 04-10
Study First Received: July 18, 2010
Last Updated: December 29, 2011
Health Authority: United States: Food and Drug Administration

Keywords provided by Onconova Therapeutics, Inc.:
cancer
solid malignancy
tumor
malignant neoplasm
histologically confirmed solid malignancy

Additional relevant MeSH terms:
Neoplasms
Gemcitabine
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Radiation-Sensitizing Agents

ClinicalTrials.gov processed this record on July 23, 2014