Dose Escalation Study of Gemcitabine and ON 01910.Na in Solid Tumors

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Onconova Therapeutics, Inc.
ClinicalTrials.gov Identifier:
NCT01125891
First received: May 17, 2010
Last updated: November 27, 2012
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. This study is designed to answer that question.


Condition Intervention Phase
Malignant Neoplasmas
Solid Tumors
Drug: gemcitabine
Drug: ON 01910.Na
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 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 [ Time Frame: Start of treatment to 30 days after end of treatment. ] [ Designated as safety issue: Yes ]
    Incidence of adverse events, including laboratory parameters, as assessed by NCI CTCAE v3.0.

  • Maximum tolerated dose (MTD) of ON 01910.Na [ Time Frame: Escalation phase of protocol. ] [ Designated as safety issue: Yes ]
    MTD will be defined as the highest dose level of ON 01910.Na at which none of the first three patients or no more than one of six patients experienced dose limiting toxicity (DLT) in course 1.


Secondary Outcome Measures:
  • Pharmacokinetics [ Time Frame: Confirmation phase of protocol. ] [ Designated as safety issue: No ]
    Plasma concentration values of ON 01910.Na will be analyzed to determine if gemcitabine has an effect on pharmacokinetic parameters of ON 01910.Na.

  • Tumor measurements [ Time Frame: Screening to 30 days after end of treatment. ] [ Designated as safety issue: No ]
    Tumors will be measured to determine response according to RECIST criteria.

  • Pharmacodynamics, ex vivo [ Time Frame: Confirmation phase of protocol. ] [ Designated as safety issue: No ]
    Use tumor tissue obtained by biopsy to assess the pharmacodynamic activity of the ON 01910.Na and gemcitabine combination.


Enrollment: 39
Study Start Date: January 2009
Study Completion Date: September 2011
Primary Completion Date: September 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: gemcitabine and ON 01910.Na 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 Name: Gemzar
Drug: ON 01910.Na
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.
Other Name: rigosertib sodium

Detailed Description:

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.

  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.
  • 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 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.
  • 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.
  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: NCT01125891

Locations
United States, Colorado
University of Colorado Cancer Center
Denver, Colorado, United States, 80045
United States, New York
Roswell Park Cancer Institute
Buffalo, New York, United States, 14263
Sponsors and Collaborators
Onconova Therapeutics, Inc.
Investigators
Study Chair: Antonio Jimeno, MD, PhD University of Colorado at Denver Health and Sciences Center
  More Information

Additional Information:
Publications:
Responsible Party: Onconova Therapeutics, Inc.
ClinicalTrials.gov Identifier: NCT01125891     History of Changes
Obsolete Identifiers: NCT00822939
Other Study ID Numbers: 04-09
Study First Received: May 17, 2010
Last Updated: November 27, 2012
Health Authority: United States: Food and Drug Administration

Keywords provided by Onconova Therapeutics, Inc.:
gemcitabine hydrochloride
Gemzar
ON 01910.Na

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 August 20, 2014