Eribulin Mesylate and Gemcitabine Hydrochloride in Treating Patients With Metastatic Solid Tumors or Solid Tumors That Cannot be Removed by Surgery

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT00410553
First received: December 11, 2006
Last updated: June 30, 2014
Last verified: April 2014
  Purpose

This phase I trial is studying the side effects and best dose of eribulin mesylate and gemcitabine hydrochloride in treating patients with metastatic or unresectable solid tumors. Drugs used in chemotherapy, such as eribulin mesylate and gemcitabine hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more tumor cells.


Condition Intervention Phase
Recurrent Endometrial Carcinoma
Recurrent Ovarian Epithelial Cancer
Stage III Endometrial Carcinoma
Stage III Ovarian Epithelial Cancer
Stage IV Endometrial Carcinoma
Stage IV Ovarian Epithelial Cancer
Unspecified Adult Solid Tumor, Protocol Specific
Drug: eribulin mesylate
Drug: gemcitabine hydrochloride
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase I Study of Halichondrin B Analog E7389 in Combination With Gemcitabine in Patients With Refractory or Advanced Solid Tumors

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Maximum tolerated dose of eribulin mesylate administered with gemcitabine hydrochloride in advanced/metastatic solid tumors [ Time Frame: Course 1 ] [ Designated as safety issue: Yes ]
    The Common Terminology Criteria for Adverse Events (CTCAE version 3 will be used to grade toxicity.

  • Recommended phase II dose of eribulin mesylate in combination with gemcitabine hydrochloride [ Time Frame: Course 1 ] [ Designated as safety issue: Yes ]
    Defined as one dose level below the dose at which 2 or more patients experience a DLT. If =< 1 DLT is observed at dose level 5, then this will be the RPTD.

  • Safety, tolerability, toxicity profile, and dose-limiting toxicity of eribulin mesylate [ Time Frame: From the time of their first treatment with eribulin mesylate ] [ Designated as safety issue: Yes ]
    Graded using the CTCAE version 3.

  • Pharmacokinetic profiles of eribulin mesylate and gemcitabine hydrochloride [ Time Frame: Days 1, 2, 3, 5, and 8 of course 1 ] [ Designated as safety issue: No ]
    Plasma samples for the determination of eribulin mesylate plasma concentration will be analyzed in conjunction with Eisai Pharmaceuticals. Plasma samples for the determination of gemcitabine plasma concentration will be analyzed through methods developed at the Princess Margaret Hospital.


Secondary Outcome Measures:
  • Preliminary clinical antitumor activity of eribulin mesylate [ Time Frame: Baseline, every 2 courses, and 4 weeks post-treatment ] [ Designated as safety issue: No ]
    Assessed using radiologic images (CT scans). Measured by Response Evaluation Criteria in Solid Tumors (RECIST) criteria.

  • Objective response rate in patients with measurable disease [ Time Frame: Baseline, every 2 courses, and 4 weeks post-treatment ] [ Designated as safety issue: No ]
    Measured by RECIST criteria. All tests will be two-sided and a p-value of 0.05 or less will be considered statistically significant. Standard descriptive statistics, such as the mean, median, range and proportion, will be used to summarize the patient sample and to estimate parameters of interest. 95% confidence intervals will be provided for estimates of interest where possible.

  • Duration of response in patients with measurable disease [ Time Frame: From the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented ] [ Designated as safety issue: No ]
    Estimated using the Kaplan-Meier method.

  • Time to disease progression in patients with measurable disease [ Time Frame: From start of treatment until the criteria for progression are met ] [ Designated as safety issue: No ]
    Estimated using the Kaplan-Meier method.


Enrollment: 45
Study Start Date: November 2006
Primary Completion Date: October 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (combination chemotherapy)
Patients receive eribulin mesylate IV and gemcitabine hydrochloride IV over 30 minutes on days 1, 8, and 15 OR on days 1 and 8. Courses repeat every 28 or 21 days* in the absence of disease progression or unacceptable toxicity.
Drug: eribulin mesylate
Given IV
Other Names:
  • B1939
  • E7389
  • ER-086526
  • halichrondrin B analog
Drug: gemcitabine hydrochloride
Given IV
Other Names:
  • dFdC
  • difluorodeoxycytidine hydrochloride
  • gemcitabine
  • Gemzar

Detailed Description:

OBJECTIVES:

I. Determine the recommended phase II dose (RPTD) of E7389 (eribulin mesylate) when given in combination with gemcitabine (gemcitabine hydrochloride) in patients with advanced cancer.

II. Determine the safety, tolerability, and toxicity profile of E7389 and gemcitabine given in combination.

III. Assess the antitumor activity of E7389 in combination with gemcitabine in patients with measurable disease.

IV. Determine the pharmacokinetic profile of E7389 and gemcitabine to assess for any possible interactions between the two agents.

OUTLINE: This is a multicenter, dose-escalation study. Patients receive eribulin mesylate intravenously (IV) and gemcitabine hydrochloride IV over 30 minutes on days 1, 8, and 15 OR on days 1 and 8.

Courses repeat every 28 or 21 days* in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of eribulin mesylate and gemcitabine hydrochloride until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity (DLT). NOTE: *If DLT is observed at the first dose level of the 28-day schedule, subsequent patients are treated on days 1 and 8 of the 21-day schedule; patients enrolled in the expansion cohort (patients with ovarian or endometrial cancer or chemotherapy-naive or minimally pre-treated cancer) receive treatment according to the 21-day schedule.

After completion of study treatment, patients are followed at 4 weeks and then every 3 months thereafter.

  Eligibility

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

Inclusion Criteria:

  • Patients must have histologically confirmed malignancy that is metastatic or unresectable and for which standard curative antineoplastic drug treatments do not exist or are no longer effective:

    • Ovarian/Endometrial Expansion Cohort: Patients must have histologically or cytologically confirmed ovarian or endometrial malignancy that is metastatic or unresectable and for which standard curative antineoplastic drug treatments do not exist or are no longer effective
  • CHEMOTHERAPY: Patients may have had up to two prior chemotherapy regimens for advanced or metastatic incurable solid tumors; prior (neo) adjuvant chemotherapy is allowed and not considered among the maximum of two prior regimens; patients must have completed any prior chemotherapy at least 4 weeks prior to registration; prior treatment with gemcitabine is not allowed

    • Chemo Naïve/Minimally Pre-Treated Cohort: Patients may not have received any prior chemotherapy for metastatic disease; prior adjuvant chemotherapy is allowed; patients must have completed any prior chemotherapy at least 4 weeks prior to registration; prior treatment with gemcitabine is not allowed
    • RADIATION: patients may have received prior radiation, however this must have been completed at least 4 weeks prior to registration; patients must not have had more than 40% of their bone marrow irradiated and must have either measurable disease outside the field or progression post radiation therapy
    • SURGERY: patients may have had prior surgery; patients must be at least 4 weeks from any major surgery prior to registration on the study
  • Eastern Cooperative Oncology Group (ECOG) performance status (PS) =< 2 (Karnofsky >= 60%)
  • Life expectancy > 3 months
  • Leukocytes >= 3 x 10^9/L
  • Absolute neutrophil count >= 1.5 x 10^9/L
  • Platelets >= 100 x 10^9/L
  • Total bilirubin within normal institutional limits
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal
  • Creatinine clearance >= 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal
  • Since cytochrome P450 (CYP)3A4 appears to be the major enzyme responsible for the human hepatic metabolism of E7389 in vitro, the concurrent use of inhibitors and inducers of CYP3A4 are prohibited during the study treatment period; concurrent use of CYP3A4 substrates are allowed, however, use caution and monitor the patient for potential drug interactions
  • The effects of E7389 on the developing human fetus are unknown; for this reason and because antitubulin agents as well as other therapeutic agents used in this trial are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately
  • Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

  • Patients who have had chemotherapy, biologic therapy, hormonal therapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered to < Common Terminology Criteria for Adverse Events (CTCAE) grade 2 from adverse events due to agents administered more than 4 weeks earlier are not eligible to participate in this study; grade 1 persisting toxicities or those deemed irreversible will not be exclusionary; patients who have received prior gemcitabine are also excluded
  • Patients may not be receiving any other investigational agents concurrently; patients should not be receiving any other anticancer therapy while on study, such as hormonal, biologic, or targeted therapies
  • Patients with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to E7389 or gemcitabine used in study
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
  • Pregnant women are excluded from this study because E7389 is an antitubulin agent with the potential for teratogenic or abortifacient effects; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with E7389, breastfeeding should be discontinued if the mother is treated with E7389; these potential risks may also apply to other agents used in this study
  • Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with E7389; in addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy; appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated
  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: NCT00410553

Locations
Canada, Ontario
The Ottawa Hospital Cancer Centre (Ottawa Health Research Institute) Civic Campus
Ottawa, Ontario, Canada, K1Y 4E9
University Health Network-Princess Margaret Hospital
Toronto, Ontario, Canada, M5G 2M9
Sponsors and Collaborators
Investigators
Principal Investigator: Rakesh Goel University Health Network-Princess Margaret Hospital
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00410553     History of Changes
Other Study ID Numbers: NCI-2009-00172, NCI-2009-00172, CDR0000520315, PMH-PHL-048, PHL-048, 7444, N01CM00032, N01CM17107
Study First Received: December 11, 2006
Last Updated: June 30, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Carcinoma
Neoplasms
Endometrial Neoplasms
Neoplasms, Glandular and Epithelial
Ovarian Neoplasms
Neoplasms by Histologic Type
Uterine Neoplasms
Genital Neoplasms, Female
Urogenital Neoplasms
Neoplasms by Site
Uterine Diseases
Genital Diseases, Female
Endocrine Gland Neoplasms
Ovarian Diseases
Adnexal Diseases
Endocrine System Diseases
Gonadal Disorders
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

ClinicalTrials.gov processed this record on August 19, 2014