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A Phase I Study of Halichondrin B Analog E7389 in Combination With Gemcitabine in Patients With Refractory or Advanced Solid Tumors

Phase 1
18 Years
Open (Enrolling)
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

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Trial Information

A Phase I Study of Halichondrin B Analog E7389 in Combination With Gemcitabine in Patients With Refractory or Advanced Solid Tumors


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.

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 >=

- 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

Type of Study:


Study Design:

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

Outcome Measure:

Maximum tolerated dose of eribulin mesylate administered with gemcitabine hydrochloride in advanced/metastatic solid tumors

Outcome Description:

The Common Terminology Criteria for Adverse Events (CTCAE version 3 will be used to grade toxicity.

Outcome Time Frame:

Course 1

Safety Issue:


Principal Investigator

Rakesh Goel

Investigator Role:

Principal Investigator

Investigator Affiliation:

University Health Network-Princess Margaret Hospital


United States: Food and Drug Administration

Study ID:




Start Date:

November 2006

Completion Date:

Related Keywords:

  • 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
  • Carcinoma
  • Adenoma
  • Neoplasms
  • Endometrial Neoplasms
  • Neoplasms, Glandular and Epithelial
  • Ovarian Neoplasms