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A Two Arm Phase I Dose Escalation Trial of Vinflunine With Erlotinib or Pemetrexed in Refractory Solid Tumors


Phase 1
18 Years
N/A
Not Enrolling
Both
Unspecified Adult Solid Tumor, Protocol Specific

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Trial Information

A Two Arm Phase I Dose Escalation Trial of Vinflunine With Erlotinib or Pemetrexed in Refractory Solid Tumors


OBJECTIVES:

Primary

- Define the maximum tolerated dose (MTD) of vinflunine and pemetrexed disodium in
patients with unresectable or metastatic solid tumors.

- Define the MTD of vinflunine and erlotinib hydrochloride in these patients.

Secondary

- Determine the preliminary safety and efficacy (reported descriptively per patient
response; tumor specific response rate reported if applicable) of these regimens.

- Correlate CYP3A4 activity, as measured by midazolam clearance, with vinflunine plasma
clearance.

OUTLINE: This is a nonrandomized, open-label, dose-escalation study. Patients are assigned
to 1 of 2 treatment groups.

- Group 1: Patients receive pemetrexed disodium IV over 10 minutes and vinflunine IV over
20 minutes on day 1.

Cohorts of 3-6 patients receive escalating doses of pemetrexed disodium and vinflunine 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. Additional
patients may be treated at the MTD.

- Group 2: Patients receive vinflunine IV over 20 minutes on day 1 and oral erlotinib
hydrochloride once daily on days 2-21 of course 1 and on days 1-21 of all subsequent
courses.

Cohorts of 3-6 patients receive escalating doses of erlotinib hydrochloride and vinflunine
until the 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. Additional patients may be treated at
the MTD.

In both groups, courses repeat every 21 days in the absence of unacceptable toxicity.

Blood samples are collected on day 1 of course 1 for pharmacodynamic studies.

After completion of study treatment, patients are followed for 30-40 days.

Inclusion Criteria


DISEASE CHARACTERISTICS:

- Histologically confirmed solid tumors

- Advanced/unresectable or metastatic disease

- Refractory to standard therapy OR no standard therapy exists

- No lymphoma

- Measurable or evaluable disease

- Measurable disease is defined as at least one target lesion measuring ≥ 20 mm by
conventional techniques or ≥ 10 mm by spiral CT scan

- Evaluable disease includes ascites, pleural effusion, bone metastases, pulmonary
lymphangitic spread, and lesions not meeting above criteria as measurable

- Patients with clinically significant ascites or pleural effusions that
cannot be controlled by drainage are not eligible

- Brain metastases allowed if CNS-directed treatment has been given, patient has been
off CNS-directed therapy for > 3 months, and CNS disease has been clinically and
radiographically stable for at least 8 weeks

PATIENT CHARACTERISTICS:

- Life expectancy > 3 months

- ECOG performance status 0-2

- Absolute neutrophil count ≥ 1,500/μL

- Platelet count ≥ 100,000/μL

- Creatinine clearance ≥ 60 mL/min

- Patients assigned to group 1 with creatinine clearance 45-80 mL/min must be able
to withhold NSAIDS during pemetrexed disodium administration

- Total bilirubin ≤ 1.5 mg/dL

- AST and ALT ≤ 3 times upper limit of normal (ULN) OR ≤ 5 times ULN if due to known
liver metastases

- No New York Heart Association class III or IV heart failure

- No unstable angina

- No myocardial infarction within the past 6 months

- No poorly controlled hypertension

- No prior allergic reaction to any vinca alkaloid

- No uncontrolled active infection or severe illness

- Able to receive vitamin B12 and folate supplementation and dexamethasone during
chemotherapy

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception during and for 3 months after last
dose of chemotherapy

PRIOR CONCURRENT THERAPY:

- At least 4 weeks since prior chemotherapy, investigational agents, or surgery

- Concurrent cytochrome P450/CYP3A4 inducers or inhibitors are allowed provided patient
has been on a stable dose for ≥ 2 weeks prior to study entry

- No concurrent ketoconazole, itraconazole, ritonavir, amprenavir, or indinavir

- No concurrent enzyme-inducing antiepileptic drugs (EIAEDs) (e.g., phenytoin,
carbamazepine, phenobarbital, primidone, or oxcarbazepine) for patients assigned to
group 2

Type of Study:

Interventional

Study Design:

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

Outcome Measure:

Maximum tolerated dose (MTD) of vinflunine and pemetrexed disodium

Outcome Description:

The MTD is defined as the dose cohort where approximately 0.20 of patients experience DLT. Standard "groups of three" phase I dose escalation design will be used in each arm. Each dose cohort will accrue a minimum of three patients.The estimated MTD is the dose level below the dose that induced dose limiting toxicity (DLT) in one third or more of patients

Outcome Time Frame:

1 year

Safety Issue:

Yes

Principal Investigator

Elizabeth C. Dees, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

UNC Lineberger Comprehensive Cancer Center

Authority:

United States: Food and Drug Administration

Study ID:

LCCC 0509

NCT ID:

NCT00320073

Start Date:

August 2006

Completion Date:

January 2010

Related Keywords:

  • Unspecified Adult Solid Tumor, Protocol Specific
  • unspecified adult solid tumor, protocol specific
  • Neoplasms

Name

Location

Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel HillChapel Hill, North Carolina  27599-7570