Vinflunine and Erlotinib or Pemetrexed in Treating Patients With Unresectable or Metastatic Solid Tumors

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as vinflunine, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Erlotinib and pemetrexed may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving vinflunine together with erlotinib or pemetrexed may kill more tumor cells. PURPOSE: This phase I trial is studying the side effects and best dose of vinflunine when given together with erlotinib or pemetrexed in treating patients with unresectable or metastatic solid tumors.

Detailed Description
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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.

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

Conditions
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Unspecified Adult Solid Tumor, Protocol Specific

Intervention / Treatment
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* Drug: erlotinib hydrochloride
* Drug: pemetrexed disodium
* Drug: vinflunine


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A<br>Pemetrexed, Vinflunine, Folate, B12, Dexamethasone, Ondansetron, Midazolam | Drug: pemetrexed disodium<br>* Pemetrexed is administered intravenously over 10 minutes, every 21 days<br>Drug: vinflunine<br>* Vinflunine is administered intravenously over 20 minutes and should be given after pemetrexed, every 21 days<br>|
| Experimental: Arm B<br>Vinflunine, Erlotinib, Ondansetron, Midazolam | Drug: erlotinib hydrochloride<br>* 75 mg to 150mg<br>Drug: vinflunine<br>* Vinflunine is administered intravenously over 20 minutes and should be given after pemetrexed, every 21 days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose (MTD) of vinflunine and pemetrexed disodium | 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 | 1 year | 
| Maximum tolerated dose (MTD) of vinflunine and continuously dosed erlotinib | 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 | 1 year | 
| Maximum tolerated dose (MTD) of vinflunine and intermittently dosed erlotinib | 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 | 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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unspecified adult solid tumor, protocol specific