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

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

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.

Study Overview

• Status: Completed
• Conditions: Unspecified Adult Solid Tumor, Protocol Specific
• Intervention / Treatment: Drug: pemetrexed disodium; Drug: vinflunine; Drug: erlotinib hydrochloride

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 41
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599-7295
      • Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: UNC Lineberger Comprehensive Cancer Center
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Elizabeth C. Dees, MD, UNC Lineberger Comprehensive Cancer Center

Study record dates

Study Major Dates

• Study Start: August 1, 2006
• Primary Completion (Actual): October 1, 2008
• Study Completion (Actual): January 1, 2010

Study Registration Dates

• First Submitted: April 27, 2006
• First Submitted That Met QC Criteria: April 27, 2006
• First Posted (Estimate): May 3, 2006

Study Record Updates

• Last Update Posted (Estimate): May 16, 2012
• Last Update Submitted That Met QC Criteria: May 14, 2012
• Last Verified: May 1, 2012

More Information

Terms related to this study

• Keywords: unspecified adult solid tumor, protocol specific
• Additional Relevant MeSH Terms: Neoplasms; Molecular Mechanisms of Pharmacological Action; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Folic Acid Antagonists; Erlotinib Hydrochloride; Pemetrexed
• Other Study ID Numbers: LCCC 0509; CDR0000550148 (Other Identifier: PDQ number)