Temodar and Sutent as Therapy for Melanoma

February 3, 2009 updated by: Northern California Melanoma Center

Temodar and Sutent as Therapy for Patients With Malignant Melanoma, a Phase I/II Study

This study is designed to evaluate the safety and appropriate dose of the combination of Temodar and Sutent as first-line therapy for patients with metastatic malignant melanoma (Phase 1). Once the safety and appropriate dose is determined, additional patients will be studied at that dose to determine if there is clinical benefit as determined by the primary end-point of progression-free survival (PFS) at 6 months and additional secondary endpoints (Phase II).

Study Overview

Status

Terminated

Conditions

Intervention / Treatment

Detailed Description

Patients with unresectable metastatic melanoma have a dismal prognosis. The disease responds poorly to currently available chemotherapies and biological agents. The median survival in this patient population is 6 - 10 months and has not improved significantly in decades. The FDA approved DTIC in 1975 and high dose intravenous bolus rIL-2 in 1998 and these are the only agents approved for therapy of patients with metastatic melanoma.

In a Phase III trial reported in 2000, temozolomide (Temodar, Schering-Plough) demonstrated equivalent overall survival to DTIC in patients with metastatic melanoma, and had the advantages of providing improved progression-free survival, ease of administration (oral), and crossing the blood-brain barrier. Temozolomide and DTIC are both precursors of an active metabolite, monomethyl triazenoimidazole carboxamide (MTIC). SU11248 (Sutent, Pfizer) is a multi-targeted receptor tyrosine kinase inhibitor which targets 3 distinct vascular endothelial growth factor receptor (VEGFR-1, -2, and -3), platelet-derived growth factor receptor alpha and beta (PDGFR-α and -β), KIT receptor tyrosine kinases, and fms-related tyrosine kinase 3/Flk2 (FLT3). Although other angiogenic factors have been identified, VEGF is the most potent and specific regulator of angiogenesis and SU11248 targets not just one, but all 3 VEGF signaling pathways. Dacarbazine (DTIC) causes transcriptional up-regulation of VEGF in melanoma cells and this has been postulated as a possible mechanism of escape from chemotherapy efficacy. Temozolomide, which acts through the same metabolite, MTIC, would be expected to have the same activity. PDGFR-α and -β are important new targets in tumor cell proliferation and angiogenesis. PDGF signaling pathways have been implicated in the development and growth of solid tumors. Inhibition of PDGF receptors has been shown to inhibit angiogenesis, tumor vascular maturation and maintenance, and tumor cell proliferation - inducing tumor regression. In a murine model, the combination of chemotherapy with VEGF and PDFG receptor inhibitors resulted in a remarkable survival advantage.

The study is an open-label, single arm trial. The patient sample will be approximately 56-62 individuals, males and females 18 years of age or older with measurable metastatic melanoma. Study participants must meet a number of laboratory criteria in order to be admitted into the study. The study duration is expected to be approximately 2 years. Patients will be offered treatment for up to 1 year and are expected to complete a median of 6 cycles of treatment.

An interim analysis of safety will be conducted after completion of treatment of 6 patients in each cohort and a determination will be made as to whether or not to continue to the next cohort according to the specifications in the protocol. If an acceptable dosing regimen is found, the study will proceed to a Phase II portion. Progression-free survival will be determined for the 6 month time point when all patients have completed the study. The study has ≥90% power to detect an increase in the 6-month progression-free survival rate from ≤15%, the result expected for patients receiving available first-line therapy, to ≥35% for patients receiving the combination of temozolomide and SU11248, based on a one group chi-square test with a 0.05 two-sided significance level.

Study Type

Interventional

Enrollment (Actual)

7

Phase

  • Phase 2
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • California
      • San Francisco, California, United States, 94109
        • Northern California Melanoma Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Patients with histologically confirmed, (surgically incurable or unresectable)stage IV metastatic malignant melanoma.
  • Patients must not have received any prior cytokine or chemotherapy for stage IV disease.
  • ECOG performance status of 0-1.
  • Age greater than or equal to 18 years.

  • Adequate hematologic, renal and liver function as defined by laboratory values performed within 28 days prior to initiation of dosing.

    • Absolute neutrophil count (ANC) greater than or equal to 1500/uL
    • Platelet count greater than or equal to 100,000/uL
    • Hemoglobin greater than or equal to 10.0 g/dL
    • Serum creatinine ≤ 1.5 upper limit of laboratory normal
    • Total serum bilirubin less than or equal to1.5 times upper limit of laboratory normal
    • LDH less than or equal to 2 times upper limit of laboratory normal
    • Serum aspartate transaminase (ASAT/SGOT) or serum alanine transaminase (ALAT/SGPT) ≤ 2.5 times upper limit of laboratory normal, and ≤ 5 times upper limit of laboratory normal in cases of liver metastasis
  • Patients must have recovered from effects of major surgery.
  • Women of childbearing potential should be using an effective method of contraception. Women of childbearing potential must have a negative urine or serum pregnancy test up to 28 days prior to commencement of dosing and be practicing medically approved contraceptive precautions for at least 6 months after completion of treatment as directed by their physician.
  • Men should use an effective method of contraception during treatment and for at least 6 months after completion of treatment as directed by their physician.
  • Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before trial entry.
  • Before study entry, written informed consent must be obtained. Written informed consent must be obtained from the patient prior to performing any study-related procedures.

Exclusion Criteria:

  • Major surgery or radiation therapy within 4 weeks of starting the study treatment.
  • Evidence of brain metastases.
  • NCI CTCAE Version 3.0 grade 3 hemorrhage within 4 weeks of starting the study treatment.
  • History of or known spinal cord compression, or carcinomatous meningitis, or evidence of symptomatic brain or leptomeningeal disease on screening CT or MRI scan.
  • Any of the following within the 6 months prior to study drug administration: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident or transient ischemic attack, or pulmonary embolism.
  • Ongoing cardiac dysrhythmias of NCI CTCAE Version 3.0 grade equal to or greater than 2.
  • Prolonged QTc interval on baseline EKG.
  • Uncontrolled hypertension (>150/100 mm Hg despite optimal medical therapy).
  • Pre-existing thyroid abnormality with thyroid function that cannot be maintained in the normal range with medication.
  • Known active infection.
  • Concurrent treatment on another clinical trial. Supportive care trials or non-treatment trials, e.g. QOL, are allowed.
  • Treatment with drugs with dysrhythmic potential including terfenadine, quinidine, procainamide, disopyramide, sotalol, probucol, bepridil, haloperidol, risperidone, and/or indapamide.
  • Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration, or may interfere with the interpretation of study results, and in the judgment of the investigator would make the subject inappropriate for entry into this study.
  • Frequent vomiting or medical condition which could interfere with oral medication intake (e.g. partial bowel obstruction).
  • Previous cancer (unless a DRS interval of at least 5 years) or concurrent malignancies at other sites with the exception of surgically cured carcinoma in-situ of the cervix and basal or squamous cell carcinoma of the skin.
  • Known clinically uncontrolled infectious disease including HIV positivity or AIDS-related illness.
  • Pregnant or nursing.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Single arm, Open Label
Single arm, Open Label Temodar and Sutent
Drug: Temozolomide and SU11248
First Cohort: Temozolomide 100 mg/m2 orally week 1 and week 3 of a 28-day cycle; SU11248, 25 mg/day orally on weeks 2, 3, and 4 or a 28 day cycle.
Other Names:
  • Temozolomide is also known as Temodar
  • SU11248 is also known as Sutent

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Safety and tolerability of this combination
Time Frame: March 2006 through October 2007
March 2006 through October 2007
Determine the Maximum Tolerated Dose (MTD) of this combination
Time Frame: March 2006 through October 2007
March 2006 through October 2007

Secondary Outcome Measures

Outcome Measure
Time Frame
Progression-free survival (PFS) at 6 months
Time Frame: March 2006 through October 2007
March 2006 through October 2007
Progression-free survival (PFS)
Time Frame: March 2006 through October 2007
March 2006 through October 2007
Overall survival (OS)
Time Frame: October 2006 through January 2009
October 2006 through January 2009
Objective Response Rate (RR)in patients with measurable lesions
Time Frame: March 2006 through October 2007
March 2006 through October 2007
Duration of Objective Response in patients with measurable lesions
Time Frame: March 2006 through October 2007
March 2006 through October 2007
Correlation of outcome with MGMT promoter methylation
Time Frame: March 2006 through October 2007
March 2006 through October 2007

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Northern California Melanoma Center

Collaborators

Pfizer
Schering-Plough

Investigators

  • Principal Investigator: Lynn E. Spitler, MD, Northern California Melanoma Center

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

March 1, 2006

Primary Completion (Actual)

October 1, 2007

Study Completion (Actual)

January 1, 2009

Study Registration Dates

First Submitted

March 12, 2006

First Submitted That Met QC Criteria

March 16, 2006

First Posted (Estimate)

March 17, 2006

Study Record Updates

Last Update Posted (Estimate)

February 5, 2009

Last Update Submitted That Met QC Criteria

February 3, 2009

Last Verified

February 1, 2009

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • Temodar/Sutent

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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