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

Phase 1/Phase 2
18 Years
Not Enrolling
Metastatic Malignant Melanoma

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Trial Information

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

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.

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

- 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

- 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

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

- 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

- 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.

Type of Study:


Study Design:

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

Outcome Measure:

Safety and tolerability of this combination

Outcome Time Frame:

March 2006 through October 2007

Safety Issue:


Principal Investigator

Lynn E. Spitler, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Northern California Melanoma Center


United States: Food and Drug Administration

Study ID:




Start Date:

March 2006

Completion Date:

January 2009

Related Keywords:

  • Metastatic Malignant Melanoma
  • Metastatic Malignant Melanoma
  • Melanoma



Northern California Melanoma Center San Francisco, California  94109