Temodar (Temozolomide) and Sutent (SU11248) as Therapy for Patients with Malignant Melanoma, A Phase I/II Study

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-A and -B), 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-alpha and -beta 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 PDGF receptor inhibitors resulted in a remarkable survival advantage.

The primary end-point of the study is to determine safety and tolerability of this combination and to determine the Maximum Tolerated Dose (MTD) of this combination. The secondary endpoints are to determine progression-free survival (PFS) at 6 months, progression-free survival, overall survival, objective Response Rate (RR) in patients with measurable lesions, duration of objective response in patients with measurable lesions, and correlation of outcome with MGMT promoter methylation.

Inclusion Criteria (conditions the patient must meet)

1. Patients with histologically confirmed, (surgically incurable or unresectable) stage IV metastatic malignant melanoma.
2. Patients must not have received any prior cytokine or chemotherapy for stage IV disease. The following are allowed:
   • Adjuvant cytokine or vaccine therapy for resected stage I to III disease.
   • Previous vaccine therapy (other than cytokine) for stage IV disease.
   • Palliative surgery for stage IV disease.
   • Prior cytokine or chemotherapy for local-regional disease by isolated limb perfusion therapy.
   • All patients must have discontinued prior allowable therapy for at least 4 weeks prior to initiation of dosing.
3. ECOG performance status of 0-1.
4. Age greater than or equal to 18 years.
5. Adequate hematologic, renal and liver function as defined by laboratory values performed within 28 days prior to initiation of dosing.
6. Absolute neutrophil count (ANC) ≥1500/µL
7. Platelet count ≥100,000/µL
8. Hemoglobin ≥10.0 g/dL
9. Serum creatinine ≤ 1.5 upper limit of laboratory normal
10. Total serum bilirubin ≤1.5 times upper limit of laboratory normal
11. LDH ≤2 times upper limit of laboratory normal
12. 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
13. Patients must have recovered from effects of major surgery.
14. 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.
15. 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.
16. 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.
17. 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
Patients who exhibit any of the following conditions at screening will not be eligible for admission into the study:

1. Major surgery or radiation therapy within 4 weeks of starting the study treatment.
2. Evidence of brain metastases.
3. NCI CTCAE Version 3.0 grade 3 hemorrhage within 4 weeks of starting the study treatment.
4. History of or known spinal cord compression, or carcinomatous meningitis, or evidence of symptomatic brain or leptomeningeal disease on screening CT or MRI scan.
5. 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.
6. Ongoing cardiac dysrhythmias of NCI CTCAE Version 3.0 grade ≥2.
7. Prolonged QTc interval on baseline EKG.
8. Uncontrolled hypertension (>150/100 mm Hg despite optimal medical therapy).
9. Pre-existing thyroid abnormality with thyroid function that cannot be maintained in the normal range with medication.
10. Known active infection.
11. Concurrent treatment on another clinical trial. Supportive care trials or non-treatment trials, e.g. QOL, are allowed.
12. Treatment with drugs with dysrhythmic potential including terfenadine, quinidine, procainamide, disopyramide, sotalol, probucol, bepridil, haloperidol, risperidone, and/or indapamide.
13. 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.
14. Frequent vomiting or medical condition which could interfere with oral medication intake (e.g. partial bowel obstruction).
15. 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.
16. Known clinically uncontrolled infectious disease including HIV positivity or AIDS-related illness.
17. Pregnant or nursing.

Treatment Regimen
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.

Patients will receive Temodar orally for 7 days on and then 7 days off continuously (28-day cycle). There will receive Sutent orally for 3 weeks of the 28-day cycle beginning on day 8 of each cycle. Thus, they will receive Sutent for 3 weeks at the end of the 28-day cycle followed by 1 week rest at the beginning of the next 28-day cycle. Patients will be treated in cohorts of 6 patients each, with escalation of the dose of Temodar or Sutent in each subsequent cohort if there is no untoward toxicity.

Once the appropriate dosing regimen is determined, the patient population at this dose will be expanded to 50 in the Phase II portion of the study.