I. Gibbens

The effects of sorafenib--an oral multikinase inhibitor targeting the tumour and tumour vasculature--were evaluated in patients with advanced melanoma enrolled in a large multidisease Phase II randomised discontinuation trial (RDT). Enrolled patients received a 12-week run-in of sorafenib 400 mg twice daily (b.i.d.). Patients with changes in bi-dimensional tumour measurements <25% from baseline were then randomised to sorafenib or placebo for a further 12 weeks (ie to week 24). Patients with > or =25% tumour shrinkage after the run-in continued on open-label sorafenib, whereas those with > or =25% tumour growth discontinued treatment. This analysis focussed on secondary RDT end points: changes in bi-dimensional tumour measurements from baseline after 12 weeks and overall tumour responses (WHO criteria) at week 24, progression-free survival (PFS), safety and biomarkers (BRAF, KRAS and NRAS mutational status). Of 37 melanoma patients treated during the run-in phase, 34 were evaluable for response: one had > or =25% tumour shrinkage and remained on open-label sorafenib; six (16%) had <25% tumour growth and were randomised (placebo, n=3; sorafenib, n=3); and 27 had > or =25% tumour growth and discontinued. All three randomised sorafenib patients progressed by week 24; one remained on sorafenib for symptomatic relief. All three placebo patients progressed by week-24 and were re-started on sorafenib; one experienced disease re-stabilisation. Overall, the confirmed best responses for each of the 37 melanoma patients who received sorafenib were 19% stable disease (SD) (ie n=1 open-label; n=6 randomised), 62% (n=23) progressive disease (PD) and 19% (n=7) unevaluable. The overall median PFS was 11 weeks. The six randomised patients with SD had overall PFS values ranging from 16 to 34 weeks. The most common drug-related adverse events were dermatological (eg rash/desquamation, 51%; hand-foot skin reaction, 35%). There was no relationship between V600E BRAF status and disease stability. DNA was extracted from the biopsies of 17/22 patients. Six had V600E-positive tumours (n=4 had PD; n=1 had SD; n=1 unevaluable for response), and 11 had tumours containing wild-type BRAF (n=9 PD; n=1 SD; n=1 unevaluable for response). In conclusion, sorafenib is well tolerated but has little or no antitumour activity in advanced melanoma patients as a single agent at the dose evaluated (400 mg b.i.d.). Ongoing trials in advanced melanoma are evaluating sorafenib combination therapies.

7508 Background: BAY 43–9006 (BAY) prevents tumor cell proliferation and angiogenesis via blockade of the RAF/MEK/ERK pathway at the level of RAF (RAF-1, wild-type B-RAF, V599E B-RAF) kinase and inhibition of the receptor tyrosine kinases VEGFR-2 and PDGFR-β. In phase I/II trials, BAY was generally well tolerated as a single agent or with concomitant chemotherapy. Methods: This single-centre, open-label, phase I, dose-escalation study was performed to determine the safety profile and maximum tolerated dose (MTD) of BAY administered at 200 (cohort 1) or 400 (cohort 2) mg bid in combination with repeated 21-day cycles of DTIC 1000 mg/m2. In an extension phase (cohort 3), patients (pts) received the MTD of BAY plus DTIC 1000 mg/m2. Results: Pts with metastatic melanoma were enrolled (ECOG PS 0–1) into cohorts 1 (n=3) 2 (n=6) and 3 (n=3). 1 pt died due to PD. The most common drug-related AEs were dermatologic (rash, flushing, hand-foot skin reaction [HFS]); gastrointestinal (nausea, diarrhoea, constipation, vomiting), constitutional (fatigue/lethargy) or blood/bone-marrow-related, and were generally grade (gr) 1–2 in severity and transient. 1 pt in cohort 2 experienced dose-limiting toxicity of gr 3 HFS. No drug-related gr 3/4 AEs occurred in cohort 1. Gr 3/4 drug-related AEs in cohort 2 were mostly resolved and included gr 4 hypercalcemia; gr 3 low hemoglobin; gr 3 pancreatic hemorrhage; gr 3 pancreatitis; gr 3 leucopenia that occurred in 1 pt each and gr 3/4 neutropenia in 2 pts. Gr 3/4 laboratory abnormalities were rare. According to RECIST, of the 11 evaluable pts after cycle 2, 2 pts had PR; 2 pts had response not reaching PR; 1 pt had SD; and 6 pts had PD. Conclusions: Continuous BAY 400 mg bid is safe and well tolerated and shows preliminary anti-tumor activity in combination with DTIC 1000 mg/m2. The MTD of BAY is 400 mg bid in combination with DTIC 1000 mg/m2. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bayer, Bayer Healthcare Bayer, CFSB, Deutsche Bank, Medacorp AstraZeneca, Bayer AG Bayer Bayer

Temozolomide is an alkylating agent with activity in the treatment of melanoma metastatic to the brain. Lomustine is a nitrosurea that crosses the blood brain barrier and there is evidence to suggest that temozolomide may reverse resistance to lomustine. A multicentre phase I/II study was conducted to assess the maximum-tolerated dose (MTD), safety and efficacy of the combination of temozolomide and lomustine in melanoma metastatic to the brain. Increasing doses of temozolomide and lomustine were administered in phase I of the study to determine the MTD. Patients were treated at the MTD in phase II of the study to six cycles, disease progression or unacceptable toxicity. Twenty-six patients were enrolled in the study. In phase I of the study, the MTD was defined as temozolomide 150 mg m(-2) days 1-5 every 28 days and lomustine 60 mg m(-2) on day 5 every 56 days. Dose-limiting neutropaenia and thrombocytopaenia were observed at higher doses. Twenty patients were treated at this dose in phase II of the study. No responses to therapy were observed. Median survival from starting chemotherapy was 2 months. The combination of temozolomide and lomustine in patients with brain metastases from melanoma does not demonstrate activity. The further evaluation of this combination therefore is not warranted.

METHOD: The safety of oral sorafenib up to a maximum protocol-specified dose combined with dacarbazine in patients with metastatic, histologically confirmed melanoma was investigated in a phase I dose-escalation study and the activity of the combination was explored in an open-label phase II study. RESULTS: In the phase I study, three patients were treated with sorafenib 200 mg twice daily (b.i.d.) plus 1000 mg m(-2) dacarbazine on day 1 of a 21-day cycle and 15 patients had the sorafenib dose escalated to 400 mg b.i.d. without reaching the maximum tolerated dose of the combination. In the phase II study (n=83), the overall response rate was 12% (95% CI: 6, 21): one complete and nine partial, with median response duration of 46.7 weeks. Stable disease was the best response in 37%; median duration was 13.3 weeks. Median overall survival (OS) was 37.0 weeks (95% CI: 33.9, 46.0). CONCLUSION: Oral sorafenib combined with dacarbazine had acceptable toxicity and some antineoplastic activity against metastatic melanoma.