Combination chemotherapy with sunitinib (IND 74019; NSC 736511) for untreated extensive-stage small cell lung cancer (SCLC): CALGB 30504 phase IB safety results

Abstract

BACKGROUND: CALGB conducted a phase IB trial to determine the dose of sunitinib that can be safely combined with cisplatin and etoposide in extensive SCLC. METHODS: Patients with PS 0-1, adequate organ function and extensive SCLC were eligible. The treatment plan was cisplatin 80 mg/m2 d1 and etoposide 100 mg/m2 d1-3 every 21 d up to 6 cycles. Three cohorts of 6 patients at dose levels of 25, 37.5, or 50 mg/day days 1-14 every 21 days were planned. Every 2 week conference calls were held to assess toxicity. Toxicity during cycle 1 was evaluated for dose limiting toxicity (DLT). In cohort 1 prophylactic granulocyte growth factor support was not allowed. RESULTS: In cohort 1, there were no protocol defined DLTs. However most patients had prolonged neutropenia and required delayed start of cycle 2 chemotherapy. In cohort 1, two patients requiring treatment delays for neutropenia were given granulocyte growth factor support during cycles 3-6 and were able to receive therapy as scheduled without DLT. The trial was amended to give prophylactic granulocyte growth factor support to all patients from cycle 1 onward while repeating the sunitinib 25 mg d 1-14 level 1 dose for cohort 2. Of 6 patients on cohort 2, two patients died from complications of febrile neutropenia and a third had febrile neutropenia with neutrophil count of zero cycle 3 d 10. When the second patient died on cohort 2, sunitinib concurrent with chemotherapy in this setting was deemed unsafe, and sunitinib was immediately and permanently stopped for all remaining patients. The trial has been amended to a randomized phase II trial in which maintenance sunitinib after chemotherapy is being evaluated. CONCLUSIONS: The combination of sunitinib 25 mg/day days 1-14 to standard dose cisplatin and etoposide appeared to cause prolonged neutropenia and an unacceptable rate of treatment-related mortality. Granulocyte growth factor given after chemotherapy in this setting did not prevent severe neutropenia and infections. This combination of chemotherapy and sunitinib is not recommended, even with growth factor support.