J. C. Trent

Heart failure associated with sunitinib malate: a multitargeted receptor tyrosine kinase inhibitor.

Sunitinib malate is a novel multitargeted receptor tyrosine kinase inhibitor with established efficacy in the treatment of metastatic renal cell carcinoma and imatinib‐resistant gastrointestinal stromal tumor. This report describes the development of heart failure in cancer patients who received this novel agent.

Phase I Trial of a Combination of the Multikinase Inhibitor Sorafenib and the Farnesyltransferase Inhibitor Tipifarnib in Advanced Malignancies

Purpose: We evaluated the safety, maximum tolerated dose, pharmacokinetics, and biological effects of the combination of the Raf-1, RET, KIT, platelet-derived growth factor receptor, and vascular endothelial growth factor receptor 2 kinase inhibitor sorafenib and the farnesyltransferase inhibitor tipifarnib. Experimental Design: A standard 3 + 3 phase I dose-escalation design was used with a 28-day cycle (sorafenib daily and tipifarnib for 21 days, by mouth). Results: Fifty patients were treated; 43 reached restaging evaluation after cycle 2. The most common side effects were grade 1 to 2 rash, hyperglycemia, and diarrhea. Dose-limiting toxicity was rash, and the recommended phase II dose is sorafenib 400 mg p.o. qam/200 mg p.o. qpm and tipifarnib p.o. 100 mg bd. Despite the low doses of tipifarnib, one quarter of patients had 50 reduction in farnesyltransferase levels. Interestingly, six of eight patients with medullary thyroid cancer had durable stable disease (n = 3) or partial remissions (n = 3), lasting 12 to 26+ months. Five of the six responders had available tissue, and RET gene mutations were identified in them. Prolonged (6 months) stable disease was also seen in nine patients as follows: papillary thyroid cancer (n = 4; 18+ to 27+ months), adrenocortical cancer (n = 2; 7 and 11 months), and one each of melanoma (platelet-derived growth factor receptor mutation positive; 14 months), renal (6 months), and pancreatic cancer (6 months). Conclusions: Our study shows that the combination of tipifarnib and sorafenib is well tolerated. Activity was seen, especially in patients with medullary thyroid cancer, a tumor characterized by RET mutations. (Clin Cancer Res 2009;15(22):70618)

A phase II study of low-dose protracted irinotecan in patients with advanced sarcomas.

10064 Background: Irinotecan was designed in 1983 and showed activity in preclinical and Phase I trials in solid tumors including osteosarcoma and rhabdomyosarcoma. A wide variety of schedules were used, ranging from weekly to monthly administrations. Dose limiting toxicities were mainly diarrhea and myelosuppression. This IRB-approved phase II trial evaluated the efficacy and toxicity of irinotecan via a low-dose protracted schedule in adult patients with pretreated advanced sarcoma. METHODS Patients with inoperable locally advanced or metastatic sarcoma that had received or refused standard chemotherapy for their disease were treated by 16 mg/m2 of irinotecan daily, intravenously over one hour, for 5 days x 2 weeks, with a 2-day rest, repeated in 21-day cycles. The primary end point was tumor response, defined as complete or partial response at 6 weeks or stable disease lasting at least 12 weeks. RESULTS Between April 2003 and June 2007, 38 patients (25 males and 13 females) with a median age of 48 years (range, 21-71 years) entered the study. Patients received a median of 2 cycles (range, 0 to 8 cycles). 2 patients underwent surgery and 1 patient is still with no evidence of recurrent disease. 7 patients required early discontinuation of therapy due to toxicities, mainly diarrhea. 16 patients developed progressive disease after 2 cycles, 11 presented stable disease and 6 had partial response after 2 cycles. Among the patients with stable disease after 2 cycles, 3 achieved a partial response, 4 remained stable and 4 progressed after 4 cycles. The response rate was 26%. The median time to progression and overall survival for all 38 patients was 6 weeks and 41 months, respectively. 1 of the 2 chondrosarcoma patients responded to treatment while the other one had transient stable disease. 5 of 7 Ewing sarcoma patients responded to this therapy (71%). CONCLUSIONS Irinotecan is an interesting therapy option in selected type of sarcoma in advanced and pretreated patient population. Its toxicity profile remains limiting due to diarrhea despite a low dose protracted-schedule delivery. However, myelotoxicity seems reduced on this regimen.