Phase I Trial of Sorafenib in Combination with IFN α-2a in Patients with Unresectable and/or Metastatic Renal Cell Carcinoma or Malignant Melanoma

Abstract

Purpose: To determine the safety, maximum tolerated dose, pharmacokinetics, and efficacy, and to evaluate biomarkers, of the multikinase inhibitor sorafenib plus IFN a-2a in advanced renal cell carcinoma (RCC) or melanoma. Experimental Design: Patients received 28-day cycles of continuous, oral sorafenib twice daily and s.c. IFN thrice weekly: sorafenib 200 mg twice daily plus IFN 6 million IU (MIU) thrice weekly (cohort1); and sorafenib 400 mg twice daily plus IFN 6 MIU thrice weekly (cohort 2); or plus IFN 9 MIU thrice weekly (cohort 3). Tumor response was assessed by Response Evaluation Criteria in Solid Tumors and dynamic contrast-enhanced ultrasonography. Results: Thirteen patients received at least one dose of sorafenib plus IFN (12 RCC; one melanoma). The maximum tolerated dose was not reached [only one dose-limiting toxicity (grade 3 asthenia)]. Most frequently reported drug-related adverse events were grade 2 or less in severity, including fatigue, diarrhea, nausea, alopecia, and hand-foot skin reaction. One (7.7%) RCC patient achieved partial response and eight (61.5%) had stable disease (including the melanoma patient). Good responders assessed by dynamic contrast-enhanced ultrasonography had increased progression-free survival and overall survival, relative to poor responders. IFN had no effect on the pharmacokinetics of sorafenib. There were no significant changes in absolute values of lymphocytes, levels of proangiogenic cytokines, or inhibition of phosphorylated extracellular signalregulated kinase inTcells or natural killer cells, with combination therapy. Conclusions: This sorafenib combination was well tolerated, with preliminary antitumor activity in advanced RCC and melanoma patients. There were no drug-drug interactions and the recommended dose for future studies is sorafenib 400 mg twice daily plus IFN 9 MIU.Renal cell carcinoma (RCC) and melanoma have poor prognoses when diagnosed in advanced stages (1), and are associated with a median survival of V12 months (2, 3). RCC accounts for 80% to 95% of kidney tumors, and f30% of RCC patients have metastatic disease at diagnosis (1, 4, 5).The Raf/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK signaling pathway, which regulates cell proliferation and survival (6), is implicated in the onset and development of RCC (7) and melanoma (6). Overactivation of Raf-1 is detected in 55% of RCC biopsies in the absence of oncogenic ras/raf mutations (7). Clear cell carcinomas, which account for 75% to 85% of renal tumors, are characterized by loss of the von Hippel-Lindau tumor-suppressor gene (8), leading to overexpression of proangiogenic vascular endothelial growth factor (VEGF) and platelet-derived growth factor-h (9, 10). Activating b-raf mutations occur in >60% of melanomas, of which f90% are V600E (11, 12). The V600E b-raf mutant is constitutively active and implicated in tumor development (12). Inhibiting Raf/MEK/ERK signaling induces apoptosis in melanoma cells, but not in normal melanocytes, suggesting that oncogenic b-raf ma...

Propofol promotes apoptosis and suppresses the HOTAIR-mediated mTOR/p70S6K signaling pathway in melanoma cells

“…Cell proliferation of murine melanoma B16F10 cells was determined by MTT assay kit (Beyotime Institute of Biotechnology, Haimen, China) according to the manufacturer's protocol. B16F10 cells (1x10 4 ) were plated on 96-well culture plates and co-cultured with different concentrations (0-10 µM) of propofol (Sigma-Aldrich; Merck KGaA, Darmstadt, Germany; Fig. 1) for 24 or 48 h at 37˚C.…”

“…There is a rising trend in the number of melanoma cases worldwide (3). Among the industrial cities in South China, the morbidity of melanoma is much higher compared with the Chinese average rate, due to complex environmental factors (4).…”

Sorafenib, a Multikinase Inhibitor, Enhances the Response of Melanoma to Regional Chemotherapy

“…Indeed, sorafenib can enhance the effects of radiation, rapamycin, and the small-molecule inhibitor ABT-737, which inhibits the Bcl-2 protein (18)(19)(20). In phase I and II studies, melanoma patients treated with sorafenib combined with carboplatin and paclitaxel, temozolomide, dacarbazine, or IFNα-2a showed a greater response compared with historical control and, in one study of dacarbazine alone, with little enhancement of toxicity (14,(21)(22)(23). To date, however, no studies have examined whether sorafenib can augment the response to the alkylating agents melphalan and temozolomide in the unique setting of regional therapy of advanced in-transit melanoma using either isolated limb infusion (ILI) or isolated limb perfusion.…”

Sorafenib for the treatment of solid malignancies: what about the cancer microenvironment?

“…One of the first trials confirmed its efficacy in advanced, metastasized renal cell carcinoma, but only after immunotherapy with interleukin (IL)-2 and interferon (IFN)-alpha. 5 This highlights the need for a combined therapy, that uses immunotherapy together with tyrosine kinase inhibitors to target not only the cancer cell, but also the cancer microenvironment. This is of very special importance, as these drugs may indeed affect the malignant cell, but they also disrupt the local cancer niche, as proven by the very recent paper of Zhang et al 6 The group stated that sorafenib may actually kill some of the cancer cells, but it also promotes the dissemination of the cancer due to its "off target" effects on the niche, especially on the NK cells.…”