A multi-histology trial of fostamatinib in patients with advanced colorectal, non-small cell lung, head and neck, thyroid, and renal cell carcinomas, and pheochromocytomas

Abstract

Purpose A multi-cohort phase II study of fostamatinib, an oral multi-kinase inhibitor, was conducted to determine the response rate in patients with advanced colorectal (CRC), thyroid, non-small-cell lung, head and neck, and renal cell carcinomas, and pheochromocytomas. Methods Patients received 200 mg fostamatinib BID in 4-week cycles with response assessed every 2 cycles. Blood was collected for pharmacokinetic analysis and measurements of circulating tumor cells (CTCs) and circulating endothelial (progenitor) cells (CE(P)Cs). Results A total of 37 patients (22 CRC), median of 4 prior therapies, were enrolled. Due to toxicities in four of the first five patients, the study was amended to incorporate a dose escalation phase for each histology. The maximum-tolerated dose (MTD) was established at 50 mg BID in CRC but was not established for the other cancers. Common grade 3/4 toxicities included transaminitis, hyperbilirubinemia, and hypertension. Pharmacokinetic profile was similar to previous reports. Seventy-three percent of CRC patients had liver involvement and 91% had prior anti-angiogenic therapy. Patients with abnormal liver tests at baseline were more likely to experience grade ≥2 hepatotoxicity than those with normal tests (44% versus 0%). No responses were observed; disease stabilization rate was 27% in CRC. Reduction in CECs following treatment was associated with a better disease stabilization rate (75% versus 0%) in CRC. Conclusion Fostamatinib had limited anti-tumor activity in this first clinical trial in patients with advanced refractory solid tumors; reduction in CECs and CEPs was indicative of anti-angiogenic effects. Abnormal liver testing at baseline appeared to influence drug tolerability.

Novel targeted therapeutics for MEN2

“…Also in this case, the compound was inadvertently found to block RET kinase activity (Clemens et al 2009). A recent multi-histology trial evaluated four thyroid cancer patients (papillary and follicular type), two of whom achieved SD as their best response (Park et al 2013). In addition, one of the two patients with pheochromocytoma had durable SD.…”

Implementation of Validated Pharmacodynamic Assays in Multiple Laboratories: Challenges, Successes, and Limitations

“…In contrast, drugs that do not induce DNA damage (the kinase inhibitor fostamatinib and rapamycin (15, 16, 17)) did not induce a γH2Ax signal in CTCs. A limitation of the approach was the necessity of testing CTCs 24 hours after drug administration due to limitations within the clinic and the uncertainty around CTC half-life in the circulation (estimated to be 1 to 2 hours; 18).…”

THERAPY OF ENDOCRINE DISEASE: Response and toxicity of small-molecule tyrosine kinase inhibitors in patients with thyroid carcinoma: a systematic review and meta-analysis

“…This may result in subsequent RAS activation and can therefore induce resistance to RAF inhibitors (42). Owing to the lack of clearly effective therapies, new kinase inhibitors such as vemurafenib and fostamatinib have already been studied in small numbers of TC patients (43,44). Furthermore, several combinations of TKIs or a TKI combined with other targeted therapies such as sorafenib and everolimus have been examined.…”