Original Article

Cancer Chemotherapy and Pharmacology

, Volume 71, Issue 4, pp 981-990

First online:

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

  • Sook Ryun ParkAffiliated withDivision of Cancer Treatment and Diagnosis, National Cancer Institute
  • , Giovanna SperanzaAffiliated withDivision of Cancer Treatment and Diagnosis, National Cancer Institute
  • , Richard PiekarzAffiliated withDivision of Cancer Treatment and Diagnosis, National Cancer Institute
  • , John J. WrightAffiliated withDivision of Cancer Treatment and Diagnosis, National Cancer Institute
  • , Robert J. KindersAffiliated withApplied/Developmental Research Directorate, SAIC-Frederick, Inc., Frederick National Laboratory for Cancer Research
  • , Lihua WangAffiliated withApplied/Developmental Research Directorate, SAIC-Frederick, Inc., Frederick National Laboratory for Cancer Research
  • , Thomas PfisterAffiliated withApplied/Developmental Research Directorate, SAIC-Frederick, Inc., Frederick National Laboratory for Cancer Research
  • , Jane B. TrepelAffiliated withCenter for Cancer Research, National Cancer Institute
  • , Min-Jung LeeAffiliated withCenter for Cancer Research, National Cancer Institute
    • , Sylvia AlarconAffiliated withCenter for Cancer Research, National Cancer Institute
    • , Seth M. SteinbergAffiliated withCenter for Cancer Research, National Cancer Institute
    • , Jerry CollinsAffiliated withDivision of Cancer Treatment and Diagnosis, National Cancer Institute
    • , James H. DoroshowAffiliated withDivision of Cancer Treatment and Diagnosis, National Cancer InstituteCenter for Cancer Research, National Cancer Institute
    • , Shivaani KummarAffiliated withDivision of Cancer Treatment and Diagnosis, National Cancer InstituteCenter for Cancer Research, National Cancer Institute Email author 

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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 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 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 vs. 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 vs. 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.

Keywords

Fostamatinib R406 R935788 Solid tumors Angiogenesis