title: 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: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors: Division of Cancer Treatment and Diagnosis, National Cancer Institute, 31 Center Drive, 3A44, Bethesda, MD 20892, USA.
authors: Sook Ryun
authors: SR
authors: Park
authors: Giovanna
authors: G
authors: Speranza
authors: Richard
authors: R
authors: Piekarz
authors: John J
authors: JJ
authors: Wright
authors: Robert J
authors: RJ
authors: Kinders
authors: Lihua
authors: L
authors: Wang
authors: Thomas
authors: T
authors: Pfister
authors: Jane B
authors: JB
authors: Trepel
authors: Min-Jung
authors: MJ
authors: Lee
authors: Sylvia
authors: S
authors: Alarcon
authors: Seth M
authors: SM
authors: Steinberg
authors: Jerry
authors: J
authors: Collins
authors: James H
authors: JH
authors: Doroshow
authors: Shivaani
authors: S
authors: Kummar
mesh_terms: D000310:Adrenal Gland Neoplasms / Q000188:drug therapy; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000631:Aminopyridines; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy; D002292:Carcinoma, Renal Cell / Q000188:drug therapy; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000188:drug therapy; D042783:Endothelial Cells / Q000473:pathology; D005260:Female; D006258:Head and Neck Neoplasms / Q000188:drug therapy; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy; D008175:Lung Neoplasms / Q000188:drug therapy; D008297:Male; D008875:Middle Aged; D009025:Morpholines; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D010078:Oxazines / Q000009:adverse effects / Q000627:therapeutic use*; D010673:Pheochromocytoma / Q000188:drug therapy; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011725:Pyridines / Q000009:adverse effects / Q000627:therapeutic use*; D011743:Pyrimidines; D013964:Thyroid Neoplasms / Q000188:drug therapy
chemical_list: D000631:Aminopyridines; D009025:Morpholines; D010078:Oxazines; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011743:Pyrimidines; C523665:fostamatinib
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