title: Phase I study of sorafenib in combination with docetaxel and prednisone in chemo-naïve patients with metastatic castration-resistant prostate cancer.
abstract: OBJECTIVE
  We performed a dose-escalation study to investigate the safety of sorafenib in combination with docetaxel and prednisone in chemo-naïve patients with metastatic castration-resistant prostate cancer (mCRPC).
  
  
  METHODS
  Six patients were included per dose level. Following docetaxel infusion on day 1 (75 mg/m(2)/q3 weeks), sorafenib was administered at 200 mg BID on days 2-19 (dose level 1), at 200 mg BID on days 1-21 (dose level 2), at 400 mg BID on days 2-19 (dose level 3), at 400 mg BID on days 1-21 (dose level 4). Maximal tolerated dose (MTD) was exceeded if ≥2 patients experienced dose-limiting toxicities (DLT) during cycle 1. The recommended phase 2 dose for sorafenib was defined as one dose level below MTD. If MTD was not reached, the highest feasible dose would be selected to treat an expanded cohort to confirm safety.
  
  
  RESULTS
  Two DLTs were observed during sorafenib dose-escalation consisting of grade 4 febrile neutropenia (dose level 2) and grade 3 hand-foot syndrome (HFS) (dose level 3). Our pharmacokinetic results showed an increased exposure to docetaxel across all dose levels during sorafenib comedication. The main grade ≥3 toxicities were neutropenia (35 %), HFS (27 %), and febrile neutropenia (19 %). The prostate-specific antigen (PSA) response rate was 74 %. Median overall survival was 25.2 months.
  
  
  CONCLUSIONS
  Three-weekly docetaxel and prednisone could be combined with sorafenib at 400 mg BID on days 1-21 without reaching MTD. However, we observed a pharmacokinetic interaction between sorafenib and docetaxel, associated with significant toxicities, raising concerns about the safety of this combination in mCRPC.
authors: Medical Oncology Unit, St-Luc University Hospital, Catholic University of Louvain, 1200 Brussels, Belgium.
authors: Feby
authors: F
authors: Mardjuadi
authors: Jacques
authors: J
authors: Medioni
authors: Joseph
authors: J
authors: Kerger
authors: Lionel
authors: L
authors: D'Hondt
authors: Jean-Luc
authors: JL
authors: Canon
authors: Lionel
authors: L
authors: Duck
authors: Flora
authors: F
authors: Musuamba
authors: Stephane
authors: S
authors: Oudard
authors: Marylene
authors: M
authors: Clausse
authors: Anne
authors: A
authors: Moxhon
authors: Jean-Pascal
authors: JP
authors: Machiels
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001557:Benzenesulfonates / Q000008:administration & dosage; D018572:Disease-Free Survival; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004357:Drug Synergism; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009376:Neoplasms, Hormone-Dependent / Q000097:blood / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D009536:Niacinamide / Q000031:analogs & derivatives; D009919:Orchiectomy; D010671:Phenylurea Compounds; D010865:Pilot Projects; D011241:Prednisone / Q000008:administration & dosage; D011446:Prospective Studies; D011471:Prostatic Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D011725:Pyridines / Q000008:administration & dosage; D000077157:Sorafenib; D043823:Taxoids / Q000008:administration & dosage; D013739:Testosterone / Q000097:blood
chemical_list: D001557:Benzenesulfonates; D010671:Phenylurea Compounds; D011725:Pyridines; D043823:Taxoids; D000077143:Docetaxel; D009536:Niacinamide; D013739:Testosterone; D000077157:Sorafenib; D011241:Prednisone