title: A dose-ranging study of cabozantinib in men with castration-resistant prostate cancer and bone metastases.
abstract: BACKGROUND
  Cabozantinib is an oral MET/VEGFR2 inhibitor. A recent phase II study of cabozantinib (100 mg daily) showed improved bone scans in subjects with metastatic castration-resistant prostate cancer (mCRPC), but adverse events (AE) caused frequent dose reductions. This study was designed to determine the efficacy and tolerability of cabozantinib at lower starting doses.
  
  
  METHODS
  An adaptive design was used to determine the lowest active daily dose among 60, 40, and 20 mg. The primary endpoint was week 6 bone scan response, defined as ≥30% decrease in bone scan lesion area. The secondary endpoint was change in circulating tumor cells (CTC).
  
  
  RESULTS
  Among 11 evaluable subjects enrolled at 40 mg, there were 9 partial responses (PR), 1 complete response, and 1 stable disease (SD). Of 10 subjects subsequently enrolled at 20 mg, there were 1 PR, 5 SDs, and 4 with progressive disease. Among 13 subjects enrolled on the 40 mg expansion cohort, there were 6 PRs and 7 SDs. No subjects required dose reduction or treatment interruption at 6 or 12 weeks; 3 subjects at dose level 0 discontinued due to AEs by 12 weeks. At 40 mg, median treatment duration was 27 weeks. 58% of subjects with ≥5 CTCs/7.5 mL at baseline converted to <5.
  
  
  CONCLUSIONS
  Cabozantinib 40 mg daily was associated with a high rate of bone scan response. Cabozantinib 40 mg daily was associated with better tolerability than previously reported for cabozantinib 100 mg daily. These observations informed the design of phase III studies of cabozantinib in mCRPC.
authors.affiliation: Massachusetts General Hospital Cancer Center, Boston, Massachusetts 02114, USA. rjlee@partners.org
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Lee
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Saylor
authors.forename: M Dror
authors.initials: MD
authors.lastname: Michaelson
authors.forename: S Michael
authors.initials: SM
authors.lastname: Rothenberg
authors.forename: Malgorzata E
authors.initials: ME
authors.lastname: Smas
authors.forename: David T
authors.initials: DT
authors.lastname: Miyamoto
authors.forename: Carol A
authors.initials: CA
authors.lastname: Gurski
authors.forename: Wanling
authors.initials: W
authors.lastname: Xie
authors.forename: Shyamala
authors.initials: S
authors.lastname: Maheswaran
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Haber
authors.forename: Jonathan G
authors.initials: JG
authors.lastname: Goldin
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Smith
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000813:Anilides / Q000008:administration & dosage* / Q000009:adverse effects; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000556:secondary* / Q000601:surgery; D015331:Cohort Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D009360:Neoplastic Cells, Circulating; D009919:Orchiectomy; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology* / Q000601:surgery; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D011725:Pyridines / Q000008:administration & dosage* / Q000009:adverse effects; D016896:Treatment Outcome
chemical_list: D000813:Anilides; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C558660:cabozantinib; D017430:Prostate-Specific Antigen
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