title: A phase II study of the potent PARP inhibitor, Rucaparib (PF-01367338, AG014699), with temozolomide in patients with metastatic melanoma demonstrating evidence of chemopotentiation.
abstract: OBJECTIVE
  poly(ADP ribose) polymerase inhibition has been shown to potentiate the cytotoxicity of DNA damaging agents. A phase I study of rucaparib and temozolomide showed that full-dose temozolomide could be given during PARP inhibition. We report the results of a phase II study of intravenous rucaparib 12 mg/m(2) and oral temozolomide 200 mg/m(2) on days 1-5 every 28 days in patients with advanced metastatic melanoma.
  
  
  METHODS
  Patients with chemotherapy naïve measurable metastatic melanoma, performance status ≤2 and good end-organ function were recruited. Treatment was given until progression. A two stage phase II design was used, with response rate the primary endpoint. Population pharmacokinetics and pharmacodynamics were also explored.
  
  
  RESULTS
  Forty-six patients were recruited with 37 patients receiving at least 2 cycles and 17 patients at least 6 cycles. Myelosuppression occurred with 25 patients (54 %) requiring a 25 % dose reduction in temozolomide. The response rate was 17.4 %, median time to progression 3.5 months, median overall survival 9.9 months, and 36 % of patients were progression-free at 6 months.
  
  
  CONCLUSIONS
  This study showed that temozolomide (150-200 mg/m(2)/day) can safely be given with a PARP inhibitory dose of rucaparib, increasing progression-free survival over historical controls in metastatic melanoma patients.
authors: Institute for Cancer Research, Paul O'Gorman Building, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4HH, UK. ruth.plummer@ncl.ac.uk
authors: Ruth
authors: R
authors: Plummer
authors: Paul
authors: P
authors: Lorigan
authors: Neil
authors: N
authors: Steven
authors: Lucy
authors: L
authors: Scott
authors: Mark R
authors: MR
authors: Middleton
authors: Richard H
authors: RH
authors: Wilson
authors: Evan
authors: E
authors: Mulligan
authors: Nicola
authors: N
authors: Curtin
authors: Diane
authors: D
authors: Wang
authors: Raz
authors: R
authors: Dewji
authors: Antonello
authors: A
authors: Abbattista
authors: Jorge
authors: J
authors: Gallo
authors: Hilary
authors: H
authors: Calvert
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*; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives; D018572:Disease-Free Survival; D004357:Drug Synergism; D005260:Female; D006801:Humans; D007211:Indoles / Q000008:administration & dosage; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology; D008875:Middle Aged; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000473:pathology; D015996:Survival Rate; D000077204:Temozolomide; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D007211:Indoles; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D003606:Dacarbazine; C531549:rucaparib; D000077204:Temozolomide