title: Phase 1 dose-escalation study of the PARP inhibitor CEP-9722 as monotherapy or in combination with temozolomide in patients with solid tumors.
abstract: OBJECTIVE
  Poly(ADP-ribose) polymerase-1 (PARP-1) is a nuclear enzyme important in DNA repair. PARP-1 activation at points of DNA strand break results in poly(ADP-ribose) polymer formation, opening the DNA structure, and allowing access of other repair enzymes. CEP-9722 inhibits PARP-1 and PARP-2 and is designed to potentiate DNA-damaging chemotherapies.
  
  
  METHODS
  This dose-escalating phase 1 study assessed the safety, maximum tolerated dose (MTD), and pharmacokinetics/pharmacodynamics of CEP-9722 plus temozolomide in adults with solid tumors. Tumor response was also assessed. Participants received a 14-day cycle of CEP-9722 (days 1 and 3-5 or days 1-5), followed by 28-day cycles of CEP-9722 plus temozolomide 150 mg/m(2) on days 1-5. The initial CEP-9722 dose (cohort 1) was 150 mg/day; dose escalation followed a modified Fibonnaci sequence.
  
  
  RESULTS
  Twenty-six patients received CEP-9722 150-1,000 mg/day combined with temozolomide. Dose-limiting toxicities of asthenia and persistent weight loss at 1,000 mg/day resulted in 750 mg/day being defined as the MTD and recommended dose for further study. Overall, 24 (92 %) patients had treatment-related adverse events (TRAEs), mostly grade 1 or 2, with nausea, vomiting, and diarrhea having the strongest relation to CEP-9722. Four patients had grade 3 TRAEs (asthenia, myositis, diarrhea, and fatigue). Systemic exposure generally increased with dosage, with high inter- and intra-patient variability at all doses. Pharmacodynamic assessment confirmed PARP inhibition although no dose response was apparent. One patient with melanoma achieved a partial response (1,000 mg/day).
  
  
  CONCLUSIONS
  CEP-9722 was adequately tolerated with temozolomide; the MTD was 750 mg/day. Only limited clinical activity was observed.
authors.affiliation: Northern Centre for Cancer Care, Newcastle upon Tyne, NE7 7DN, UK.
authors.forename: Ruth
authors.initials: R
authors.lastname: Plummer
authors.forename: Peter
authors.initials: P
authors.lastname: Stephens
authors.forename: Louiza
authors.initials: L
authors.lastname: Aissat-Daudigny
authors.forename: Anne
authors.initials: A
authors.lastname: Cambois
authors.forename: Gilbert
authors.initials: G
authors.lastname: Moachon
authors.forename: Peter D
authors.initials: PD
authors.lastname: Brown
authors.forename: Mario
authors.initials: M
authors.lastname: Campone
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D018906:Antineoplastic Agents, Alkylating / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols; D002227:Carbazoles / Q000737:chemistry; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D010797:Phthalimides / Q000737:chemistry; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011355:Prodrugs / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011379:Prognosis; D000077204:Temozolomide; D014018:Tissue Distribution; D055815:Young Adult
chemical_list: D018906:Antineoplastic Agents, Alkylating; C523456:CEP 8983; D002227:Carbazoles; D010797:Phthalimides; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011355:Prodrugs; D003606:Dacarbazine; D000077204:Temozolomide