title: An open-label, dose-escalation study to evaluate the safety and pharmacokinetics of CEP-9722 (a PARP-1 and PARP-2 inhibitor) in combination with gemcitabine and cisplatin in patients with advanced solid tumors.
abstract: Poly (ADP-ribose) polymerase-1 (PARP-1) inhibitors may potentiate chemotherapy by hindering DNA damage repair pathways. CEP-9722 is the prodrug of CEP-8983, a selective inhibitor of PARP-1 and PARP-2. Preclinical studies and a prior phase 1 study suggested that CEP-9722 may cause less myelosuppression than has been observed with other oral PARP inhibitors. The primary objective of this study was to determine the maximum-tolerated dose of CEP-9722 in combination with gemcitabine and cisplatin in patients with advanced solid tumors. All patients received cisplatin 75 mg/m(2) on day 1 and gemcitabine 1250 mg/m(2) on days 1 and 8 of a 21-day cycle. Patients who completed one cycle of chemotherapy alone continued chemotherapy in combination with CEP-9722 150, 200, 300, or 400 mg orally twice daily on days 2-7, with dose-limiting toxicity assessed in cycle 2. Patients experiencing clinical benefit could continue treatment until disease progression or unacceptable toxicity. Thirty-two patients enrolled; 18 patients completed cycle 1 and received chemotherapy plus CEP-9722. The median (range) treatment administration with CEP-9722 was five (1-12) cycles. No patient experienced dose-limiting toxicity with CEP-9722 treatment. Grade 3/4 hematologic adverse events included neutropenia (28%) and leukopenia (11%); adverse events led to discontinuation in 33% of patients. One patient achieved complete response, three had partial responses, and 11 had stable disease; however, the relative contribution of CEP-9722 and/or the chemotherapeutic agents cannot be determined from this single-arm design. This study was discontinued before determination of the maximum-tolerated dose because of highly variable CEP-8983 exposure in all cohorts and toxicity, particularly chemotherapy-induced myelosuppression.
authors.affiliation: aMedical Oncology Clinic, Institut Jules Bordet, Université Libre de Bruxelles, Brussel, Belgium bInstitut de Cancerologie de l'Ouest, Boulevard Jacques Monod, Nantes St-Herblain Cedex cDrug Development Department, Gustave Roussy Cancer Campus, Villejuif, Cedex dUniversity Paris Sud, Orsay, France.
authors.forename: Ahmad
authors.initials: A
authors.lastname: Awada
authors.forename: Mario
authors.initials: M
authors.lastname: Campone
authors.forename: Andrea
authors.initials: A
authors.lastname: Varga
authors.forename: Philippe
authors.initials: P
authors.lastname: Aftimos
authors.forename: Jean-Sébastien
authors.initials: JS
authors.lastname: Frenel
authors.forename: Rastilav
authors.initials: R
authors.lastname: Bahleda
authors.forename: Andrea
authors.initials: A
authors.lastname: Gombos
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Bourbouloux
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Soria
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D001943:Breast Neoplasms / Q000188:drug therapy; D002227:Carbazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D002945:Cisplatin / Q000008:administration & dosage; D015179:Colorectal Neoplasms / Q000188:drug therapy; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy; D008297:Male; D008545:Melanoma / Q000188:drug therapy; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D010051:Ovarian Neoplasms / Q000188:drug therapy; D010797:Phthalimides / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D000093542:Gemcitabine
chemical_list: C000597465:CEP-9722; D002227:Carbazoles; D010797:Phthalimides; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D003841:Deoxycytidine; C499320:PARP1 protein, human; C483041:PARP2 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D002945:Cisplatin; D000093542:Gemcitabine