当前位置： SCI文献检索 > CANCER CHEMOTHERAPY AND PHARMACOLOGY期刊下所有文献 > Phase 1 dose-escalation study of the PARP inhibitor CEP-9722 as monotherapy or in combination with temozolomide in patients with solid tumors.

Phase 1 dose-escalation study of the PARP inhibitor CEP-9722 as monotherapy or in combination with temozolomide in patients with solid tumors.

Abstract：

PURPOSE: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.

journal_name

Cancer Chemother Pharmacol

journal_title

Cancer chemotherapy and pharmacology

authors

Plummer R,Stephens P,Aissat-Daudigny L,Cambois A,Moachon G,Brown PD,Campone M

doi

10.1007/s00280-014-2486-9

subject

Has Abstract

pub_date

2014-08-01 00:00:00

pages

257-65

issue

eissn

0344-5704

issn

1432-0843

journal_volume

pub_type

杂志文章,多中心研究

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Phase 1 dose-escalation study of the PARP inhibitor CEP-9722 as monotherapy or in combination with temozolomide in patients with solid tumors.