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

Abstract

PurposePoly(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.MethodsThis 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/m2 on days 1–5. The initial CEP-9722 dose (cohort 1) was 150 mg/day; dose escalation followed a modified Fibonnaci sequence.ResultsTwenty-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).ConclusionsCEP-9722 was adequately tolerated with temozolomide; the MTD was 750 mg/day. Only limited clinical activity was observed.Electronic supplementary materialThe online version of this article (doi:10.1007/s00280-014-2486-9) contains supplementary material, which is available to authorized users.

A Phase I–II Study of the Oral PARP Inhibitor Rucaparib in Patients with Germline BRCA1/2-Mutated Ovarian Carcinoma or Other Solid Tumors

“…Toxicities observed with rucaparib, such as myelosuppression, fatigue, and gastrointestinal disorders, are commonly observed with other PARP inhibitors (19,23,24,37,38). Myelosuppression, which generally occurs at a lower frequency with PARP inhibitors in relation to platinum-based chemotherapy, was generally observed after several cycles of rucaparib treatment and was successfully managed with supportive care and treatment modification (dose reduction and/or (27).…”

“…Several PARP inhibitors are currently in development for the treatment of patients with tumors harboring HRD, including those with a BRCA1/2 mutation (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26). Single-agent olaparib is approved in the United States for the treatment of patients with advanced germline BRCA1/2-mutated ovarian cancer who have received three or more lines of chemotherapy (27,28).…”

PARP inhibitors: A new era of targeted therapy

“…The DNA damage resulting from the topoisomerase poisoning is counteracted by PARs. Hence PARP inhibitors can be used to antagonize the effect of PARs on the repair mechanisms, thus increasing the maintenance of persistent DNA breaks [23][24][25]. Other chemotherapeutics and biologics being used in combination with PARPi include taxane (paclitaxel), bevacizumab, gefitinib, cediranib, cetuximab, gemcitabine, capecitabine, lapatinib, dinaciclib, mitomycin and bortezomib (www.clinical.trial.gov).…”

“…These studies have led to clinical trials of PARP inhibitors in combination with chemotherapeutics that lead to DNA damage (Table 1), with the PARP inhibitor blocking the subsequent DNA repair mechanisms selectively in cancer cells. Some of the drugs being used with PARP inhibitors include platinum based DNA damaging agents such as cisplatin, carboplatin, oxaliplatin; alkylating agents like Temozolomide (TMZ) and topoisomerase inhibitors such as Camptothecin (CPT) and its derivatives (irinotecan and topotecan) [19][20][21][22][23][24][25]. TMZ therapy, when combined with radiation induces single stranded breaks (SSBs) and hence is the direct target of PARP inhibitors.…”

Effectiveness and Safety of Poly (ADP-ribose) Polymerase Inhibitors in Cancer Therapy: A Systematic Review and Meta-analysis

“…Of all the 2274 patients, several types of cancers were reported, such as ovarian, lung, breast, and gastric cancers. Besides these, many trials [26][27][28][29][30][31][32] in different kinds of cancers not eligible for inclusion are still under way. Although the results have not come out, it is possible that PARP inhibitors may work in patients against some certain types of tumors.…”