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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

Published on Aug 1, 2014in Cancer Chemotherapy and Pharmacology3.008
· DOI :10.1007/s00280-014-2486-9
Ruth Plummer30
Estimated H-index: 30
,
Peter Stephens5
Estimated H-index: 5
+ 4 AuthorsMario Campone58
Estimated H-index: 58
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.
  • References (24)
  • Citations (22)
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References24
Newest
#1Ruth Plummer (Newcastle University)H-Index: 30
#2Paul LoriganH-Index: 54
Last. Hilary Calvert (Newcastle University)H-Index: 26
view all 13 authors...
Purpose 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/m2 and oral temozolomide 200 mg/m2 on days 1–5 every 28 days in patients with advanced metastatic melanoma.
100 CitationsSource
#1Marie-France Langelier (Thomas Jefferson University)H-Index: 18
#2John M. Pascal (Thomas Jefferson University)H-Index: 29
Poly(ADP-ribose) polymerase 1 (PARP-1) regulates gene transcription, cell death signaling, and DNA repair through production of the posttranslational modification poly(ADP-ribose). During the cellular response to genotoxic stress PARP-1 rapidly associates with DNA damage, which robustly stimulates poly(ADP-ribose) production over a low basal level of PARP-1 activity. DNA damage-dependent PARP-1 activity is central to understanding PARP-1 biological function, but structural insights into the mech...
95 CitationsSource
#1Shivaani KummarH-Index: 37
#2Alice ChenH-Index: 18
Last. James H. DoroshowH-Index: 72
view all 7 authors...
The poly (ADP-ribose) polymerase (PARP) family of enzymes plays a critical role in the maintenance of DNA integrity as part of the base excision pathway of DNA repair. PARP1 is overexpressed in a variety of cancers, and its expression has been associated with overall prognosis in cancer, especially breast cancer. A series of new therapeutic agents that are potent inhibitors of the PARP1 and PARP2 isoforms have demonstrated important clinical activity in patients with breast or ovarian cancers th...
89 CitationsSource
#1Jens Samol (St George's Hospital)H-Index: 1
#2Malcolm R RansonH-Index: 49
Last. Jim Cassidy (Beatson West of Scotland Cancer Centre)H-Index: 66
view all 7 authors...
Background The aim of this phase I study was to determine the safety and tolerability and to establish the maximum tolerated dose (MTD) of orally administered olaparib (AZD2281) in combination with topotecan in patients with advanced solid tumors. Patients and methods Patients aged ≥18 years with histologically or cytologically diagnosed advanced solid tumors for whom no suitable effective therapy exists were included. Patients in four cohorts received topotecan (0.5 mg/m2/day × 3 days or 1.0 mg...
104 CitationsSource
#1Diwakar Davar (University of Pittsburgh)H-Index: 9
#2Jan H. Beumer (University of Pittsburgh)H-Index: 29
Last. Hussein TawbiH-Index: 23
view all 4 authors...
Deeper understanding of DNA repair mechanisms and their potential value as therapeutic targets in oncology heralded the clinical development of poly (ADP-ribose) polymerase (PARP) inhibitors. Although initially developed to exploit synthetic lethality in models of cancer associated with defective DNA repair, our burgeoning knowledge of PARP biology has resulted in these agents being exploited both in cancer with select chemotherapeutic agents and in non-malignant diseases. In this review article...
66 CitationsSource
Recently, the development of poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitors has brought a major breakthrough in the treatment of germline breast cancer susceptibility gene (BRCA)-mutant cancers.1-4 These agents target a DNA repair pathway via a novel mechanism of action. A better understanding of DNA damage repair mechanisms can extend the therapeutic application of this novel drug class to a wide range of sporadic cancers. Early clinical success has accelerated the develo...
21 CitationsSource
#1Jonathan A. Ledermann (UCL: University College London)H-Index: 48
#2Philipp Harter (University of Duisburg-Essen)H-Index: 37
Last. Ursula A. Matulonis (Harvard University)H-Index: 56
view all 15 authors...
randomization on completion of chemotherapy; hazard ratio for progression or death, 0.35; 95% confidence interval [CI], 0.25 to 0.49; P<0.001). Subgroup analyses of progression-free survival showed that, regardless of subgroup, patients in the olaparib group had a lower risk of progression. Adverse events more commonly reported in the olaparib group than in the placebo group (by more than 10% of patients) were nausea (68% vs. 35%), fatigue (49% vs. 38%), vomiting (32% vs. 14%), and anemia (17% v...
789 CitationsSource
#1Stephen B. KayeH-Index: 94
#2Jan LubinskiH-Index: 86
Last. Bella KaufmanH-Index: 48
view all 16 authors...
Purpose Olaparib (AZD2281), an orally active poly (ADP-ribose) polymerase inhibitor that induces synthetic lethality in BRCA1 -o rBRCA2-deficient cells, has shown promising clinical efficacy in nonrandomized phase II trials in patients with ovarian cancer with BRCA1 or BRCA2 deficiency. We assessed the comparative efficacy and safety of olaparib and pegylated liposomal doxorubicin (PLD) in this patient population. Patients and Methods In this multicenter, open-label, randomized, phase II study, ...
300 CitationsSource
#1Shivaani Kummar (NIH: National Institutes of Health)H-Index: 37
#2Alice Chen (NIH: National Institutes of Health)H-Index: 18
Last. James H. Doroshow (NIH: National Institutes of Health)H-Index: 72
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A phase I trial of ABT-888 (veliparib), a PARP inhibitor, in combination with topotecan, a topoisomerase I–targeted agent, was carried out to determine maximum tolerated dose (MTD), safety, pharmacokinetics, and pharmacodynamics of the combination in patients with refractory solid tumors and lymphomas. Varying schedules and doses of intravenous topotecan in combination with ABT-888 (10 mg) administered orally twice a day (BID) were evaluated. Plasma and urine pharmacokinetics were assessed and l...
173 CitationsSource
#1Andrew Tutt ('KCL': King's College London)H-Index: 53
#2Mark E. Robson (MSK: Memorial Sloan Kettering Cancer Center)H-Index: 64
Last. James Carmichael (AstraZeneca)H-Index: 32
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Summary Background Olaparib, a novel, orally active poly(ADP-ribose) polymerase (PARP) inhibitor, induced synthetic lethality in BRCA -deficient cells. A maximum tolerated dose and initial signal of efficacy in BRCA -deficient ovarian cancers have been reported. We therefore assessed the efficacy, safety, and tolerability of olaparib alone in women with BRCA1 or BRCA2 mutations and advanced breast cancer. Methods Women (aged ≥18 years) with confirmed BRCA1 or BRCA2 mutations and recurrent, advan...
1,577 CitationsSource
Cited By22
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#2Way Wua WongH-Index: 1
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Poly(ADP-ribose)polymerase (PARP) inhibitors (PARPi) have recently been approved for the treatment of breast and ovarian tumors with defects in homologous recombination repair (HRR). Although it has been demonstrated that PARPi also sensitize HRR competent tumors to cytotoxic chemotherapies or radiotherapy, normal cell toxicity has remained an obstacle to their use in this context. Hypoxia-activated prodrugs (HAPs) provide a means to limit exposure of normal cells to active drug, thus adding a l...
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#1Nicola MaureaH-Index: 3
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Recent advances in the field of cancer therapy have significantly improved the prognosis of oncologic patients; however, side effects associated with antineoplastic treatment remain the main cause of the high mortality of cancer survivors. The most serious adverse effect of anticancer therapy is cardiovascular toxicity, i.e. QT prolongation, arrhythmias, myocardial ischemia, stroke, hypertension, thromboembolism, left ventricular dysfunction, and heart failure, which can occur even in patients u...
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#1Anu PrakashH-Index: 1
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Advances in technology have facilitated the molecular profiling (genomic and transcriptomic) of tumours, and has led to improved stratification of patients and the individualisation of treatment regimes. To fully realize the potential of truly personalised treatment options, we need targeted therapies that precisely disrupt the compensatory pathways identified by profiling which allow tumours to survive or gain resistance to treatments. Here, we discuss recent advances in novel therapies that im...
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Purpose: Rucaparib is a potent, oral, small-molecule PARP inhibitor. This phase I–II study was the first to evaluate single-agent oral rucaparib at multiple doses. Experimental Design: Part 1 (phase I) sought to determine the MTD, recommended phase II dose (RP2D), and pharmacokinetics of oral rucaparib administered in 21-day continuous cycles in patients with advanced solid tumors. Part 2A (phase II) enrolled patients with platinum-sensitive, high-grade ovarian carcinoma (HGOC) associated with a...
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Purpose of Review Breast cancer treatment continues to evolve as targeted therapeutic strategies are developed for the various molecular subtypes of breast cancer. The PARP inhibitors represent a novel targeted therapy for tumors with defective homologous recombination DNA repair. These agents may become standard new treatment options for patients harboring BRCA1/2 mutations and show promise in BRCA1/2 wild-type patients with triple-negative breast cancers, which are treated predominantly with t...
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A phase I study of intravenous and oral rucaparib in combination with chemotherapy in patients with advanced solid tumours
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ABSTRACTIntroduction: PARP inhibitors have been extensively explored as antitumor agents and have shown potent efficacy both in vitro and in vivo. They can be used in monotherapy under the synthetic lethality concept or in combination with radiotherapy or chemotherapy, inducing a synergistic effect.Areas covered: This review covers relevant efforts in the development of PARP inhibitors with a particular focus on recently patented PARP inhibitors, combination therapy involving PARP inhibitors, tu...
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