A phase II trial of iniparib (BSI-201) in combination with gemcitabine/carboplatin (GC) in patients with platinum-sensitive recurrent ovarian cancer.

Penson, R. T.; Whalen, Charles J.; Lasonde, Brian; Krasner, Carolyn; Konstantinopoulos, P.; Stallings, T. E.; Bradley, C. R.; Birrer, M. J.; Matulonis, U.

doi:10.1200/jco.2011.29.15_suppl.5004

Cited by 27 publications

(15 citation statements)

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“…Iniparib was originally described as a prodrug of a covalent PARP inhibitor (12, 37) and more recently as a small molecule cytotoxic with some PARP inhibitory activity (14). This agent originally displayed promising activity in combination with gemcitabine and cisplatin in phase 2 trials in triple negative breast cancer (14) and ovarian cancer (38, 39) as well as anecdotal activity against BRCA2-deficient pancreatic cancer (40). Interestingly, iniparib has not been previously compared head-to-head with other PARP inhibitors in preclinical studies.…”

Section: Discussionmentioning

confidence: 99%

Failure of Iniparib to Inhibit Poly(ADP-Ribose) Polymerase In Vitro

Patel

Lorenzo

Flatten

et al. 2012

Clinical Cancer Research

201

111

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Purpose Poly(ADP-ribose) polymerase (PARP) inhibitors are undergoing extensive clinical testing for their single-agent activity in homologous recombination- (HR-) deficient tumors and ability to enhance the action of certain DNA damaging agents. Compared to other PARP inhibitors in development, iniparib (4-iodo-3-nitrobenzamide) is notable for its simple structure and the reported ability of its intracellular metabolite 4-iodo-3-nitrosobenzamide to covalently inhibit PARP1 under cell-free conditions. The present preclinical studies were performed to compare the actions iniparib with the more extensively characterized PARP inhibitors olaparib and veliparib. Experimental design The abilities of iniparib, olaparib and veliparib to i) selectively induce apoptosis or inhibit colony formation in HR-deficient cell lines, ii) selectively sensitize HR-proficient cells to topoisomerase I poisons and iii) inhibit formation of poly(ADP-ribose) polymer in intact cells were compared. Results Consistent with earlier reports, olaparib and veliparib selectively induced apoptosis and inhibited colony formation in cells lacking BRCA2 or ATM. Moreover, like earlier-generation PARP inhibitors, olaparib and veliparib sensitized cells to the topoisomerase I poisons campto-thecin and topotecan. Finally, olaparib and veliparib inhibited formation of poly(ADP-ribose) polymer in intact cells. In contrast, iniparib exhibited little or no ability to selectively kill HR-deficient cells, sensitize cells to topoisomerase I poisons, or inhibit poly(ADP-ribose) polymer formation in situ. In further experiments, iniparib also failed to sensitize cells to cisplatin, gemcitabine or paclitaxel. Conclusions While iniparib kills normal and neoplastic cells at high (>40 µM) concentrations, its effects are unlikely to reflect PARP inhibition and should not be used to guide decisions about other PARP inhibitors.

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Section: Discussionmentioning

confidence: 99%

Failure of Iniparib to Inhibit Poly(ADP-Ribose) Polymerase In Vitro

Patel

Lorenzo

Flatten

et al. 2012

Clinical Cancer Research

201

111

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“…A phase II trial of iniparib (BSI-201, BiPar Sciences; South San Francisco, CA, USA) in combination with carboplatin and gemcitabine in platinum-sensitive ovarian cancer yielded improved RR over historical RRs for chemotherapy alone (70.6% vs. 47.2%) [99]. Iniparib has also been evaluated in combination with carboplatin and gemcitabine in patients with platinum-resistant ovarian cancer.…”

Section: Targeting Dna Repair With Poly-adp-ribose Polymerase (Parp) mentioning

confidence: 99%

Investigational agents in development for the treatment of ovarian cancer

Westin¹,

Herzog²,

Coleman³

2012

Invest New Drugs

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Although significant success has been achieved in the treatment of advanced and recurrent ovarian cancer, there is clearly room for improvement. The use of targeted agents in this patient population has the promise to provide improved survival and quality of life. There are a myriad of relevant pathways under exploration in all settings of ovarian cancer. Clinical trial data are accumulating for antiangiogenic therapy, including vascular endothelial growth factor (VEGF)-specific inhibitors and multiple angiogenic signaling target inhibitors, as well as poly-ADP-ribose polymerase (PARP) inhibitors. Other types of tumorigenic pathway inhibitors, including those that target phosphatidylinositol-3-kinase (PI3K), mammalian target of rapamycin (mTOR), protein kinase B (AKT), Src, folate receptor alpha, and insulin-like growth factor-1 receptor (IGF-1R) pathways are in earlier phases of development for ovarian cancer. Attempts to target the epidermal growth factor receptor (EGFR) of ovarian tumors have been met with limited success; however, newer agents that inhibit this pathway show promise. Finally, with recognition of the role of Wee-1 in p53-deficient tumors, an inhibitor of this tyrosine kinase is being evaluated in recurrent ovarian cancer. The logistical challenge is to determine the optimal timing and proper combinations of novel agents independently as well as concomitantly with conventional chemotherapeutics. Reported results have been modest; however, our growing understanding of these pathways will be potentially reflected in greater impact on response and survival.

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“…Le Massachusetts General Hospital a mené une étude de phase II chez 41 patientes rechutant plus de six mois après la fin de la chimiothérapie adjuvante [18]. La recherche d'une mutation BRCA1 ou BRCA2 était réalisée parmi 27 de ces patientes.…”

Section: Inhibiteur De Parp Et Cancer De L'ovaireunclassified

Gynaecological cancers

Petit¹

2011

Oncologie

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A phase II trial of iniparib (BSI-201) in combination with gemcitabine/carboplatin (GC) in patients with platinum-sensitive recurrent ovarian cancer.

Cited by 27 publications

References 0 publications

Failure of Iniparib to Inhibit Poly(ADP-Ribose) Polymerase In Vitro

Failure of Iniparib to Inhibit Poly(ADP-Ribose) Polymerase In Vitro

Investigational agents in development for the treatment of ovarian cancer

Gynaecological cancers

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