Poly (ADP-ribose) polymerase-1 (PARP1) inhibitor BSI-201 in combination with temozolomide (TMZ) in malignant glioma.

Blakeley, J. O.; Ye, X.; Grossman, Stuart A.; Mikkelsen, T.; Rosenfeld, M. R.; Bradley, C. R.; Eichler, April F.; Nabors, Louis B.; Desideri, Serena; Supko, Jeffrey G.

doi:10.1200/jco.2010.28.15_suppl.2012

Cited by 9 publications

(5 citation statements)

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“…When the study opened, iniparib was dosed at 5.6 mg/kg IV days 1, 4, 8, 11 of each 21 day cycle. In April 2011, based on emerging data in primary brain tumors, the dose of iniparib was raised to 8 mg/kg on the same schedule [ 12 ]. Patients receiving 5.6 mg/kg dosing of iniparib at that time were given the choice to dose-escalate.…”

Section: Methodsmentioning

confidence: 99%

TBCRC 018: phase II study of iniparib in combination with irinotecan to treat progressive triple negative breast cancer brain metastases

Anders

Deal

Abramson

et al. 2014

Breast Cancer Res Treat

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Nearly half of patients with advanced triple negative breast cancer (TNBC) develop brain metastases (BM) and most will also have uncontrolled extracranial disease. This study evaluated the safety and efficacy of iniparib, a small molecule anti-cancer agent that alters reactive oxygen species tumor metabolism and penetrates the blood brain barrier, with the topoisomerase I inhibitor irinotecan in patients with TNBC-BM. Eligible patients had TNBC with new or progressive BM and received irinotecan and iniparib every 3 weeks. Time to progression (TTP) was the primary end point; secondary endpoints were response rate (RR), clinical benefit rate (CBR), overall survival (OS), toxicity, and health-related quality of life. Correlative endpoints included molecular subtyping and gene expression studies on pre-treatment archival tissues, and determination of germline BRCA1/2 status. Thirty-seven patients began treatment; 34 were evaluable for efficacy. Five of 24 patients were known to carry a BRCA germline mutation (4 BRCA1, 1 BRCA2). Median TTP was 2.14 months and median OS was 7.8 months. Intracranial RR was 12 %, while intracranial CBR was 27 %. Treatment was well-tolerated; the most common grade 3/4 adverse events were neutropenia and fatigue. Grade 3/4 diarrhea was rare (3 %). Intrinsic subtyping revealed 19 of 21 tumors (79 %) were basal-like, and intracranial response was associated with high expression of proliferation-related genes. This study suggests a modest benefit of irinotecan plus iniparib in progressive TNBC-BM. More importantly, this trial design is feasible and lays the foundation for additional studies for this treatment-refractory disease.Electronic supplementary materialThe online version of this article (doi:10.1007/s10549-014-3039-y) contains supplementary material, which is available to authorized users.

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Section: Methodsmentioning

confidence: 99%

TBCRC 018: phase II study of iniparib in combination with irinotecan to treat progressive triple negative breast cancer brain metastases

Anders

Deal

Abramson

et al. 2014

Breast Cancer Res Treat

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“…Olaparib (AZD2281 [previously KU‐0059436]; AstraZeneca) is a selective and potent PARP inhibitor with a half maximal inhibitory concentration (IC 50 ) in the nanomolar range for both PARP1 and PARP2 enzymes (Table 2). 6‐9, 36‐49 Although the phase 1 trial of olaparib initially enrolled patients with a range of advanced tumors, prospective enrichment of each dose escalation cohort with BRCA1 / 2 mutation carriers was carried out. After promising signals of antitumor activity, recruitment was then limited to patients with BRCA1 / 2 mutations during cohort expansion of this phase 1 trial.…”

Section: Evidence Supporting a Synthetic Lethal Strategy With Parp Inmentioning

confidence: 99%

“…Multiple other trials of single‐agent PARP inhibitors in patients with germline BRCA1 / 2 ‐mutated cancers and sporadic malignancies, as well as clinical studies involving combination regimens, are currently ongoing, including AG014699 (Pfizer), veliparib (Abbott Laboratories), and iniparib (BiPar Sciences Inc). Table 2 summarizes the patient characteristics, toxicities, and efficacy results from reported clinical trials of PARP inhibitors 6‐9, 36‐49. A critically important issue that requires continued vigilance remains the safety of chronic PARP inhibitor dosing, specifically with regard to the risk of drug‐induced DNA damage and secondary tumorigenesis.…”

Section: Evidence Supporting a Synthetic Lethal Strategy With Parp Inmentioning

confidence: 99%

Poly(ADP-Ribose) polymerase (PARP) inhibitors: Exploiting a synthetic lethal strategy in the clinic

Yap

Sandhu

Carden

et al. 2011

CA: A Cancer Journal for Clinicians

191

137

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Poly(ADP-ribose) polymerase (PARP) is an attractive antitumor target because of its vital role in DNA repair. The homologous recombination (HR) DNA repair pathway is critical for the repair of DNA double-strand breaks and HR deficiency leads to a dependency on error-prone DNA repair mechanisms, with consequent genomic instability and oncogenesis. Tumor-specific HR defects may be exploited through a synthetic lethal approach for the application of anticancer therapeutics, including PARP inhibitors. This theory proposes that targeting genetically defective tumor cells with a specific molecular therapy that inhibits its synthetic lethal gene partner should result in selective tumor cell killing. The demonstration of single-agent antitumor activity and the wide therapeutic index of PARP inhibitors in BRCA1 and BRCA2 mutation carriers with advanced cancers provide strong evidence for the clinical application of this approach. Emerging data also indicate that PARP inhibitors may be effective in sporadic cancers bearing HR defects, supporting a substantially wider role for PARP inhibitors. Drugs targeting this enzyme are now in pivotal clinical trials in patients with sporadic cancers. In this article, the evidence supporting this antitumor synthetic lethal strategy with PARP inhibitors is reviewed, evolving resistance mechanisms and potential molecular predictive biomarker assays are discussed, and the future development of these agents is envisioned. CA Cancer J Clin 2011;61:31-49.

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“…It must be borne in mind that iniparib may act via a different mechanism to the PARP inhibitors discussed above, and does not appear to have the limitation of enhanced toxicity in normal tissue [39,41,42]. …”

Section: Parp Inhibitors In Triple-negative Breast Cancermentioning

confidence: 99%

“…Following encouraging results with iniparib in combination with chemotherapy with various solid tumours [ 39 ], clinical investigators have gone on to study this agent with chemotherapy in TNBC, a disease with a biological phenotype similar to BRCA1 -defective cancers [ 40 ]. It must be borne in mind that iniparib may act via a different mechanism to the PARP inhibitors discussed above, and does not appear to have the limitation of enhanced toxicity in normal tissue [ 39 , 41 , 42 ].…”

Section: Parp Inhibitors In Triple-negative Breast Cancermentioning

confidence: 99%

Poly(ADP-ribose) polymerase inhibition: a new direction for BRCAand triple-negative breast cancer?

Plummer

2011

Breast Cancer Res

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Inhibitors of poly(ADP-ribose) polymerase (PARP)-mediated DNA repair have shown promise in early clinical studies in the treatment of specific subgroups of breast cancer. Notably, phase II trials indicate that olaparib, an oral PARP inhibitor, has activity as a single agent in BRCA-related tumours, and that a combination of iniparib, an intravenous PARP inhibitor, and chemotherapy offers a survival advantage, compared with chemotherapy alone, in triple-negative breast cancer. Phase III data on the latter indication are expected in 2011. Intriguingly, iniparib does not increase toxicity when used as a chemo-potentiating agent, suggesting that it differs in its mechanism of action from other agents in this class. Overall, PARP inhibitors represent a potentially important new class of anti-cancer agents with two potential modes of action, as single agents causing synthetic lethality and as chemo-potentiating agents.

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Poly (ADP-ribose) polymerase-1 (PARP1) inhibitor BSI-201 in combination with temozolomide (TMZ) in malignant glioma.

Cited by 9 publications

References 0 publications

TBCRC 018: phase II study of iniparib in combination with irinotecan to treat progressive triple negative breast cancer brain metastases

TBCRC 018: phase II study of iniparib in combination with irinotecan to treat progressive triple negative breast cancer brain metastases

Poly(ADP-Ribose) polymerase (PARP) inhibitors: Exploiting a synthetic lethal strategy in the clinic

Poly(ADP-ribose) polymerase inhibition: a new direction for BRCAand triple-negative breast cancer?

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