A phase I dose-escalation study of ABT-888 (veliparib) in combination with carboplatin in HER2-negative metastatic breast cancer (MBC).

Viswanathan, Sowmya; Wesolowski, Robert; Layman, Rachel M.; Alejandra, Garcimarero-Espino E.; Miller, Brandon; Chalmers, J. J.; Bejastani, S.; Zhao, Weiqiang; Pierluigu, G.; Cotrill, Jeffrey A.; Phelps, Mitch A.; Schaaf, Larry J.; Geyer, Susan; Hall, Nathan C.; Knopp, Michael V.; Shapiro, CL; Villalona‐Calero, Miguel A.; Chen, A.; Mr, Grever; Ramaswamy, B

doi:10.1200/jco.2011.29.15_suppl.tps106

Cited by 3 publications

(1 citation statement)

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“…Multiple other early phase studies are in active accrual and include ABT-888/TMZ combination in liver cancer (NCT01205828) and prostate cancer (NCT01085422); ABT-888/carboplatin combination in HER2-negative metastatic breast cancer [76]; ABT-888 plus 5-fluorouracil and oxaliplatin (modified FOLFOX-6) in patients with metastatic pancreatic cancer (57, NCT01489865); ABT-888/cisplatin/paclitaxel in advanced cervical cancer (NCT01281852); ABT-888/topotecan in advanced solid tumors (NCT01012817); ABT-888/gemcitabine in advanced solid tumors (NCT01154426); ABT-888/liposomal doxorubicin in advanced breast/ovarian (NCT01145430); ABT-888/bendamustine/ rituximab in advanced lymphoma and myeloma (NCT01326702); ABT-888/whole brain radiation in patients with CNS metastases (NCT00649207); ABT-888/gemcitabine/cisplatin (NCT01282333) in patients with advanced biliary, pancreatic, urothelial, or non-small cell lung cancer (NSCLC); and ABT-888/carboplatin /paclitaxel combination in multiple settings including phase I in advanced solid tumors (NCT01281150), phase II in unresectable NSCLC (NCT01386385) and phase I in patients with advanced solid tumors and liver and/or kidney dysfunction (NCT01366144).…”

Section: Discussionmentioning

confidence: 99%

Role of PARP Inhibitors in Cancer Biology and Therapy

Davar¹,

Beumer²,

Hamieh³

et al. 2012

CMC

114

100

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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, we briefly review the mechanisms of DNA repair and pre-clinical development of PARP inhibitors before discussing the clinical development of the various PARP inhibitors in depth.

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Section: Discussionmentioning

confidence: 99%

Role of PARP Inhibitors in Cancer Biology and Therapy

Davar¹,

Beumer²,

Hamieh³

et al. 2012

CMC

114

100

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Targeted radiosensitization with PARP1 inhibition: optimization of therapy and identification of biomarkers of response in breast cancer

Feng

Speers

Liu

et al. 2014

Breast Cancer Res Treat

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Sustained locoregional control of breast cancer is a significant issue for certain patients. Inhibition of PARP1 is a promising strategy for radiosensitization (RS). We sought to optimize therapy with PARP1 inhibition and radiation (RT) by establishing the most effective treatment schedule, degree of PARP1-mediated RS, and identify early biomarkers predictive of efficacy in breast cancer models. Using clonogenic survival assays, we assessed intrinsic radiosensitivity and RS induced by PARP1 inhibition in breast cancer cell lines. Potential biomarkers of response were evaluated using western blotting, flow cytometry, and immunofluorescence with validation in vivo using tumor xenograft experiments. Across a panel of BC and normal breast epithelial cell lines, the PARP1 inhibitor ABT-888 preferentially radiosensitizes breast cancer (vs. normal) cells with enhancement ratios (EnhR) up to 2.3 independent of intrinsic BC subtype or BRCA mutational status. Concurrent and adjuvant therapy resulted in the highest EnhR of all schedules tested. The degree of RS did not correlate with pretreatment markers of PARP1 activity, DNA damage/repair, or cell cycle distribution. Increases in PARP1 activity 24 h after RT were associated with sensitivity after combination treatment. Findings were confirmed in breast cancer xenograft models. Our study demonstrates that PARP1 inhibition improves the therapeutic index of RT independent of BC subtype or BRCA1 mutational status and that PARP1 activity may serve as a clinically relevant biomarker of response. These studies have led to a clinical trial (TBCRC024) incorporating intratreatment biomarker analyses of PARP1 inhibitors and RT in breast cancer patients.

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Phase I Safety, Pharmacokinetic, and Pharmacodynamic Study of the Poly(ADP-ribose) Polymerase (PARP) Inhibitor Veliparib (ABT-888) in Combination with Irinotecan in Patients with Advanced Solid Tumors

LoRusso

Burger

et al. 2016

Clinical Cancer Research

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Background Poly (ADP-ribose) polymerase (PARP) is essential for recognition and repair of DNA damage. In preclinical models, PARP inhibitors modulate topoisomerase I inhibitor-mediated DNA damage. This Phase I study determined the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), pharmacokinetics (PK) and pharmacodynamics (PD) of veliparib, an orally-bioavailable PARP 1/2 inhibitor, in combination with irinotecan. Methods Patients with advanced solid tumors were treated with 100 mg/m2 irinotecan on days 1 and 8 of a 21-day cycle. Twice-daily (BID) oral dosing of veliparib (10–50 mg) occurred days 3–14 (Cycle 1) and days −1–14 (subsequent cycles) followed by a 6-day rest. PK studies were conducted with both agents alone and in combination. Paired tumor biopsies were obtained after irinotecan alone and veliparib/irinotecan to evaluate PARP1/2 inhibition and explore DNA damage signals (nuclear γ-H2AX and pNBS1). Results Thirty-five patients were treated. DLTs included fatigue, diarrhea, febrile neutropenia, and neutropenia. The MTD was 100 mg/m2 irinotecan (days 1, 8) combined with veliparib 40 mg BID (days −1–14) on a 21-day cycle. Of 31 response-evaluable patients there were 6 (19%) partial responses. Veliparib exhibited linear PK, and there were no apparent PK interactions between veliparib and irinotecan. At all dose levels, veliparib reduced tumor poly(ADP-ribose) (PAR) content in the presence of irinotecan. Several samples showed increases in γ-H2AX and pNBS1 after veliparib/irinotecan compared to irinotecan alone. Conclusions Veliparib can be safely combined with irinotecan at doses that inhibit PARP catalytic activity. Preliminary antitumor activity justifies further evaluation of the combination.

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A phase I dose-escalation study of ABT-888 (veliparib) in combination with carboplatin in HER2-negative metastatic breast cancer (MBC).

Cited by 3 publications

References 0 publications

Role of PARP Inhibitors in Cancer Biology and Therapy

Role of PARP Inhibitors in Cancer Biology and Therapy

Targeted radiosensitization with PARP1 inhibition: optimization of therapy and identification of biomarkers of response in breast cancer

Phase I Safety, Pharmacokinetic, and Pharmacodynamic Study of the Poly(ADP-ribose) Polymerase (PARP) Inhibitor Veliparib (ABT-888) in Combination with Irinotecan in Patients with Advanced Solid Tumors

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