Final results of a phase 1 study of single-agent veliparib (V) in patients (pts) with either 				BRCA1/2-mutated cancer (BRCA+), platinum-refractory ovarian, or basal-like breast cancer (BRCA-wt).

Puhalla, Shannon; Beumer, Jan H.; Pahuja, Shalu; Appleman, Leonard Joseph; Tawbi, Hussein Abdul-Hassan; Stoller, Ronald G.; Lee, James J.; Lin, Yan; Kiesel, Brian F.; Yu, Jing; Tan, Antoinette R.; Belani, Chandra P.; Chew, Helen K.; García, Agustin A.; Morgan, Robert J.; Giranda, Vincent L.; Shepherd, Stacie Peacock; Chen, Alice; Chu, Edward

doi:10.1200/jco.2014.32.15_suppl.2570

Cited by 62 publications

(53 citation statements)

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“…This finding suggested the MTD would also be the dose recommended for phase II studies. Although the 20 mg BID dose of veliparib is low relative to the single-agent MTD of veliparib at 400 mg BID [19], this dose is clearly associated with pharmacodynamic target engagement, as shown by our PAR data, and as previously reported in the phase 0 study of veliparib [20]. …”

Section: Discussionsupporting

confidence: 80%

Phase I study of veliparib in combination with gemcitabine

Stoller

Schmitz

Ding

et al. 2017

Cancer Chemother Pharmacol

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Background Veliparib (ABT-888) is an oral PARP inhibitor expected to increase gemcitabine activity. This phase I determined the maximal tolerable dose (MTD), dose-limiting toxicities (DLT), antitumor activity, pharmacokinetics (PK), and pharmacodynamics (PD) of veliparib combined with gemcitabine. Methods Patients with advanced solid tumors received veliparib (10–40 mg PO BID) on chemotherapy weeks with gemcitabine 500–750 mg/m2 IV on days 1, 8, and 15 (28-day cycle), or on days 1 and 8 (21-day cycle). The MTD, DLT, adverse events, PK, and PD were evaluated. Results Eleven patients were enrolled on the 28-day schedule. The 28-day schedule was considered intolerable and amended to a 21-day schedule, with 20 patients enrolled. Grade ≥3 adverse events were myelosuppression-related. The MTD was determined to be 750 mg/m2 gemcitabine IV on days 1 and 8 and 20 mg PO veliparib BID days 1–14 on a 21-day schedule. Of 27 patients evaluable for response, 3 had PR and 15 had SD. There was no evidence of any major drug-drug interaction, and PK parameter values for veliparib, gemcitabine, and dFdU were as expected. Analysis of PBMCs showed evidence of PARP inhibition and DNA damage associated with therapy. Conclusions Gemcitabine at 750 mg/m2 IV on days 1 and 8 combined with veliparib at a dose of 20 mg PO BID days 1–14 on a 21-day schedule is relatively well-tolerated, with manageable, expected toxicities. Clinical responses were observed in a pretreated population of patients, suggesting that this combination should be further evaluated in the phase II setting.

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Section: Discussionsupporting

confidence: 80%

Phase I study of veliparib in combination with gemcitabine

Stoller

Schmitz

Ding

et al. 2017

Cancer Chemother Pharmacol

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“…We obtained the peak plasma concentrations of each compound within 24 hours of drug administration from clinical trials. The average plasma concentrations described in the literature are: 9.9 µM for veliparib (37,38), 14 µM for olaparib and 25 nM for talazoparib (39,40). Therefore, the IC50 values for olaparib and talazoparib were mainly at physiologic concentrations, whereas the IC50 values for veliparib exceeded the maximum plasma concentrations for three of the eight cell lines.…”

Section: Resultsmentioning

confidence: 99%

Pathway-Enriched Gene Signature Associated with 53BP1 Response to PARP Inhibition in Triple-Negative Breast Cancer

Hassan

Esch

Liby

et al. 2017

Molecular Cancer Therapeutics

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Treatment of patients with triple negative (ER-negative, PR-negative, HER2-negative) breast cancer remains a challenge. Although PARP inhibitors are being evaluated in clinical trials, biomarkers are needed to identify patients that will most benefit from anti-PARP therapy. We determined the response of three PARP inhibitors: veliparib, olaparib, and talazoparib in a panel of eight triple-negative breast cancer cell lines. Therapeutic responses and cellular phenotypes were elucidated using high-content imaging and quantitative immunofluorescence to assess markers of DNA damage (53BP1) and apoptosis (cleaved-PARP). We determined the pharmacodynamic changes in percentage of cells positive for 53BP1, mean number of 53BP1 foci per cell, and percentage of cells positive for cleaved-PARP. Inspired by traditional dose-response measures of cell viability, an EC50 value was calculated for each cellular phenotype for each PARP inhibitor. The EC50 values for both 53BP1 metrics strongly correlated with IC50 values for each PARP inhibitor. Pathway enrichment analysis identified a set of DNA repair and cell cycle associated genes that were associated with 53BP1 response following PARP inhibition. The overall accuracy of our 63 gene set in predicting response to olaparib in seven breast cancer patient-derived xenograft tumors was 86%. In triple-negative breast cancer patients not treated with anti-PARP therapy, the predicted response rate of our gene signature was 45%. These results indicate that 53BP1 is a biomarker of response to anti-PARP therapy in the laboratory, and our DNA damage response gene signature may be used to identify patients who are most likely to respond to PARP inhibition.

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“…This is significant because there is evidence for a dose response relationship with veliparib, and single agent activity is observed beginning at 300 mg BID (13). In germline BRCA mutation-associated cancer, a recently completed phase I study evaluated 9 dose levels of veliparib monotherapy and demonstrated a 29% overall response rate (at all dose levels combined) and a higher response rate of 60% at the RP2D (47).…”

Section: Discussionmentioning

confidence: 99%

“…In germline BRCA mutation-associated cancer, a recently completed phase I study evaluated 9 dose levels of veliparib monotherapy and demonstrated a 29% overall response rate (at all dose levels combined) and a higher response rate of 60% at the RP2D (47). The finding of higher clinical response rates with higher doses of veliparib, despite achieving 90% PARP inhibition at lower doses by PAR assay (12, 13) suggests that combinations which allow for higher PARP inhibitor dosing may be preferred in order to achieve the best therapeutic response. In this study, conversion from partial to complete responses were observed on veliparib monotherapy (300 mg BID), providing evidence of the antineoplastic activity of single agent veliparib at a high dose, and suggesting that veliparib contributed to anti-neoplastic responses.…”

Section: Discussionmentioning

confidence: 99%

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Phase I Study of Veliparib (ABT-888) Combined with Cisplatin and Vinorelbine in Advanced Triple-Negative Breast Cancer and/orBRCAMutation–Associated Breast Cancer

Rodler

Kurland

Griffin

et al. 2016

Clinical Cancer Research

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PURPOSE Cisplatin is synergistic with vinorelbine and the poly(ADP-ribose) polymerase (PARP) inhibitor veliparib, and has anti-neoplastic activity in TNBC and BRCA mutation-associated breast cancer. This phase I study assessed veliparib with cisplatin and vinorelbine. PATIENTS AND METHODS A 3+3 dose escalation design evaluated veliparib administered BID for 14 days with cisplatin (75 mg/m2 day 1) and vinorelbine (25 mg/m2 days 1,8) every 21 days, for six to ten cycles, followed by veliparib monotherapy. Pharmacokinetics, measurement of poly(ADP-ribose) in peripheral blood mononuclear cells, and preliminary efficacy were assessed. Immunohistochemistry and gene expression profiling were evaluated as potential predictors of response. RESULTS Forty-five patients enrolled in nine dose cohorts plus five in an expansion cohort at the highest dose level and recommended phase II dose, 300 mg BID. Maximum tolerated dose of veliparib was not reached. Neutropenia (36%), anemia (30%), and thrombocytopenia (12%) were the most common grade 3/4 adverse events. Best overall response for 48 patients was radiologic response with 9-week confirmation for 17 (35%; 2 complete, 15 partial), and stable disease for 21 (44%). Germline BRCA mutation presence versus absence was associated with 6-month progression-free survival (10 of 14 (71%) vs 8 of 27 (30%), mid-p=0.01). Median progression-free survival for all 50 patients was 5.5 months (95% confidence interval 4.1–6.7). CONCLUSION Veliparib at 300 mg BID combined with cisplatin and vinorelbine is well tolerated with encouraging response rates. A phase II randomized trial is planned to assess veliparib’s contribution to cisplatin chemotherapy in metastatic TNBC and BRCA mutation-associated breast cancer. Translational Relevance We hypothesize that TNBC tumors have defects in homologous recombination DNA repair similar to BRCA mutation associated tumors, which will render them sensitive to platinum therapy and PARP inhibition. This report describes a phase I study that explored the safety and efficacy of cisplatin, vinorelbine and veliparib. This combination was tolerable and reached the highest dose of veliparib in combination with chemotherapy used in breast cancer to date. Antineoplastic activity was observed both in BRCA mutation associated breast cancer and in BRCA wild-type TNBC. We measured changes in PARP activity and performed gene expression profiling and immunohistochemistry studies. Based on promising results from this study, a randomized phase II study has been developed to evaluate the addition of veliparib to cisplatin chemotherapy for patients with advanced TNBC. This study will incorporate a multi-pronged biomarker approach to identify a homologous recombination repair deficiency (HRD) phenotype that derives benefit from PARP inhibition.

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Final results of a phase 1 study of single-agent veliparib (V) in patients (pts) with either BRCA1/2-mutated cancer (BRCA+), platinum-refractory ovarian, or basal-like breast cancer (BRCA-wt).

Cited by 62 publications

References 0 publications

Phase I study of veliparib in combination with gemcitabine

Phase I study of veliparib in combination with gemcitabine

Pathway-Enriched Gene Signature Associated with 53BP1 Response to PARP Inhibition in Triple-Negative Breast Cancer

Phase I Study of Veliparib (ABT-888) Combined with Cisplatin and Vinorelbine in Advanced Triple-Negative Breast Cancer and/orBRCAMutation–Associated Breast Cancer

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