A randomized Phase II study of veliparib with temozolomide or carboplatin/paclitaxel versus placebo with carboplatin/paclitaxel in BRCA1/2 metastatic breast cancer: design and rationale

Steven J Isakoff, Shannon Puhalla, Susan M Domchek, Michael Friedlander, Bella Kaufman, Mark Robson, Melinda L Telli, Véronique Diéras, Hyo Sook Han, Judy E Garber, Eric F Johnson, David Maag, Qin Qin, Vincent L Giranda, Stacie P Shepherd, Steven J Isakoff, Shannon Puhalla, Susan M Domchek, Michael Friedlander, Bella Kaufman, Mark Robson, Melinda L Telli, Véronique Diéras, Hyo Sook Han, Judy E Garber, Eric F Johnson, David Maag, Qin Qin, Vincent L Giranda, Stacie P Shepherd

Abstract

Veliparib is an orally administered poly(ADP-ribose) polymerase inhibitor that is being studied in Phase I-III clinical trials, including Phase III studies in non-small-cell lung cancer, ovarian cancer and breast cancer. Tumor cells with deleterious BRCA1 or BRCA2 mutations are deficient in homologous recombination DNA repair and are intrinsically sensitive to platinum therapy and poly(ADP-ribose) polymerase inhibitors. We describe herein the design and rationale of a Phase II trial investigating whether the addition of veliparib to temozolomide or carboplatin/paclitaxel provides clinical benefit over carboplatin/paclitaxel with placebo in patients with locally recurrent or metastatic breast cancer harboring a deleterious BRCA1 or BRCA2 germline mutation (Trial registration: EudraCT 2011-002913-12, NCT01506609).

Keywords: BRCA1; BRCA2; DNA damage; PARP; PARP inhibitor; PARP trapping; breast cancer; synthetic lethality; veliparib.

Conflict of interest statement

Financial & competing interests disclosure

SJ Isakoff: Consultant – AbbVie, Myriad; Research support – Genentech, Pharmamar, AbbVie. S Puhalla: Consultant – AbbVie, Celldex, Pfizer; Research funding to institution, AbbVie, Covance-Bayer, Lilly, Incyte, Novartis, Pfizer, Genentech, AstraZeneca, BioMarin, Puma. S Domchek: Consulting, EMD Serono, AbbVie; Research support (institution) – AbbVie, Clovis, AstraZeneca, Pharmamar. M Friedlander: Advisory boards and honoraria – AstraZeneca, Roche and Pfizer. B Kaufman: Nothing to report. M Robson: Consulting – AstraZeneca; Research support (institution) – AbbVie, BioMarin, Medivation, AstraZeneca, Myriad. M Telli: Research funding (institution) – AbbVie, BioMarin, Medivation, Pharmamar; Consultant – AstraZeneca. V Diéras: Honoraria – AB Roche Genentech, Novartis, Pfizer, AbbVie; Symposia – Roche Genentech, Novartis, Pfizer. HS Han: Research support (institution) – AbbVie, Corcept, Incyte, Karyopharm, Merrimack, Prescient, TapImmune. JE Garber: Consulting or Advisory Role – Biogen, GTx Pharmaceuticals (spouse), Helix, Novartis (spouse), Pfizer (spouse), Pfizer, Sequenom, SV Life Sciences (spouse); Research Funding – Myriad Genetics, Novartis (spouse), Pfizer (spouse), Ambry Genetics. E Johnson, D Maag, Q Qin, VL Giranda, SP Shepherd: AbbVie employees and stock owners. AbbVie Inc. provided financial support for this study and participated in the design, study conduct, analysis and interpretation of the data, as well as the writing, review and approval of this manuscript. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Medical writing support was provided by D Eickermann, PhD, TRM Oncology, Atlanta, GA, funded by AbbVie Inc.

Figures

Figure 1. . Model of poly(ADP-ribose) polymerase…
Figure 1.. Model of poly(ADP-ribose) polymerase role in DNA damage repair and effect of poly(ADP-ribose) polymerase inhibition – BRCA mutation synthetic lethality.
(A) On detection of a single-strand break, the recruitment and activation of poly(ADP-ribose) polymerase (PARP) leads to single-strand break repair via polymers of ADP-ribosylation of histones and chromatin-remodeling enzymes, autoPARylation of PARP and recruitment of PARP-dependent DNA repair proteins. Repaired DNA can subsequently undergo replication, resulting in the survival of the cell. (B) When PARP inhibitors are present, PARP-dependent repair systems are not activated due to catalytic inhibition and/or direct trapping. This results in replication fork stalling during DNA replication, and the stalled replication fork eventually collapse, creating DSBs. In cells where homologous recombination is not impaired (BRCA-wild-type), DSBs are repaired and replication may restart, resulting in cell survival. However, in BRCA-deficient cells where hazard ratio is impaired, DSB cannot be efficiently repaired and DSB accumulates, resulting in cell death. DSB: Double-strand break; HR: Homologous recombination; RF: Replication fork; SSB: Single-strand break. Adapted with permission from Livraghi et al. BMC Med. (2015) [12]. No changes were made.
Figure 2. . Study design scheme.
Figure 2.. Study design scheme.
*A follow-up visit does not need to be conducted if the final visit is ≥30 days after last dose of study drug. Follow-up for survival continues until death or 3 years. AUC: Area under the curve; b.i.d.: Twice daily; ECOG: Eastern Cooperative Oncology Group; ER: Estrogen receptor; PgR: Progesterone receptor; q.d.: Once daily; TMZ: Temozolomide.
Figure 3. . Temozolomide dosing modification following…
Figure 3.. Temozolomide dosing modification following cycle 1.
ANC: Absolute neutrophil count; CTCAE: Common Terminology Criteria for Adverse Event; Gr: Grade; TMZ: Temozolomide.

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