Efficacy of the PARP inhibitor veliparib with carboplatin or as a single agent in patients with germline BRCA1- or BRCA2-associated metastatic breast cancer

California Cancer Consortium trial NCT01149083

George Somlo, Paul H. Frankel, Banu K. Arun, Cynthia X. Ma, Agustin A. Garcia, Tessa Cigler, Leah V. Cream, Harold A. Harvey, Joseph A. Sparano, Rita Nanda, Helen K. Chew, Timothy J. Moynihan, Linda T. Vahdat, Matthew Philip Goetz, Jan H. Beumer, Arti Hurria, Joanne Mortimer, Richard Piekarz, Sharon Sand, Josef Herzog & 7 others Lily R. Van Tongeren, Katherine V. Ferry-Galow, Alice P. Chen, Christopher Ruel, Edward M. Newman, David R. Gandara, Jeffrey N. Weitzel

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

Purpose: We aimed to establish the MTD of the poly (ADP-ribose) (PAR) polymerase inhibitor, veliparib, in combination with carboplatin in germline BRCA1- and BRCA2- (BRCA)-associated metastatic breast cancer (MBC), to assess the efficacy of single-agent veliparib, and of the combination treatment after progression, and to correlate PAR levels with clinical outcome. Experimental Design: Phase I patients received carboplatin (AUC of 5–6, every 21 days), with escalating doses (50-20 mg) of oral twice-daily (BID) veliparib. In a companion phase II trial, patients received single-agent veliparib (400 mg BID), and upon progression, received the combination at MTD. Peripheral blood mononuclear cell PAR and serum veliparib levels were assessed and correlated with outcome. Results: Twenty-seven phase I trial patients were evaluable. Dose-limiting toxicities were nausea, dehydration, and thrombocytopenia [MTD: veliparib 150 mg po BID and carboplatin (AUC of 5)]. Response rate (RR) was 56%; 3 patients remain in complete response (CR) beyond 3 years. Progression-free survival (PFS) and overall survival (OS) were 8.7 and 18.8 months. The PFS and OS were 5.2 and 14.5 months in the 44 patients in the phase II trial, with a 14% RR in BRCA1 (n = 22) and 36% in BRCA2 (n = 22). One of 30 patients responded to the combination therapy after progression on veliparib. Higher baseline PAR was associated with clinical benefit. Conclusions: Safety and efficacy are encouraging with veliparib alone and in combination with carboplatin in BRCA-associated MBC. Lasting CRs were observed when the combination was administered first in the phase I trial. Further investigation of PAR level association with clinical outcomes is warranted.

Original languageEnglish (US)
Pages (from-to)4066-4076
Number of pages11
JournalClinical Cancer Research
Volume23
Issue number15
DOIs
StatePublished - Aug 1 2017

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Carboplatin
Proxy
Breast Neoplasms
Neoplasms
Disease-Free Survival
Area Under Curve
Survival
veliparib
Poly(ADP-ribose) Polymerase Inhibitors
Dehydration
Thrombocytopenia
Nausea
Blood Cells
Research Design
Safety
Therapeutics
Serum

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Efficacy of the PARP inhibitor veliparib with carboplatin or as a single agent in patients with germline BRCA1- or BRCA2-associated metastatic breast cancer : California Cancer Consortium trial NCT01149083. / Somlo, George; Frankel, Paul H.; Arun, Banu K.; Ma, Cynthia X.; Garcia, Agustin A.; Cigler, Tessa; Cream, Leah V.; Harvey, Harold A.; Sparano, Joseph A.; Nanda, Rita; Chew, Helen K.; Moynihan, Timothy J.; Vahdat, Linda T.; Goetz, Matthew Philip; Beumer, Jan H.; Hurria, Arti; Mortimer, Joanne; Piekarz, Richard; Sand, Sharon; Herzog, Josef; Van Tongeren, Lily R.; Ferry-Galow, Katherine V.; Chen, Alice P.; Ruel, Christopher; Newman, Edward M.; Gandara, David R.; Weitzel, Jeffrey N.

In: Clinical Cancer Research, Vol. 23, No. 15, 01.08.2017, p. 4066-4076.

Research output: Contribution to journalArticle

Somlo, G, Frankel, PH, Arun, BK, Ma, CX, Garcia, AA, Cigler, T, Cream, LV, Harvey, HA, Sparano, JA, Nanda, R, Chew, HK, Moynihan, TJ, Vahdat, LT, Goetz, MP, Beumer, JH, Hurria, A, Mortimer, J, Piekarz, R, Sand, S, Herzog, J, Van Tongeren, LR, Ferry-Galow, KV, Chen, AP, Ruel, C, Newman, EM, Gandara, DR & Weitzel, JN 2017, 'Efficacy of the PARP inhibitor veliparib with carboplatin or as a single agent in patients with germline BRCA1- or BRCA2-associated metastatic breast cancer: California Cancer Consortium trial NCT01149083', Clinical Cancer Research, vol. 23, no. 15, pp. 4066-4076. https://doi.org/10.1158/1078-0432.CCR-16-2714
Somlo, George ; Frankel, Paul H. ; Arun, Banu K. ; Ma, Cynthia X. ; Garcia, Agustin A. ; Cigler, Tessa ; Cream, Leah V. ; Harvey, Harold A. ; Sparano, Joseph A. ; Nanda, Rita ; Chew, Helen K. ; Moynihan, Timothy J. ; Vahdat, Linda T. ; Goetz, Matthew Philip ; Beumer, Jan H. ; Hurria, Arti ; Mortimer, Joanne ; Piekarz, Richard ; Sand, Sharon ; Herzog, Josef ; Van Tongeren, Lily R. ; Ferry-Galow, Katherine V. ; Chen, Alice P. ; Ruel, Christopher ; Newman, Edward M. ; Gandara, David R. ; Weitzel, Jeffrey N. / Efficacy of the PARP inhibitor veliparib with carboplatin or as a single agent in patients with germline BRCA1- or BRCA2-associated metastatic breast cancer : California Cancer Consortium trial NCT01149083. In: Clinical Cancer Research. 2017 ; Vol. 23, No. 15. pp. 4066-4076.
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abstract = "Purpose: We aimed to establish the MTD of the poly (ADP-ribose) (PAR) polymerase inhibitor, veliparib, in combination with carboplatin in germline BRCA1- and BRCA2- (BRCA)-associated metastatic breast cancer (MBC), to assess the efficacy of single-agent veliparib, and of the combination treatment after progression, and to correlate PAR levels with clinical outcome. Experimental Design: Phase I patients received carboplatin (AUC of 5–6, every 21 days), with escalating doses (50-20 mg) of oral twice-daily (BID) veliparib. In a companion phase II trial, patients received single-agent veliparib (400 mg BID), and upon progression, received the combination at MTD. Peripheral blood mononuclear cell PAR and serum veliparib levels were assessed and correlated with outcome. Results: Twenty-seven phase I trial patients were evaluable. Dose-limiting toxicities were nausea, dehydration, and thrombocytopenia [MTD: veliparib 150 mg po BID and carboplatin (AUC of 5)]. Response rate (RR) was 56{\%}; 3 patients remain in complete response (CR) beyond 3 years. Progression-free survival (PFS) and overall survival (OS) were 8.7 and 18.8 months. The PFS and OS were 5.2 and 14.5 months in the 44 patients in the phase II trial, with a 14{\%} RR in BRCA1 (n = 22) and 36{\%} in BRCA2 (n = 22). One of 30 patients responded to the combination therapy after progression on veliparib. Higher baseline PAR was associated with clinical benefit. Conclusions: Safety and efficacy are encouraging with veliparib alone and in combination with carboplatin in BRCA-associated MBC. Lasting CRs were observed when the combination was administered first in the phase I trial. Further investigation of PAR level association with clinical outcomes is warranted.",
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TY - JOUR

T1 - Efficacy of the PARP inhibitor veliparib with carboplatin or as a single agent in patients with germline BRCA1- or BRCA2-associated metastatic breast cancer

T2 - California Cancer Consortium trial NCT01149083

AU - Somlo, George

AU - Frankel, Paul H.

AU - Arun, Banu K.

AU - Ma, Cynthia X.

AU - Garcia, Agustin A.

AU - Cigler, Tessa

AU - Cream, Leah V.

AU - Harvey, Harold A.

AU - Sparano, Joseph A.

AU - Nanda, Rita

AU - Chew, Helen K.

AU - Moynihan, Timothy J.

AU - Vahdat, Linda T.

AU - Goetz, Matthew Philip

AU - Beumer, Jan H.

AU - Hurria, Arti

AU - Mortimer, Joanne

AU - Piekarz, Richard

AU - Sand, Sharon

AU - Herzog, Josef

AU - Van Tongeren, Lily R.

AU - Ferry-Galow, Katherine V.

AU - Chen, Alice P.

AU - Ruel, Christopher

AU - Newman, Edward M.

AU - Gandara, David R.

AU - Weitzel, Jeffrey N.

PY - 2017/8/1

Y1 - 2017/8/1

N2 - Purpose: We aimed to establish the MTD of the poly (ADP-ribose) (PAR) polymerase inhibitor, veliparib, in combination with carboplatin in germline BRCA1- and BRCA2- (BRCA)-associated metastatic breast cancer (MBC), to assess the efficacy of single-agent veliparib, and of the combination treatment after progression, and to correlate PAR levels with clinical outcome. Experimental Design: Phase I patients received carboplatin (AUC of 5–6, every 21 days), with escalating doses (50-20 mg) of oral twice-daily (BID) veliparib. In a companion phase II trial, patients received single-agent veliparib (400 mg BID), and upon progression, received the combination at MTD. Peripheral blood mononuclear cell PAR and serum veliparib levels were assessed and correlated with outcome. Results: Twenty-seven phase I trial patients were evaluable. Dose-limiting toxicities were nausea, dehydration, and thrombocytopenia [MTD: veliparib 150 mg po BID and carboplatin (AUC of 5)]. Response rate (RR) was 56%; 3 patients remain in complete response (CR) beyond 3 years. Progression-free survival (PFS) and overall survival (OS) were 8.7 and 18.8 months. The PFS and OS were 5.2 and 14.5 months in the 44 patients in the phase II trial, with a 14% RR in BRCA1 (n = 22) and 36% in BRCA2 (n = 22). One of 30 patients responded to the combination therapy after progression on veliparib. Higher baseline PAR was associated with clinical benefit. Conclusions: Safety and efficacy are encouraging with veliparib alone and in combination with carboplatin in BRCA-associated MBC. Lasting CRs were observed when the combination was administered first in the phase I trial. Further investigation of PAR level association with clinical outcomes is warranted.

AB - Purpose: We aimed to establish the MTD of the poly (ADP-ribose) (PAR) polymerase inhibitor, veliparib, in combination with carboplatin in germline BRCA1- and BRCA2- (BRCA)-associated metastatic breast cancer (MBC), to assess the efficacy of single-agent veliparib, and of the combination treatment after progression, and to correlate PAR levels with clinical outcome. Experimental Design: Phase I patients received carboplatin (AUC of 5–6, every 21 days), with escalating doses (50-20 mg) of oral twice-daily (BID) veliparib. In a companion phase II trial, patients received single-agent veliparib (400 mg BID), and upon progression, received the combination at MTD. Peripheral blood mononuclear cell PAR and serum veliparib levels were assessed and correlated with outcome. Results: Twenty-seven phase I trial patients were evaluable. Dose-limiting toxicities were nausea, dehydration, and thrombocytopenia [MTD: veliparib 150 mg po BID and carboplatin (AUC of 5)]. Response rate (RR) was 56%; 3 patients remain in complete response (CR) beyond 3 years. Progression-free survival (PFS) and overall survival (OS) were 8.7 and 18.8 months. The PFS and OS were 5.2 and 14.5 months in the 44 patients in the phase II trial, with a 14% RR in BRCA1 (n = 22) and 36% in BRCA2 (n = 22). One of 30 patients responded to the combination therapy after progression on veliparib. Higher baseline PAR was associated with clinical benefit. Conclusions: Safety and efficacy are encouraging with veliparib alone and in combination with carboplatin in BRCA-associated MBC. Lasting CRs were observed when the combination was administered first in the phase I trial. Further investigation of PAR level association with clinical outcomes is warranted.

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U2 - 10.1158/1078-0432.CCR-16-2714

DO - 10.1158/1078-0432.CCR-16-2714

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EP - 4076

JO - Clinical Cancer Research

JF - Clinical Cancer Research

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