Phase I Trial of Veliparib, a Poly ADP Ribose Polymerase Inhibitor, Plus Metronomic Cyclophosphamide in Metastatic HER2-negative Breast Cancer

Jesus D. Anampa Mesias, Alice Chen, John Wright, Margi Patel, Christine Pellegrino, Karen Fehn, Joseph A. Sparano, Eleni Andreopoulou

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Background: Poly-ADP-ribose-polymerase is an essential nuclear enzyme, involved in base-excision repair of damaged DNA. Poly-ADP-ribose-polymerase inhibition sensitizes tumor cells to cytotoxic agents, which induce DNA damage, including cyclophosphamide (C), and metronomic dosing of C may optimize potential for synergy. Methods: The primary objective of this phase I trial was to determine the safety and identify the recommended phase II dose of the combination of low-dose oral C (50, 75, 100, and 125 mg) once daily in combination with veliparib (V) (100, 200, and 300 mg) administered twice a day (BID) for 21-day cycles using a standard 3 + 3 design in patients with metastatic human epidermal growth factor receptor 2/neu-negative breast cancer. Dose-limiting toxicity was defined as any grade 3 non-hematologic toxicity or grade 4 thrombocytopenia/neutropenia occurring during cycle 1. Results: A total of 31 patients were enrolled; 19 were treated with 50 mg of C and 12 were treated at higher doses (75, 100, or 125 mg), with V doses ranging from 50 to 300 mg BID. The recommended phase II dose of the combination was V 200 mg orally BID plus C 125 mg orally daily, with nausea and headache dose-limiting at higher V dose levels. Objective response or stable disease for at least 24 weeks occurred in 3 (43%) of 7 patients with known deleterious germline BRCA mutations and 2 (11%) of 19 patients with negative/unknown mutation status (P = .1). Conclusion: The combination of oral continuous dosing of V (200 mg orally BID) with metronomic C (50, 75, 100, and 125 mg daily) is well-tolerated and shows antitumor activity in patients with BRCA-mutation-associated metastatic human epidermal growth factor receptor 2/neu-negative breast cancer.

Original languageEnglish (US)
JournalClinical Breast Cancer
DOIs
StateAccepted/In press - 2017

Fingerprint

Cyclophosphamide
Breast Neoplasms
Poly(ADP-ribose) Polymerases
Mutation
Germ-Line Mutation
Cytotoxins
Neutropenia
DNA Repair
Nausea
DNA Damage
Headache
veliparib
Poly(ADP-ribose) Polymerase Inhibitors
Safety
DNA
Enzymes
Neoplasms
human ERBB2 protein

Keywords

  • Breast cancer
  • Combination treatment
  • Cyclophosphamide
  • Metronomic
  • Veliparib

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Phase I Trial of Veliparib, a Poly ADP Ribose Polymerase Inhibitor, Plus Metronomic Cyclophosphamide in Metastatic HER2-negative Breast Cancer. / Anampa Mesias, Jesus D.; Chen, Alice; Wright, John; Patel, Margi; Pellegrino, Christine; Fehn, Karen; Sparano, Joseph A.; Andreopoulou, Eleni.

In: Clinical Breast Cancer, 2017.

Research output: Contribution to journalArticle

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title = "Phase I Trial of Veliparib, a Poly ADP Ribose Polymerase Inhibitor, Plus Metronomic Cyclophosphamide in Metastatic HER2-negative Breast Cancer",
abstract = "Background: Poly-ADP-ribose-polymerase is an essential nuclear enzyme, involved in base-excision repair of damaged DNA. Poly-ADP-ribose-polymerase inhibition sensitizes tumor cells to cytotoxic agents, which induce DNA damage, including cyclophosphamide (C), and metronomic dosing of C may optimize potential for synergy. Methods: The primary objective of this phase I trial was to determine the safety and identify the recommended phase II dose of the combination of low-dose oral C (50, 75, 100, and 125 mg) once daily in combination with veliparib (V) (100, 200, and 300 mg) administered twice a day (BID) for 21-day cycles using a standard 3 + 3 design in patients with metastatic human epidermal growth factor receptor 2/neu-negative breast cancer. Dose-limiting toxicity was defined as any grade 3 non-hematologic toxicity or grade 4 thrombocytopenia/neutropenia occurring during cycle 1. Results: A total of 31 patients were enrolled; 19 were treated with 50 mg of C and 12 were treated at higher doses (75, 100, or 125 mg), with V doses ranging from 50 to 300 mg BID. The recommended phase II dose of the combination was V 200 mg orally BID plus C 125 mg orally daily, with nausea and headache dose-limiting at higher V dose levels. Objective response or stable disease for at least 24 weeks occurred in 3 (43{\%}) of 7 patients with known deleterious germline BRCA mutations and 2 (11{\%}) of 19 patients with negative/unknown mutation status (P = .1). Conclusion: The combination of oral continuous dosing of V (200 mg orally BID) with metronomic C (50, 75, 100, and 125 mg daily) is well-tolerated and shows antitumor activity in patients with BRCA-mutation-associated metastatic human epidermal growth factor receptor 2/neu-negative breast cancer.",
keywords = "Breast cancer, Combination treatment, Cyclophosphamide, Metronomic, Veliparib",
author = "{Anampa Mesias}, {Jesus D.} and Alice Chen and John Wright and Margi Patel and Christine Pellegrino and Karen Fehn and Sparano, {Joseph A.} and Eleni Andreopoulou",
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journal = "Clinical Breast Cancer",
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T1 - Phase I Trial of Veliparib, a Poly ADP Ribose Polymerase Inhibitor, Plus Metronomic Cyclophosphamide in Metastatic HER2-negative Breast Cancer

AU - Anampa Mesias, Jesus D.

AU - Chen, Alice

AU - Wright, John

AU - Patel, Margi

AU - Pellegrino, Christine

AU - Fehn, Karen

AU - Sparano, Joseph A.

AU - Andreopoulou, Eleni

PY - 2017

Y1 - 2017

N2 - Background: Poly-ADP-ribose-polymerase is an essential nuclear enzyme, involved in base-excision repair of damaged DNA. Poly-ADP-ribose-polymerase inhibition sensitizes tumor cells to cytotoxic agents, which induce DNA damage, including cyclophosphamide (C), and metronomic dosing of C may optimize potential for synergy. Methods: The primary objective of this phase I trial was to determine the safety and identify the recommended phase II dose of the combination of low-dose oral C (50, 75, 100, and 125 mg) once daily in combination with veliparib (V) (100, 200, and 300 mg) administered twice a day (BID) for 21-day cycles using a standard 3 + 3 design in patients with metastatic human epidermal growth factor receptor 2/neu-negative breast cancer. Dose-limiting toxicity was defined as any grade 3 non-hematologic toxicity or grade 4 thrombocytopenia/neutropenia occurring during cycle 1. Results: A total of 31 patients were enrolled; 19 were treated with 50 mg of C and 12 were treated at higher doses (75, 100, or 125 mg), with V doses ranging from 50 to 300 mg BID. The recommended phase II dose of the combination was V 200 mg orally BID plus C 125 mg orally daily, with nausea and headache dose-limiting at higher V dose levels. Objective response or stable disease for at least 24 weeks occurred in 3 (43%) of 7 patients with known deleterious germline BRCA mutations and 2 (11%) of 19 patients with negative/unknown mutation status (P = .1). Conclusion: The combination of oral continuous dosing of V (200 mg orally BID) with metronomic C (50, 75, 100, and 125 mg daily) is well-tolerated and shows antitumor activity in patients with BRCA-mutation-associated metastatic human epidermal growth factor receptor 2/neu-negative breast cancer.

AB - Background: Poly-ADP-ribose-polymerase is an essential nuclear enzyme, involved in base-excision repair of damaged DNA. Poly-ADP-ribose-polymerase inhibition sensitizes tumor cells to cytotoxic agents, which induce DNA damage, including cyclophosphamide (C), and metronomic dosing of C may optimize potential for synergy. Methods: The primary objective of this phase I trial was to determine the safety and identify the recommended phase II dose of the combination of low-dose oral C (50, 75, 100, and 125 mg) once daily in combination with veliparib (V) (100, 200, and 300 mg) administered twice a day (BID) for 21-day cycles using a standard 3 + 3 design in patients with metastatic human epidermal growth factor receptor 2/neu-negative breast cancer. Dose-limiting toxicity was defined as any grade 3 non-hematologic toxicity or grade 4 thrombocytopenia/neutropenia occurring during cycle 1. Results: A total of 31 patients were enrolled; 19 were treated with 50 mg of C and 12 were treated at higher doses (75, 100, or 125 mg), with V doses ranging from 50 to 300 mg BID. The recommended phase II dose of the combination was V 200 mg orally BID plus C 125 mg orally daily, with nausea and headache dose-limiting at higher V dose levels. Objective response or stable disease for at least 24 weeks occurred in 3 (43%) of 7 patients with known deleterious germline BRCA mutations and 2 (11%) of 19 patients with negative/unknown mutation status (P = .1). Conclusion: The combination of oral continuous dosing of V (200 mg orally BID) with metronomic C (50, 75, 100, and 125 mg daily) is well-tolerated and shows antitumor activity in patients with BRCA-mutation-associated metastatic human epidermal growth factor receptor 2/neu-negative breast cancer.

KW - Breast cancer

KW - Combination treatment

KW - Cyclophosphamide

KW - Metronomic

KW - Veliparib

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