Jesus Anampa1, Alice Chen2, John Wright2, Margi Patel1, Christine Pellegrino1, Karen Fehn1, Joseph A Sparano1, Eleni Andreopoulou3. 1. Department of Medical Oncology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY. 2. Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD. 3. Department of Medical Oncology, Weill Cornell Medicine/New York Presbyterian Hospital, New York, NY. Electronic address: ela9082@med.cornell.edu.
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.
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 humanepidermal 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 humanepidermal growth factor receptor 2/neu-negative breast cancer.
Authors: Antoinette R Tan; Nancy Chan; Brian F Kiesel; Mark N Stein; Rebecca A Moss; Jyoti Malhotra; Joseph Aisner; Mansi Shah; Murugesan Gounder; Hongxia Lin; Michael P Kane; Yong Lin; Jiuping Ji; Alice Chen; Jan H Beumer; Janice M Mehnert Journal: Cancer Chemother Pharmacol Date: 2021-10-20 Impact factor: 3.333