Abstract P6-12-08: Phase I study of low dose oral cyclophosphamide (C) plus the poly-ADP-ribose- polymerase (PARP) inhibitor veliparib (V) in women with HER2/neu-negative inoperable locally advanced/metastatic breast cancer (MBC): NCI P8853
Authors: Anampa JD , Patel M , Pellegrino C , Fehn K , Makower D , Oh S-y , Noah K , Chen A , Sparano JA , Andreopoulou E 
Published: March 2017

Abstract
BACKGROUND: PARP, an essential nuclear enzyme, is involved in the recognition of DNA damage and facilitation of DNA base-excision repair (BER). PARP inhibition sensitizes tumor cells to cytotoxic agents which induce DNA damage, including C. Metronomic dosing of C may optimize potential for synergy with PARP inhibitors, and also inhibits angiogenesis (Kerbel et al, Nat Rev Cancer, 4:423-36, 2004) and may enhance anti-tumor immunity (Ghiringhelli et al. Cancer Immunol Immunother 56:641–648, 2007) V is an oral small molecule inhibitor of PARP which potentiates the antineoplastic activity of DNA damaging agents such as C in MX-1 breast xenograft model (Donawho et al Clin Cancer Res 13:2728-37, 2007). We performed a phase I trial of metronomic dose oral C plus V in patients with MBC.
METHODS: The primary objective was to determine the safety and identify the recommended phase II dose (RPTD) of the combination of low-dose oral C once daily in combination with V (100, 200, 300 mg) administered BID for 21 days using a standard 3+3 design. Eligibility included HER2/neu negative MBC, ECOG PS 0-1, and at least 1 prior chemotherapy regimen for MBC. Dose limiting toxicity (DLT) was defined as any Grade 3 non-hematological toxicity or Grade 4 thrombocytopenia/neutropenia occurring during cycle 1. After the RPTD of V was shown to be 200 mg BID with C 50 mg daily, the trial was amended to increase the C dose to 75, 100 and then 125 mg daily until hematologic toxicity was dose-limiting.
RESULTS: 31 patients were enrolled, 19 treated with 50 mg of C and 12 treated at higher doses (75-125 mg), with V doses ranging from 50 mg-300 mg BID (see table);5 patients with not evaluable due to rapid disease progression (N=2), non-compliance (N=2), or tumor pain that was not a DLT (N=1). Median age was 52 years (28-72 years), 14 (45 %) had triple negative disease, all had at least 1 prior chemotherapy regimen for metastasis (median 2, range 1-8), and, 7 had germline BRCA mutations, (3 BRCA1 and 4 BRCA2). When combined with 50 mg C daily, RPTD of V was 200 mg PO BID, with nausea being DLT at 300 mg BID. DLT was not observed in any of the 9 additional patients. The median number of cycles given was 3 (range 1-14). Clinical benefit (response or stable disease for at least 24 weeks) occurred in 3/7 (43%), 1/3 (33%) and 1/16(6%) for BRCA mutated, BRCA negative and BRCA unknown, respectively. Median progression-free survival was 4.3 months (1.2-10.9 months) for BRCA mutated patients and 2 months (0.7-10 months) for non-mutated.
CONCLUSIONS: The combination of oral continuous dosing of V (200 mg PO BID) with metronomic C (50, 75, 100 and 125 mg daily) is well tolerated and shows antitumor activity in patients with BRCA mutation associated MBC. The RPTD is C 125 mg daily plus V 200 mg BID, although further escalation of the C dose may be feasible since DLT was not seen at this dose level.
Dose LevelsDose Level# Patients/Evaluable# DLTType of DLTDL 1 :V 50mg , C 50mg3/30 DL 2 :V 100 mg, C 50mg4/30 DL 3 :V 200 mg, C 50mg6/61HeadacheDL 4 :V 300 mg, C 50mg6/52Nausea (N=2)DL 3A :V 200 mg; C 75mg3/30 DL 3B :V 200 mg, C 100mg6/30 DL 3C :V 200 mg, C 125mg3/30
Citation Format: Anampa JD, Patel M, Pellegrino C, Fehn K, Makower D, Oh S-y, Noah K, Chen A, Sparano JA, Andreopoulou E. Phase I study of low dose oral cyclophosphamide (C) plus the poly-ADP-ribose- polymerase (PARP) inhibitor veliparib (V) in women with HER2/neu-negative inoperable locally advanced/metastatic breast cancer (MBC): NCI P8853 [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-12-08.