Abstract P4-16-08: Neoadjuvant depot hydroxy-progesterone and vitamin D3 in large operable and locally advanced breast cancer: Planned safety and response analysis of a phase III randomized controlled trial
Authors: Parmar V , Nair NS , Hawaldar R , Vanamali V , Gupta S , Shet T , Badwe RA 
Published: August 2014

Abstract
Background- The active metabolite of Vitamin D, 1,25-dihydroxycholecalciferol (Arachitol), and D3 analogs are known to be cytotoxic, anti-proliferative, pro-apoptotic[2] and potentiate responsiveness to cytotoxic agents such as doxorubicin.[3] Depot hydroxy-progesterone caproate (DHPC) has shown benefit in disease-free and overall survival when given as a single dose prior to definitive surgery in women with node positive operable breast cancer. [1] We undertook a factorial randomized controlled phase III study to evaluate the safety and efficacy of these interventions in the neoadjuvant setting in patients with operable and locally advanced breast cancer (NCT01608451).
Methods- The study was planned as a phase III, 2×2 factorial, randomized controlled trial with a sample size of 800. Women with high-risk (clinically T2N2, T3N1-3, all M0) operable or locally advanced breast cancer who were planned for neoadjuvant chemotherapy prior to surgery, were recruited in the study. Patients were randomized (2×2) to one of the following 4 arms: patients in Arm A received standard 4 cycles of anthracycline-based neoadjuvant chemotherapy followed by surgery, those in Arm B received 500 mg of DHPC 5-14 days prior to each cycle of chemotherapy and prior to surgery, those in Arm C received intramuscular injection of 300,000 IU Arachitol, and those in Arm D received a combination of both the experimental interventions at similar time points. The primary endpoint was disease-free survival and the secondary endpoints were overall survival, pathological complete response (pCR, defined as absence of invasive cancer in breast and axillary lymph nodes in the surgical specimen), and toxicity (defined by NCI Common Toxicity Criteria). We are reporting here a planned analysis of the secondary endpoints, after recruitment of 1/6th of total sample size, on toxicity and responses in the study arms.
Results- From September 2007 to December 2010, 120 patients were recruited in the study, 27 in Arm A, 33 in Arm B, 29 in Arm C and 31 in Arm D. The arms were balanced with respect to known prognostic variables including age, clinical tumor size, clinical nodal status and ER/PR and HER2 status. Of the 120 patients, 44(36.6%) were ER &/or PR positive with HER2 negative tumors, 27(22.3%) triple negative, 41(33.9%) ER &/or PR any with HER2 positive, and receptor status was unknown in 6.6%. The rates of all grades and grade III-IV febrile neutropenia, hepatic dysfunction, renal dysfunction and dyselectrolytemia were not different between the 4 arms. Surgery was performed in 114 of 120 patients(95.0%). The pCR rates in DHPC arm vs no DHPC was 5/51(9.8%) and 5/59(8.5%) respectively. The pCR rates in Arachitol versus no Arachitol arms were 5/55(9.0%) in both arms.
Conclusions- The addition of depot hydroxy-progesterone and vitamin D3 in neoadjuvant setting were found to be safe and well tolerated. Further details of toxicity, response and the ongoing study will be presented at the Symposium.
References:
1. Badwe RA et al. J Clin Oncol.2011 Jul 20;29(21):2845-51
2. James SY et al. J Steroid Biochem Mol Biol.1996 Jul;58(4):395-401
3. Chaudhary M et al. Cancer Chemother Pharmacol.2001;47(5):429-36.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-16-08.