Abstract OT3-04-01: A phase I of olaparib with radiation therapy in patients with inflammatory, loco-regionally advanced or metastatic TNBC (triple negative breast cancer) or patient with operated TNBC with residual disease
Authors: Kirova YM , Ezzalfani M , Rodrigues M , Pierga J-Y , Salomon A , Stern M-H , Laki F , Mosseri V , Berger F , Neffrati S , Armanet S , Fourquet A 
Published: February 2018

Abstract
Background and discussion: TNBC shares clinical and pathological features with hereditary BRCA1-related breast cancers, and in sporadic TNBC; dysregulation of BRCA1 has been frequently observed together with other defects in homologous recombination pathways. Preclinical studies have shown that breast cancer cell lines with a triple-negative phenotype are more sensitive to PARP1 inhibitors compared with non-TNBC cells. These lines of evidence provide a strong rationale for developing a new therapeutic approach to TNBC based on targeting the DNA-repair defects via PARP inhibition in these cancers that the most aggressive are the inflammatory, loco-regional advanced and metastatic breast cancer, as well as operated patients with residual disease (after primary systemic treatment-PST).
The aim of this study is to determine the Maximal Tolerated Dose of Olaparib administered with concurrent loco regional RT in the previously described population of patients.
Trial design: Olaparib (oral administration) will be administered at a starting dose of 50 mg bid. The other dose levels will be: 100 mg bid, 150 mg bid, 200 mg bid. The 25 mg bid dose will be included in the model to deal with unexpected high toxicity of the starting dose. Seven days prior to their first fraction of radiation therapy, patients will begin taking Olaparib at the assigned dose twice daily each day. All patients will receive radiotherapy on day 8 after the start of Olaparib of 50 Gy to the whole breast (or chest wall) with or withour lymph nodes (LN) in 25 daily fractions and 5 weeks.
Eligibility Criteria: Women aged &gt;18 years with histologically confirmed TNBC with loco-regional RT indication as :
Non-operated:
Inflammatory and/or advanced BC (T≥3 and/or N≥1) BC in progression during PST (containing anthracyclines or taxanes or the combination of both or containing platinium-based chemotherapy) or inoperable after PST.
Non operable metastatic BC (all T, all N, M1; with evaluable disease).
Or patients operated after PST and surgery with residual disease (non-pCR and pN+ disease, evaluable according to RECIST 1.1 criteria).
Specific aims
To assess the safety profile of Olaparib administered with concurrent RT.
This study should be completed by a methylation study of BRCA1 and RAD51 promoters.
Statistics Phase I dose-finding based on toxicity will be conducted in a sequential and adaptive Bayesian scheme, using the method of Time-to-event Continual Reassessment Method to determine the Maximum Tolerated Dose (MTD) of Olaparib associated with RT. The primary endpoint is Dose-Limiting Toxicity (DLT) occurring within 6 weeks after the end of RT (12 -13 weeks from the first drug intake, depending on the period of the radiotherapy treatment). Dose allocation will be centrally defined, based on DLT observed in all patients previously evaluated, by modeling the probability of DLT. An empiric model will be used for the dose-toxicity relationship. No intra-patient dose-escalation is permitted. No dose skipping in escalation is permitted. The MTD is defined as the dose associated with 25% of DLT.
Target accrual: Twenty-four to 30 pts are expected to be enrolled.
Contact: youlia.kirova@curie.fr
Citation Format: Kirova YM, Ezzalfani M, Rodrigues M, Pierga J-Y, Salomon A, Stern M-H, Laki F, Mosseri V, Berger F, Neffrati S, Armanet S, Fourquet A. A phase I of olaparib with radiation therapy in patients with inflammatory, loco-regionally advanced or metastatic TNBC (triple negative breast cancer) or patient with operated TNBC with residual disease [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT3-04-01.