Abstract OT2-03-01: A phase one trial of olaparib with radiation therapy in patients with triple negative breast cancer: RADIOPARP
Authors: Kirova Youlia M. , Loirat Delphine , Berger Frederique , Rodrigues Manuel , Bazire Louis , Chilles Anne , Pierga Jean Yves , Ricci Francesco , Sablin Marie Paule , Salomon Anne Vincent , Laki Fatima , Bertrand Claire , Ezzili Cyrine , Raizoville Laurence , Mosseri Veronique , Neffati Souhir , Ezzalfani Monia , Fourquet Alain 
Published: March 2020

Abstract
Background Preclinical studies have shown that breast cancer (BC) cell lines with a triple-negative phenotype are more sensitive to PARP1 inhibitors compared with non-TNBC cells. All 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 TNBC. Research hypothesis for patients with inoperable TNBC, there is a lack of systemic therapy to combine with radiotherapy (RT) in order to control the loco-regional disease. For patients with TNBC operated with residual disease (after neoadjuvant chemotherapy), a new strategy with postoperative RT in combination with new drugs could improve loco regional outcome. Rational for the study is the radiosensitization by olaparib in TNBC. The aim of the proposed phase I study is to determine the Maximal Tolerated Dose (MTD) of olaparib monotherapy administered with concurrent loco regional radiotherapy in patients who have TNBC inoperable after neoadjuvant chemotherapy or with residual disease after surgery. Primary objective: To determine the Maximal Tolerated Dose (MTD) of olaparib administered with concurrent RT in patients with TNBC. Secondary objectives • To assess the safety profile of concurrent olaparib-RT; evaluate efficacy profile and patient outcome, explore biomarkers of concurrent olaparib-RT activity. Study Overview: olaparib (orally, tablets) is administered at a starting dose of 50 mg bid. The other dose levels are: 50mg-100 mg - 150 mg-200 mg bid. Seven days prior to their first fraction of RT, patients will start olaparib at the assigned dose twice daily each day. All patients will receive RT on day 8 after the start of olaparib as following: normofractionated radiotherapy to whole breast or chest wall with or without the lymph node areas (LN). Patients will be assigned to olaparib one week before RT and during breast radiation (5 to 6 weeks). Total treatment duration will be: 6 to 7 weeks. Eligibility Women aged &gt;18 years. With histologically confirmed TNBC with indication for pre or post-operative or exclusive RT; ECOG &lt;2; Life expectancy &gt; 6 months; Adequate hematologic, renal and hepatic function; Urine or serum negative pregnancy test; Ability to swallow and retain oral medications and affiliated to the French Social Security System. Sample size and Analysis: 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 radiotherapy. The primary endpoint is Dose-Limiting Toxicity (DLT) occurring within 4-6 weeks after the end of the radiotherapy (12 or 13 weeks from the first drug intake, depending on the period of RT length). 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. The MTD is defined as the dose associated with 25% of DLT. Four dose levels are considered as previously described. Cohort of size 3 is used with the TITE-CRM design. So, three patients will be included at the first dose level (50mg bid daily). At least three patients fully observed are required at a given dose level before dose escalation following the TITE-CRM method. Every new patient will be treated at the best current recommended dose proceed (50mg bid, 100mg bid, 150mg bid and 200mg bid daily), i.e. the dose associated with an estimated level of toxicity that is judged acceptable (25% DLT). Twenty-four to 30 patients are expected to be enrolled. Contact: youlia.kirova@curie.fr Acknowledgements: AstraZeneca for their support
Citation Format: Youlia M. Kirova, Delphine Loirat, Frederique Berger, Manuel Rodrigues, Louis Bazire, Anne Chilles, Jean Yves Pierga, Francesco Ricci, Marie Paule Sablin, Anne Vincent Salomon, Fatima Laki, Claire Bertrand, Cyrine Ezzili, Laurence Raizoville, Veronique Mosseri, Souhir Neffati, Monia Ezzalfani, Alain Fourquet. A phase one trial of olaparib with radiation therapy in patients with triple negative breast cancer: RADIOPARP [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT2-03-01.