Abstract OT2-03-02: A pilot trial of hyperthermia in combination with olaparib in breast cancer patients with chest wall recurrences
Authors: Bhattacharya Saveri , Schiewer Matthew , Murphy Rita C. , Anne Pramila Rani , Simone Nicole , Ad Voichita Bar , Khalaf Maysa Abu , Silver Daniel P. , Jaslow Rebecca , Fellin Frederick M. , Zibelli Allison M. , Lopez Ana Maria , Berger Adam , Tsangaris Theodore N. , Lazar Melissa A. , Willis Alliric I. , Stauffer Paul , Hurwitz Mark D. 
Published: March 2020

Abstract
Background: Chest wall recurrences represent a significant source of morbidity for breast cancer patients causing symptoms including bleeding, ulceration, infection and pain. Approximately 5 to 10% of breast cancer patients undergoing a mastectomy will have a chest wall or nodal recurrence within ten years after surgery. Loco-regional recurrence isolated to the chest wall occurs in 50 to 70% of these patients and only one third of these patients having synchronous metastases. After radiation, patients with unresectable isolated loco-regional breast cancer have very few treatment options. Hyperthermia, temperature elevation to 40° to 45°C for 60 minutes, is a potent radiotherapy and chemotherapy sensitizer without significant toxicity. Additionally, superficial hyperthermia can improve the complete response and local control in breast cancer patients with chest wall disease. Chest wall hyperthermia induces degradation of the BRCA2 protein, thereby leading to defective homologous recombination DNA repair, and sensitization to PARP-1 inhibitors. Krawczyk and colleagues (2017) showed that mild hyperthermia innately sensitizes homologous recombination proficient tumor cells to treatment with a PARP-1 inhibitor in pre-clinical models. Olaparib, is an oral targeted therapy that is an inhibitor of the poly ADP ribose polymerase (PARP) and is currently approved for treatment for patients with metastatic ovarian cancer and metastatic breast cancer with BRCA1 or BRCA2 mutation. Our hypothesis is that the combination of olaparib and chest wall hyperthermia will be a safe and tolerable combination for breast cancer patients with chest wall metastases. Trial Design: In this novel dose-escalation pilot trial, breast cancer patients with chest wall recurrences will be treated with olaparib at the appropriate dose level, concurrently with chest wall hyperthermia involving heating the skin to 43 ° Celsius for 1 hour. We plan to treat patients first with olaparib given twice a day in tablet form at the appropriate dose level for one week and then add hyperthermia twice a week for 3 weeks, for a total duration of 4 weeks of treatment. Eligibility criteria: Female breast cancer patients regardless of ER/PR/HER2 status who have chest wall recurrences greater than 2 cm are eligible for this study. Patients are eligible after any line of therapy and if they have wild-type germ-line BRCA1 or BRCA2 status. Specific Aims: We will evaluate the safety and determine the maximum tolerated dose of the combination of olaparib and chest wall hyperthermia. We will assess the local progression free survival, one-year progression free survival, overall response and quality of life scores for these patients. We plan to obtain skin biopsies to evaluate biomarkers of homologous recombination deficiency including BRCA1, BRCA2, RAD51 as well as γH2AX as an indicator of DNA damage. Statistical Methods: A 3+3 dose-escalation design will be used to determine the MTD of olaparib in combination with hyperthermia. We will initially enroll 3 subjects at each dose level. If one of the three experiences that level of toxicity, we will accrue 3 more subjects at that dose. If at any time there are two or more dose-limiting toxicities (in the 3-6 subjects) on a given dose, we will terminate accrual to the trial. No patient will be treated at a higher dose until the 3 or 6 patients have completed their 30 day toxicity evaluation period at the current dose. The survival endpoints of PFS and local PFS will be analyzed using log-rank test with Kaplan-Meier curves, as well as Cox proportional hazard models. Present Accrual and target accrual: Target accrual is 12 patients in the next two years. This study opened in May of 2019 at Thomas Jefferson University in Philadelphia, PA with full support from AstraZeneca. Clinical trial information: NCT03955640
Citation Format: Saveri Bhattacharya, Matthew Schiewer, Rita C. Murphy, Pramila Rani Anne, Nicole Simone, Voichita Bar Ad, Maysa Abu Khalaf, Daniel P. Silver, Rebecca Jaslow, Frederick M. Fellin, Allison M. Zibelli, Ana Maria Lopez, Adam Berger, Theodore N. Tsangaris, Melissa A. Lazar, Alliric I. Willis, Paul Stauffer, Mark D. Hurwitz. A pilot trial of hyperthermia in combination with olaparib in breast cancer patients with chest wall recurrences [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 OT2-03-02.