Final results of a phase 1 evaluation of niraparib and everolimus in advanced ovarian and metastatic breast cancer (303)

Abstract

Objectives: To evaluate the safety and efficacy of the combination of niraparib and everolimus in a heavily pretreated PARP naïve population of advanced ovarian and metastatic breast cancer patients. Methods: An open-label, Phase I cohort study with a standard 3+3 design with four planned cohorts. All patients were PARP naïve. The planned schema was as follows: · Cohort 1 – Niraparib 100mg daily and everolimus 5mg MWF · Cohort 2 – Niraparib 200mg daily and everolimus 5mg MWF · Cohort 3 – Niraparib 200mg daily and everolimus 1mg daily · Cohort 4 – Niraparib 200mg daily and everolimus 5mg daily After two DLTs were experienced in cohort 2, four additional patients were enrolled at cohort 1 dose levels to confirm the safety of the combination at this dose and schedule. Results: Fourteen patients were enrolled in this study, and the safety evaluation has been completed. Three patients were not evaluable due to not completing the first cycle of treatment; two patients experienced DLTs, and one patient had rapid disease progression during the first week of cycle 1. Twelve patients had high-grade serous ovarian cancer, one patient had clear cell ovarian cancer, and one patient had breast cancer. Two dose-limiting toxicities (thrombocytopenia and hypertension) occurred in cohort 2. Of the 11 evaluable patients who received at least one complete cycle of treatment, the response rate was 18%, and the clinical benefit rate was 45%. One patient achieved a PR, and three patients had stable disease. The median progression-free survival for patients deriving clinical benefit was six months. There were 154 attributed adverse events; of these, 17 were grade 3 or grade 4 events (11%). The most common toxicities requiring intervention were thrombocytopenia (9.7%), hypertension (7.1%), nausea (4.6%), and stomatitis (3.9%). No new toxicities with this combination were evident. All patients had comprehensive molecular profiling prior to enrollment. Patient-reported outcomes were collected using the Treatment-Related Symptom Checklist (TRSC) and HRQOL-LASA and will be presented separately. Conclusions: The combination of niraparib and everolimus appears to provide some support for efficacy at the lowest doses. However, based on the DLTs experienced in cohort 2, the treatment proved to be too toxic to explore further at higher doses than niraparib 100mg daily and everolimus 5mg MWF. Objectives: To evaluate the safety and efficacy of the combination of niraparib and everolimus in a heavily pretreated PARP naïve population of advanced ovarian and metastatic breast cancer patients. Methods: An open-label, Phase I cohort study with a standard 3+3 design with four planned cohorts. All patients were PARP naïve. The planned schema was as follows: · Cohort 1 – Niraparib 100mg daily and everolimus 5mg MWF · Cohort 2 – Niraparib 200mg daily and everolimus 5mg MWF · Cohort 3 – Niraparib 200mg daily and everolimus 1mg daily · Cohort 4 – Niraparib 200mg daily and everolimus 5mg daily After two DLTs were experienced in cohort 2, four additional patients were enrolled at cohort 1 dose levels to confirm the safety of the combination at this dose and schedule. Results: Fourteen patients were enrolled in this study, and the safety evaluation has been completed. Three patients were not evaluable due to not completing the first cycle of treatment; two patients experienced DLTs, and one patient had rapid disease progression during the first week of cycle 1. Twelve patients had high-grade serous ovarian cancer, one patient had clear cell ovarian cancer, and one patient had breast cancer. Two dose-limiting toxicities (thrombocytopenia and hypertension) occurred in cohort 2. Of the 11 evaluable patients who received at least one complete cycle of treatment, the response rate was 18%, and the clinical benefit rate was 45%. One patient achieved a PR, and three patients had stable disease. The median progression-free survival for patients deriving clinical benefit was six months. There were 154 attributed adverse events; of these, 17 were grade 3 or grade 4 events (11%). The most common toxicities requiring intervention were thrombocytopenia (9.7%), hypertension (7.1%), nausea (4.6%), and stomatitis (3.9%). No new toxicities with this combination were evident. All patients had comprehensive molecular profiling prior to enrollment. Patient-reported outcomes were collected using the Treatment-Related Symptom Checklist (TRSC) and HRQOL-LASA and will be presented separately. Conclusions: The combination of niraparib and everolimus appears to provide some support for efficacy at the lowest doses. However, based on the DLTs experienced in cohort 2, the treatment proved to be too toxic to explore further at higher doses than niraparib 100mg daily and everolimus 5mg MWF.