Patient Reported Outcomes and Final Results of Phase 1 Evaluation of the Safety and Clinical Activity of Sapanisertib in Combination with Serabelisib and Paclitaxel in Patients with Advanced Ovarian, Endometrial, or Breast Cancer (044)

Abstract

<b>Objectives:</b> To evaluate the safety, efficacy, and patient-reported outcomes of the combination of paclitaxel, sapanisertib, and serabelisib. <b>Methods:</b> This is an open-label cohort study of sapanisertib (TAK-228) and serabelisib (TAK-117) given on days 2-4, 9-11, 16-18, and 23-25 with paclitaxel on days 1, 8, and 15 of a 28-day cycle. A traditional 3+3 dose escalation design with a maximum of five dosing cohorts was used. All five cohorts plus an expansion cohort were presented. Patient-reported outcomes utilizing the Therapy-Related Symptom Checklist (TRSC) and Health-Related Quality of Life – Linear Analogue Self-Assessment (HRQOL-LASA) were also evaluated. <b>Results:</b> Enrollment has been completed, and the overall results are summarized in Table 1. Nineteen patients have been enrolled, a majority of which were heavily pretreated, with the average number of prior regimens exceeding four. Overall, the combination of the three drugs was well-tolerated, except by patients in cohort 5. One dose-limiting toxicity occurred in the last patient enrolled. About 503 adverse events have been reported to date, but only 45 (9%) grade 3 or 4 events. Results of the TRSC and HRQOL show that patients generally tolerated the therapy well and maintained or improved their quality of life while on therapy in cohorts 1-4. As expected, patients with higher symptom scores had a corresponding diminished quality of life. Three patients had a complete response (CR), four had a partial response (PR), and four patients had stable disease (SD). The overall response rate is currently 47% in 15 evaluable patients. The clinical benefit rate is 73%, and the progression-free survival currently stands at approximately 11 months. All patients received comprehensive genomic profiling, and seven patients had received prior everolimus or temsirolimus. <b>Conclusions:</b> Overall, the combination of sapanisertib, serabelisib, and paclitaxel was safe and well-tolerated throughout the first four cohorts. Preliminary efficacy results appear very promising, especially for patients with PI3K/AKT/mTOR pathway mutations. The positive effects of the combination were routinely seen in the lowest dosing cohorts, and clinical benefit was even seen in patients who had previously failed everolimus or temsirolimus. There were few serious adverse events, and most side effects were managed with routine supportive care interventions. Data from the HRQOL and TRSC confirm that this combination was well tolerated and support further evaluation of this therapy.