Phase I Study Of Mtorc1-2 Inhibitor Sapanisertib (Tak-228) In Combination With Carboplatin Plus Paclitaxelin Patients With Advanced Solid Malignancies And Mtor Pathway Alterations.

Abstract Introduction: Pre-clinical models show that the addition of the mTORC1/2 inhibitor sapanisertib (TAK-228) restores sensitivity to platinum chemotherapy and dramatically enhances paclitaxel-induced cancer cell killing. Carboplatin plus paclitaxel is an established therapy in a variety of cancers including non-small cell lung cancer, ovarian cancer and others. This phase 1 study (NCT03430882) assessed the safety and tolerability of sapanisertib in combination with carboplatin plus paclitaxel in patients with advanced solid malignancies enriched with mTOR pathway alterations. Methods: Eligible patients, enriched for mTOR pathway aberrant tumors by CLIA-certified next-generation sequencing, received increasing sapanisertib doses on day 2-4 of each week at 2mg (Dose level 1; 4 patients), 3mg (Dose level 2; 4 patients) and 4mg (Dose level 3; 4 patients) combined with carboplatin (AUC 5) intravenously every 3 weeks on day 1 of each cycle plus paclitaxel 40mg/m2 (Dose levels 1-3), 60mg/m2 (Dose level 4; 7 patients) on day 1, 8, and 15 of each cycle. Results: Among the patients enrolled, males were 8/19 (42%), median age was 59 (range: 33-74). Of the 12 patients treated with Dose levels 1-3, 11 patients were evaluable for dose-limiting toxicities (DLTs) and no DLTs were observed. Seven patients were treated in Dose level 4 and among the 6 patients that were evaluable for DLTs, 1 patient had a DLT. Genomic alterations included PI3K/PTEN in 11/19 (58%), NF1 in 2/19 (10.5%), NF2 in 2/19 (10.5%), TSC1 in 1/19 (5%), TSC2 in 1/19 (5%), and EWSR1-POU5F1 fusion in 1/19 (5%). Of 17 patients evaluable for response, disease control rate (CR+PR+SD) was 76.4 % including 2 patients who achieved partial response. Responders were a patient with sarcomatoid renal cell carcinoma harboring EWSR1-POU5F1 fusion, who remains on therapy for more than 18 months. In addition, a patient with castrate resistant prostate cancer who progressed on cabazitaxel but harbors PTEN loss and remained on therapy for 7.3 months. There were no unanticipated toxicities. Grade 3-4 treatment-related adverse events included anemia (4/19; 21%), neutropenia (4/19; 21%), thrombocytopenia (2/19; 10.5%), and transaminitis (1/19; 5%). Conclusion: Sapanisertib in combination with carboplatin plus paclitaxel demonstrated a manageable safety profile, with preliminary antitumor activity observed in patients with advanced malignancies harboring mTOR pathway alterations. Citation Format: Omar Alhalabi, Aung Naing, Roman Groisberg, Andrew Hahn, Shizhen Zhang, Samantha C. Berkey, Apostolia M. Tsimberidou, Jordi Rodon, Timothy A. Yap, Shubham Pant, Amishi Y. Shah, Amado Zurita-Saavedra, Nizar Tannir, Funda Meric-Bernstam, Vivek Subbiah. Phase I study of mTORC1-2 inhibitor sapanisertib (TAK-228) in combination with carboplatin plus paclitaxelin patients with advanced solid malignancies and mTOR pathway alterations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT109.