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Ref Type Abstract
Authors 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 and Vivek Subbiah
Title 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 Text 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.


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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
PTEN loss prostate cancer predicted - sensitive Carboplatin + Paclitaxel + Sapanisertib Case Reports/Case Series Actionable In a Phase I trial, combination treatment with Paraplatin (carboplatin), Taxol (paclitaxel), and Sapanisertib (MLN0128) led to a partial response in a castrate resistant prostate cancer harboring PTEN loss (Cancer Res 2021;81(13_Suppl):Abstract nr CT109; NCT03430882). detail...