Reference Detail

Ref Type

Abstract

PMID

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

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer Resarch	81	13_Suppl	July 2021

URL

https://cancerres.aacrjournals.org/content/81/13_Supplement/CT109

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...