Sapanisertib

Shows activity

Also known as:

TAK-228 MLN0128 INK128 CB-228

Cancer types include:

breast cancer liver cancer ovarian cancer uterine cancer

TrialFetch AI Analysis

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Overview

Sapanisertib (also known as TAK‑228, MLN0128, INK128, CB‑228) is an orally available, ATP‑competitive inhibitor of the mTOR kinase that targets both mTOR complex 1 (mTORC1) and complex 2 (mTORC2). It has been evaluated mainly in phase I–II trials across multiple cancers, often after prior therapy including rapalogs. (pubmed.ncbi.nlm.nih.gov)

Mechanism of action

Sapanisertib inhibits mTOR’s kinase activity, leading to suppression of downstream signaling (e.g., p-S6K, p‑4EBP1 and AKT Ser473), thereby more completely blocking the PI3K–AKT–mTOR pathway than allosteric mTORC1 inhibitors. Preclinical studies with INK128 (sapanisertib) demonstrate on‑target pathway inhibition and antitumor effects across models. (pubmed.ncbi.nlm.nih.gov)

Efficacy

Endometrial cancer (randomized phase II): Paclitaxel plus sapanisertib did not significantly improve median PFS versus paclitaxel alone in advanced/recurrent disease (5.6 vs 3.7 months; HR 0.82; p=0.139). In the endometrioid subset, PFS was 5.7 vs 3.3 months (HR 0.66). The sapanisertib-only and sapanisertib+PI3K inhibitor arms were closed for futility. (pubmed.ncbi.nlm.nih.gov)
Metastatic renal cell carcinoma (single‑arm phase II, heavily pretreated): Objective response rate (ORR) 5.3% (2/38); median PFS 2.5 months. Genomic alterations in MTOR/TSC/PTEN did not correlate with benefit. (ascopubs.org)
Pancreatic neuroendocrine tumors (phase II, rapalog‑resistant): No objective responses in stage 1; median PFS 5.2 months; study halted for futility per two‑stage design. (pubmed.ncbi.nlm.nih.gov)
TSC1/TSC2‑mutated metastatic urothelial carcinoma (phase II): Among 13 evaluable patients, no objective responses; trial terminated early for futility. (ascopubs.org)
HR‑positive/HER2‑negative metastatic breast cancer (phase Ib/II, with endocrine therapy after prior everolimus): Sapanisertib 4 mg QD plus exemestane or fulvestrant achieved clinical benefit rate at 16 weeks (CBR‑16) of 45% in “everolimus‑sensitive” and 23% in “everolimus‑resistant” cohorts; ORR 8% and 2%, respectively. (pubmed.ncbi.nlm.nih.gov)

Safety

Across studies, the most frequent adverse events include gastrointestinal toxicities (nausea, diarrhea, stomatitis), rash, fatigue/asthenia, and on‑pathway metabolic effects (notably hyperglycemia and hypertriglyceridemia). Dose‑limiting toxicities commonly involve hyperglycemia, rash, stomatitis, and fatigue. Maximum tolerated doses in early studies included 3–6 mg once daily (schedule‑dependent) or 30–40 mg once weekly; 4 mg once daily was the recommended dose in several combinations. (pubmed.ncbi.nlm.nih.gov)

Dosing/schedules explored

Multiple schedules have been investigated: - Continuous once‑daily dosing (e.g., 3–6 mg QD); intermittent QD 3 days‑on/4 days‑off or 5 days‑on/2 days‑off; and once‑weekly dosing (30–40 mg). Food reduces Cmax but not overall exposure. Combination dosing commonly used 4 mg QD. (pubmed.ncbi.nlm.nih.gov)

Interpretation

As a dual mTORC1/2 inhibitor, sapanisertib has shown biological activity and manageable but characteristic on‑target toxicities. Thus far, single‑agent efficacy signals in unselected, heavily pretreated solid tumors have been limited, and biomarker‑selected settings (e.g., TSC1/2‑mutant urothelial carcinoma) have not yet demonstrated clear benefit. Combination approaches (e.g., with endocrine therapy after prior everolimus) have shown modest activity in specific contexts, meriting further investigation. (ascopubs.org)

Active trials using Sapanisertib

Found 3 active trials using this drug:

Open-Label Umbrella Study to Evaluate Safety and Efficacy of Sapanisertib and Serabelisib (PIKTOR) in Various Combinations in Patients With HR+/HER2- Advanced or Metastatic Breast Cancer

Sponsor: Faeth Therapeutics (industry) Phase: 1/2 Start date: April 30, 2026

TrialFetch AI summary: Enrolling women with previously treated HR+/HER2− advanced/metastatic breast cancer, ECOG 0–1, with measurable/evaluable disease and no prior PI3K/AKT/mTOR inhibitor exposure. Treatment is fulvestrant plus oral PIKTOR, a dual PI3K/mTOR pathway blockade regimen combining serabelisib, a PI3K-alpha inhibitor, and sapanisertib, an mTORC1/2 kinase inhibitor, with dose escalation focused on safety and recommended dosing.

ClinicalTrials.gov ID: NCT07558733

A Phase I/II Trial of Sapanisertib in Combination With Cabozantinib in β-catenin-mutated Hepatocellular Carcinoma (SAPHIRE)

Sponsor: National Cancer Institute (NCI) (federal) Phase: 1/2 Start date: Feb. 6, 2025

TrialFetch AI summary: Adults with advanced/metastatic hepatocellular carcinoma, enriched for β‑catenin (CTNNB1)–mutated disease (Phase II requires CLIA-confirmed mutation, Child-Pugh A, ECOG 0–2, prior ICI), randomized to cabozantinib alone vs cabozantinib plus sapanisertib (TAK‑228), an oral ATP-competitive mTORC1/2 inhibitor. Allows controlled HBV/HCV and treated/stable brain mets; excludes prior cabozantinib and strong CYP3A4 inhibitors.

ClinicalTrials.gov ID: NCT06811116

An Open-label, Multi-Center, Phase 2 Clinical Trial Evaluating Sapanisertib and Serabelisib (PIKTOR) With Paclitaxel, and a Substudy Evaluating PIKTOR With Paclitaxel Plus an Insulin-Suppressing Diet, in Patients With Advanced or Recurrent Endometrial Cancer

Sponsor: Faeth Therapeutics (industry) Phase: 2 Start date: Dec. 12, 2024

TrialFetch AI summary: Adults with advanced or recurrent endometrioid endometrial carcinoma harboring a PI3K/AKT/mTOR pathway alteration, post 1–4 prior regimens including platinum and typically a checkpoint inhibitor, receive sapanisertib (mTORC1/2 inhibitor) plus serabelisib (PI3Kα inhibitor) combined with paclitaxel; a substudy adds an insulin‑suppressing diet. Key exclusions include uncontrolled CNS disease, significant cardiac issues, CYP3A modulator use, gastric pH–raising meds, QTc >480 ms, and poorly controlled diabetes or insulin use.

ClinicalTrials.gov ID: NCT06463028