sapanisertib (CB-228)

P2, N=17, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Nov 2025 --> Nov 2026

P1, N=22, Active, not recruiting, National Cancer Institute (NCI) | N=85 --> 22 | Trial completion date: Jun 2026 --> Nov 2026 | Trial primary completion date: Jun 2026 --> Nov 2025

Pharmaco-transcriptomic analysis revealed that IL3RA-high AML exhibited selective sensitivity to venetoclax and sapanisertib, suggesting potential synergistic opportunities. In conclusion, IL3RA overexpression defines a clinically and biologically distinct subgroup of AML, with unique therapeutic vulnerabilities. Continued research efforts are warranted to integrate CD123-directed therapies into the upfront AML treatment paradigm.

P1, N=50, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Oct 2025 --> Oct 2026

Despite the advent of venetoclax-based regimens, resistance mechanisms remain a major clinical challenge, particularly in patients with high-risk mutations such as TP53, MUC4, HLA-B and FLT3. Here, we evaluate two rational combination therapies, LY3009120 (pan-RAF) plus sapanisertib (mTOR) (LS), and ruxolitinib (JAK1/2) plus ulixertinib (ERK) (RU), across ten AML cell lines and a zebrafish embryo xenograft model...Mutation response analyses and clustering highlighted TP53, MUC4, HLA-B and FLT3 as correlates of LS and RU sensitivity, supporting mutation-informed prioritization. Collectively, our results nominate LS and RU as promising candidates, particularly in AML with TP53, FLT3, HLA-B or MUC4 alterations, and motivate prospective validation in stratified AML cohorts.

Sapanisertib plus fulvestrant provided the greatest PFS benefit (HR 0.34, 95% CI 0.14-0.82) but had a high discontinuation rate (>15%). Among the approved therapies, ribociclib plus ET (HR 0.57, 95% CI 0.39-0.84), capivasertib plus fulvestrant (HR 0.62, 95% CI 0.51-0.75), and elacestrant (HR 0.70, 95% CI 0.55-0.89) demonstrated superior efficacy...Ipatasertib and alpelisib showed the greatest benefits in patients with PI3K/PTEN/AKT alterations. Antibody-drug conjugates (ADCs), such as trastuzumab deruxtecan and sacituzumab govitecan, outperformed standard chemotherapy, albeit with higher toxicity...Grant Assignment Decree No. 1369 adopted on 01.09.2023 by the Italian Ministry of University and Research (MUR).

P2, N=6452, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2025 --> Dec 2026 | Trial primary completion date: Dec 2025 --> Dec 2026

Vertical inhibition of the RAS/MEK/ERK pathway by targeting SHP2 or SOS1 and the downstream kinases MEK (trametinib) or ERK (temuterkib) was highly effective. Inhibition of upstream tyrosine receptor kinases with nintedanib in combination with batoprotafib or BI-3406 was also effective, and in combination with sotorasib, demonstrated synergy in spheroids harboring KRAS G12C. Dual inhibition of the RAS/MEK/ERK and PI3K/AKT/mTOR pathways by batoprotafib or sotorasib with either the mTORC1/2 inhibitor sapanisertib or the AKT inhibitor ipatasertib demonstrated combination activity, primarily in spheroids harboring KRAS G12C. The BCL-2 inhibitor venetoclax in combination with sotorasib, batoprotafib or BI-3406 resulted in additive and synergistic cytotoxicity. Lastly, concurrent inhibition of the KRAS pathway with sotorasib and batoprotafib demonstrated combination activity in spheroids containing KRAS G12C.

The combination of ipatasertib with the MEK inhibitor selumetinib or the ERK inhibitor ravoxertinib resulted in additive and/or greater-than-additive cytotoxicity in approximately half the cell lines screened. The V600E mutation-specific BRAF inhibitor vemurafenib and the KRAS G12C selective inhibitor sotorasib in combination with ipatasertib were active in the eight BRAF V600E and four KRAS G12C mutant-containing cell lines, respectively. Vertical inhibition of the PI3K/AKT/mTOR pathway with the mTORC1/2 kinase inhibitor sapanisertib demonstrated additive and/or greater-than-additive effects in multiple cell lines. In early experiments, there was a correlation between the response to ipatasertib and selumetinib in two patient-derived tumor lines grown as mct-spheroids and the corresponding patient-derived xenografts. All data are accessible via the PubChem BioAssay public database.

Across multiple in vitro and in vivo CRC models, navitoclax enhanced PI3K/MTOR inhibition (copanlisib, sapanisertib, and dactolisib) and induced apoptosis. Furthermore, we identify BCL-xL as the major BCL-2 family target important for the response to this combination in this setting. This provides a strong rationale for MTORC1/2 and BCL-2 family inhibition as a potential treatment strategy for PIK3CA mutant CRCs.

P1, N=85, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Jun 2025 --> Jun 2026 | Trial primary completion date: Jun 2025 --> Jun 2026

Multi-node PI3K/AKT/mTOR pathway inhibition with serabelisib, sapanisertib and ISD is highly effective in preclinical models of endometrial and breast cancer, supporting continued clinical development in these and other solid tumours.