sapanisertib (CB-228)

P2, N=17, Active, not recruiting, National Cancer Institute (NCI) | N=209 --> 17 | Trial completion date: Jun 2024 --> Nov 2025

P1, N=50, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Oct 2024 --> Oct 2025

P2, N=40, Not yet recruiting, Faeth Therapeutics | N=120 --> 40 | Initiation date: Sep 2024 --> Dec 2024

P2, N=134, Completed, Imperial College London | Active, not recruiting --> Completed | Trial completion date: Dec 2022 --> Nov 2023 | Trial primary completion date: Dec 2022 --> Nov 2023

In our study, we investigated how phosphoinositide 3-kinase (PI3K)/AKT/mTOR pathway inhibitors (TAK-228, everolimus and TAK-117) affect PD-L1 expression and function in preclinical bladder cancer cell models. These preclinical findings suggest that mTOR inhibition with TAK-228 can increase PD-L1 levels, potentially impacting the specific immune response against UC cells. This highlights the rationale for exploring the combination of mTOR inhibitors with ICIs in patients with advanced UC.

P1, N=19, Completed, Avera McKennan Hospital & University Health Center | Active, not recruiting --> Completed | N=30 --> 19

P1, N=94, Not yet recruiting, Peking Union Medical College Hospital; Peking Union Medical College Hospital

Although the primary endpoint was no met, sapanisertib and paclitaxel combination demonstrated clinical activity in a heavily pretreated population of mUC. This trial generates insight for future combination of sapaniserib with immunotherapy and/or antibody drug conjugates.

P1; Recruiting --> Active, not recruiting

P2, N=120, Not yet recruiting, Faeth Therapeutics

P1; Trial completion date: Sep 2024 --> Jun 2025 | Trial primary completion date: Sep 2024 --> Jun 2025

P1, N=37, Completed, M.D. Anderson Cancer Center | Trial primary completion date: Jun 2022 --> Jul 2023

P2, N=49, Active, not recruiting, National Cancer Institute (NCI)

P2, N=39, Completed, Bradley A. McGregor, MD | Active, not recruiting --> Completed | Trial completion date: Aug 2024 --> Apr 2024

Dual targeting of Aurora A kinase and mTOR resulted in marginal clinical benefit in a population of patients with refractory solid tumors, including pancreatic adenocarcinoma, though individual patients experienced significant response to therapy. Correlatives indicate apoptotic response and tumor immune cell infiltrate may affect clinical outcomes.

P2, N=35, Active, not recruiting, National Cancer Institute (NCI)

P1, N=40, Terminated, National Cancer Institute (NCI) | Trial completion date: Mar 2025 --> Oct 2023 | Active, not recruiting --> Terminated; Other - Lapse in funding

P2, N=16, Active, not recruiting, National Cancer Institute (NCI)

Employing human NF2-deficient meningioma lines, we compared mTOR inhibitors rapamycin (first-generation), INK128 (second-generation), and RMC-6272 (third-generation) using in vitro dose-response testing, cell-cycle analysis, and immunoblotting. Furthermore, in vivo studies in mice revealed effective blockage of meningioma growth by RMC-6272, compared with vehicle controls. Our study in preclinical models of NF2 supports possible future clinical evaluation of third-generation, investigational mTORC1 inhibitors, such as RMC-5552, as a potential treatment strategy for NF2.

P1, N=40, Active, not recruiting, National Cancer Institute (NCI)

The combination of sapanisertib and ziv-aflibercept was generally tolerable and demonstrated anti-tumor activity in heavily pre-treated patients with advanced malignancies.

P1, N=83, Completed, National Cancer Institute (NCI) | Active, not recruiting --> Completed | Trial completion date: Jan 2025 --> Jan 2024

P1, N=83, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Jan 2024 --> Jan 2025

P1/2, N=46, Completed, Dana-Farber Cancer Institute | Active, not recruiting --> Completed | Phase classification: P2 --> P1/2

The safety profile of mTORC1/2 inhibitor sapanisertib in combination with metformin was generally tolerable, with anti-tumor activity observed in patients with advanced malignancies harboring PTEN/ AKT/mTOR pathway alterations.

P1, N=36, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Aug 2023 --> Jun 2024 | Trial primary completion date: Aug 2023 --> Jun 2024

In summary, single-agent sapanisertib had a good safety profile but limited target inhibition or efficacy in ALL as a single agent. This trial was registered at ClinicalTrials.gov as NCT02484430.

P1, N=50, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Oct 2023 --> Oct 2024

Bi-steric inhibitors had strong growth inhibition, eliminated phosphorylated 4EBP1, and induced more apoptosis than rapamycin or MLN0128. De novo purine synthesis was selectively inhibited by bi-sterics through reduction in JUN and its downstream target PRPS1 and appeared to be the cause of apoptosis. Hence, bi-steric mTORC1-selective inhibitors are a therapeutic strategy to treat tumors driven by mTORC1 hyperactivation.

P1; Trial completion date: Sep 2023 --> Sep 2024 | Trial primary completion date: Sep 2023 --> Sep 2024

Importantly, the dual mTOR inhibitor MLN0128 (50 nM, 48 h) down-regulated CYB561 expression and the iron metabolism-related proteins transferrin receptor, divalent metal transporter 1, and ferritin heavy chain 1, whereas the mTOR agonist MHY1485 rescued the down-regulation of CYB561 knockdown on iron metabolism-related proteins. We conclude that CYB561 promotes the proliferation of BC cells by regulating iron metabolism through the activation of the Akt/mTOR signaling pathway.

P1, N=37, Completed, M.D. Anderson Cancer Center | Active, not recruiting --> Completed | Trial completion date: Jan 2023 --> Jul 2023

Priming patients' chemotherapy-pretreated metastatic TNBC with PIKTOR led to very prolonged response/disease control with subsequent cis/nab pac, followed by pembrolizumab, in 3 of 10 treated patients. Our multi-omics approach revealed a higher number of genomic alterations, reductions in MMR, and alterations in immune and stress response pathways post-PIKTOR in patients who had durable responses.

P2, N=209, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Jun 2023 --> Jun 2024 | Trial primary completion date: Jun 2023 --> Jun 2024

We could distinguish between effects of the two compounds that were overlapping or similar, although with differences in potency and or/time-course, and effects that were diverging or even opposite. Among the latter, especially relevant is the difference in the profile of microglia activation, with rapamycin being an overall inhibitor of microglia activation, whereas sapanisertib was found to induce an M2-profile, which is usually associated with poor clinical outcomes.

The last year ushered in novel approaches of varying success for managing advanced renal cell carcinoma, including triplet therapy, HIF-2α inhibitors, metabolic pathway inhibitors, and dual mTOR inhibitors. Pembrolizumab remains the only modern therapy available in the adjuvant setting, and the waters surrounding cytoreductive nephrectomy are still murky.

P2, N=12, Completed, Baylor Research Institute | Active, not recruiting --> Completed

Median progression free survival was 3.84 months. Sapanisertib in combination with carboplatin plus paclitaxel demonstrated a manageable safety profile, with preliminary antitumor activity observed in advanced malignancies harboring mTOR pathway alterations.

Detection of the enrollment mutations in treatment arms was observed in 51.8% - 85.7% of patients tested by ctDNA with overall variant concordance between tissue and ctDNA of at least 73.6%. These findings support the use of liquid biopsy as a tool for understanding genomic profiles of cancer patients both at diagnosis and progression, less invasively than standard tissue biopsies. In addition, 7 patients were identified as MSI-H, suggesting that blood-based testing could complement tissue testing for identifying patients who may benefit from targeted therapy.

The venetoclax/INK128 regimen exerts significant anti-leukemic activity in various preclinical models through mechanisms involving MCL-1 down-regulation and BAK/BAX activation, and offers potential advantages over PI3K or AKT inhibitors in cells with constitutive AKT activation. This regimen is active against primary and venetoclax resistant AML cells, and in in vivoAML models. Further investigation of this strategy appears warranted.

P2, N=7, Terminated, Calithera Biosciences, Inc | N=50 --> 7 | Trial completion date: Mar 2025 --> Mar 2023 | Recruiting --> Terminated | Trial primary completion date: Sep 2023 --> Mar 2023; Sponsor decision