serabelisib (MLN1117) / Takeda, Faeth Therap, Eli Lilly - LARVOL DELTA

Sapanisertib and serabelisib (PIKTOR) with paclitaxel and a diet substudy in patients with advanced/recurrent endometrial cancer (GOG-3111). (ASCO 2025) - P1, P2 | "The primary objective is to evaluate the objective response rate (ORR) and secondary objective is to evaluate efficacy via progression-free survival (PFS), PFS at 6 months, overall survival, clinical benefit rate, duration of response; and safety/tolerability of PIKTOR + paclitaxel. The substudy rationale is to evaluate the impact of diet on treatment tolerability and efficacy."

Clinical • IO biomarker • Metastases • Endometrial Cancer • Oncology • Solid Tumor • IR • PIK3CA

Multi-node inhibition targeting mTORC1, mTORC2 and PI3Kα potently inhibits the PI3K/AKT/mTOR pathway in endometrial and breast cancer models. (PubMed, Br J Cancer) - "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."

Journal • Preclinical • Breast Cancer • Endometrial Cancer • Oncology • Solid Tumor • EIF4EBP1 • PIK3CA

Multi-node PI3K/AKT/mTOR pathway inhibition with sapanisertib and serabelisib achieves superior efficacy in endometrial cancer models versus single node inhibitors (SGO 2025) - No abstract available

Clinical • Preclinical • Endometrial Cancer • Oncology • Solid Tumor

Combination of Serabelisib and Insulin Suppressing Diet with or Without Nab-paclitaxel in Subjects with Advanced Solid Tumors with PIK3CA Mutations (clinicaltrials.gov) - P1 | N=68 | Active, not recruiting | Sponsor: Faeth Therapeutics | Trial completion date: Sep 2024 ➔ Dec 2025 | Trial primary completion date: Sep 2024 ➔ Dec 2025

Trial completion date • Trial primary completion date • Colon Adenocarcinoma • Colon Cancer • Colorectal Adenocarcinoma • Colorectal Cancer • Endometrial Cancer • Oncology • Ovarian Cancer • Solid Tumor • PIK3CA • PTEN

A phase 2 randomized, double-blind trial of ART-001, a selective PI3Kα inhibitor, for the treatment of slow-flow vascular malformations. (PubMed, Orphanet J Rare Dis) - "ART-001 was effective and well-tolerated in patients with SFVMs. These results support the further development of ART-001 in SFVMs and other PIK3CA-related overgrowth syndromes to confirm clinical benefits and long-term safety."

Clinical • Journal • P2 data • Pain • Pediatrics • PIK3CA

Sapanisertib and Serabelisib (PIKTOR) With Paclitaxel and a Substudy With Diet in Patients With Advanced/Recurrent Endometrial Cancer (clinicaltrials.gov) - P2 | N=40 | Recruiting | Sponsor: Faeth Therapeutics | Not yet recruiting ➔ Recruiting

Enrollment open • Metastases • Endometrial Cancer • Oncology • Solid Tumor

Sapanisertib and Serabelisib (PIKTOR) With Paclitaxel and a Substudy With Diet in Patients With Advanced/Recurrent Endometrial Cancer (clinicaltrials.gov) - P2 | N=40 | Not yet recruiting | Sponsor: Faeth Therapeutics | N=120 ➔ 40 | Initiation date: Sep 2024 ➔ Dec 2024

Enrollment change • Metastases • Trial initiation date • Endometrial Cancer • Oncology • Solid Tumor

Enhancing immunotherapy through PD-L1 upregulation: the promising combination of anti-PD-L1 plus mTOR inhibitors. (PubMed, Mol Oncol) - "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."

IO biomarker • Journal • Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • Urothelial Cancer • CD8 • EGF • IFNB1 • IFNG

Design, synthesis and bioevaluation of dual EGFR-PI3Kα inhibitors for potential treatment of NSCLC. (PubMed, Bioorg Chem) - "A series of dual EGFR/PI3Kα inhibitors was synthesized using pharmacophore hybridization of the third-generation EGFR inhibitor olmutinib and the PI3Kα selective inhibitor TAK-117. Compound 30k exhibited a significant antiproliferative effect in NCI-H1975 cells with a higher selectivity profile than olmutinib. The potential antitumor mechanism, molecular binding modes, and in vitro metabolic stability of compound 30k were also clarified."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • PIK3CA

X31025: Evaluation of the Safety and Tolerability of TAK-228 With TAK-117 and Paclitaxel in Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=19 | Completed | Sponsor: Avera McKennan Hospital & University Health Center | Active, not recruiting ➔ Completed | N=30 ➔ 19

Combination therapy • Enrollment change • Metastases • Trial completion • Oncology • Solid Tumor • PI3K

Sapanisertib and Serabelisib (PIKTOR) With Paclitaxel, Serabelisib With Paclitaxel, and Paclitaxel Alone in Patients With Advanced/Recurrent Endometrial Cancer (clinicaltrials.gov) - P2 | N=120 | Not yet recruiting | Sponsor: Faeth Therapeutics

Metastases • New P2 trial • Endometrial Cancer • Oncology • Solid Tumor

Serabelisib, sapanisertib (PIKTOR) and paclitaxel: A combinatorial approach to improve PI3K/mTOR/AKT pathway inhibition and treatment response in solid tumors. (ASCO 2024) - P1 | "Simultaneous inhibition of PI3K-alpha, mTORC1 and mTORC2 with PIKTOR offers potential for superior PI3K/mTOR/AKT pathway inhibition, suggesting that rational drug combination approaches may offer two important benefits: (1) more complete PI3K/mTOR/AKT pathway inhibition by targeting multiple signaling nodes, and (2) greater tumor cell cytotoxicity by sensitization to taxanes. These data, combined with the promising efficacy and safety signal from PIKTOR plus paclitaxel in a Phase 1 trial (NCT03154294), provide a compelling rationale for further clinical investigation. Future studies will focus on tumors known to have high rates of PI3K mutations including gynecologic tumors where there is a high unmet need."

Breast Cancer • Colorectal Cancer • Endometrial Cancer • Gynecologic Cancers • Oncology • Ovarian Cancer • Solid Tumor • EIF4EBP1 • PIK3CA

Combination of Serabelisib and Insulin Suppressing Diet With or Without Nab-paclitaxel in Subjects With Advanced Solid Tumors With PIK3CA Mutations (clinicaltrials.gov) - P1 | N=68 | Active, not recruiting | Sponsor: Faeth Therapeutics | Recruiting ➔ Active, not recruiting | Phase classification: P1b ➔ P1

Combination therapy • Enrollment closed • Metastases • Phase classification • Colon Cancer • Colorectal Adenocarcinoma • Colorectal Cancer • Endometrial Cancer • Gastrointestinal Cancer • Oncology • Ovarian Cancer • Solid Tumor • PIK3CA • PTEN

A randomized phase 2 study of sapanisertib in combination with paclitaxel versus paclitaxel alone in women with advanced, recurrent, or persistent endometrial cancer. (PubMed, Gynecol Oncol) - P2 | "Our findings support inclusion of chemotherapy combinations with investigational agents for advanced or metastatic disease. The primary endpoint was not met and toxicity was manageable."

Combination therapy • Journal • Metastases • P2 data • Endometrial Cancer • Oncology • Solid Tumor

Design, synthesis and bioevaluation of PI3Kα-selective inhibitors as potential colorectal cancer drugs. (PubMed, Eur J Med Chem) - "In this study, we have designed and synthesized three series of substituted benzoxazole derivatives based on the clinical candidate TAK-117 (8a)...The potential antitumor mechanism and in vitro metabolic stability of 18a were also investigated. Notably, pharmacokinetic assays indicated that 18a had a higher plasma exposure, a higher maximum concentration and shorter elimination time compared to 8a."

Journal • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • PIK3CA

Pilot clinical trial and phenotypic analysis in chemotherapy-pretreated, metastatic triple-negative breast cancer patients treated with oral TAK-228 and TAK-117 (PIKTOR) to increase DNA damage repair deficiency followed by cisplatin and nab paclitaxel. (PubMed, Biomark Res) - P2 | "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."

Journal • Metastases • Tumor mutational burden • Breast Cancer • Immune Modulation • Oncology • Solid Tumor • Triple Negative Breast Cancer • HRD • PIK3CA • TMB • TP53BP1

Serabelisib regulates GSDMD-mediated pyroptosis, apoptosis and migration of hepatoma cells via the PI3K/Akt/E-cadherin signaling pathway. (PubMed, Adv Clin Exp Med) - "Serabelisib inhibited the PI3K/AKT signaling pathway, thereby inhibiting EMT and promoting apoptosis and pyroptosis in HepG2 and HuH-6 cells."

Journal • Bladder Cancer • Gastrointestinal Cancer • Genito-urinary Cancer • Hepatoblastoma • Hepatocellular Cancer • Hepatology • Liver Cancer • Oncology • Solid Tumor • Urothelial Cancer • CDH1 • PIK3CA

TAK-228 and TAK-117 Followed by Cisplatin and Nab Paclitaxel for Metastatic Triple Negative Breast Cancer (clinicaltrials.gov) - P2 | N=12 | Completed | Sponsor: Baylor Research Institute | Active, not recruiting ➔ Completed

Metastases • Trial completion • Breast Cancer • Gastrointestinal Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • AR

A phase 2 study of investigational TORC1/2 inhibitor TAK-228 and TAK-228 plus investigational PI3Kα-selective inhibitor TAK-117 vs everolimus in adults with advanced or metastatic clear-cell renal cell carcinoma (ccRCC) that has progressed on VEGF-targeted therapy (ESMO 2017) - P2; "Secondary endpoints are OS, TTP, ORR, CBR, safety, and QoL. As of January 24, 2017, 54 pts have been screened."

P2 data • Retrospective data • Renal Cell Carcinoma

Patient reported outcomes and final results of phase 1 evaluation of the safety and clinical activity of sapanisertib in combination with serabelisib and paclitaxel in patients with advanced ovarian, endometrial, or breast cancer (SGO 2022) - No abstract available

Clinical • Combination therapy • P1 data • Patient reported outcomes • Breast Cancer • Endometrial Cancer • Oncology • Solid Tumor

Recent Advances of PI3 Kinase Inhibitors: Structure Anticancer Activity Relationship Studies. (PubMed, Mini Rev Med Chem) - "The PI3K inhibitors which are under clinical trial studies include GDC-0032, INK1117 for PI3K-α, and AZD8186 for PI3K-β. This review primarily focuses on the structural insights and structure anticancer activity relationship studies of recent PI3K inhibitors including their clinical stages of development and therapeutic values."

Journal • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • PIK3CA • PIK3CB • PIK3CD • PIK3CG

Randomized Phase II Trial of Sapanisertib ± TAK-117 vs. Everolimus in Patients With Advanced Renal Cell Carcinoma After VEGF-Targeted Therapy. (PubMed, Oncologist) - "Sapanisertib with or without TAK-117 was less tolerable and did not improve efficacy vs. everolimus in patients with advanced ccRCC who had relapsed after or were refractory to VEGF-targeted therapies. Dual mTORC1/2 inhibition may not be an effective therapeutic approach for these patients."

Journal • P2 data • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • PIK3CA

Randomized Phase II Trial of Sapanisertib ± TAK-117 vs. Everolimus in Patients With Advanced Renal Cell Carcinoma After VEGF-Targeted Therapy (The Oncologist) - P2 | N=96 | NCT02724020 | Sponsor: Millennium Pharmaceuticals, Inc. | "This phase II study evaluated the efficacy and safety of single-agent sapanisertib and sapanisertib plus the PI3Kα inhibitor TAK-117, vs. everolimus in patients with advanced clear cell renal cell carcinoma (ccRCC) that had progressed on or after VEGF-targeted therapy....There were no significant differences in PFS among the 3 groups or across any subgroups. Median PFS was 3.8 months with everolimus vs. 3.6 months with sapanisertib (HR, 1.33; 95% CI, 0.75-2.36), and 3.1 months with sapanisertib plus TAK-117 (HR, 1.37; 95% CI, 0.75-2.52). No significant differences in overall survival were seen among groups. Overall response rate was 16.7%, 0%, and 7.1%, respectively."

P2 data • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Kidney Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor

Combination of Serabelisib and Insulin Suppressing Diet With or Without Nab-paclitaxel in Subjects With Advanced Solid Tumors With PIK3CA Mutations (clinicaltrials.gov) - P1b | N=68 | Recruiting | Sponsor: Faeth Therapeutics | Trial completion date: Nov 2023 ➔ Sep 2024 | Trial primary completion date: Nov 2023 ➔ Sep 2024

Combination therapy • Trial completion date • Trial primary completion date • Colon Cancer • Colorectal Adenocarcinoma • Colorectal Cancer • Endometrial Cancer • Gastrointestinal Cancer • Oncology • Ovarian Cancer • Solid Tumor • PIK3CA • PTEN

Comparative molecular dynamics analyses on PIK3CA hotspot mutations with PI3Kα specific inhibitors and ATP. (PubMed, Comput Biol Chem) - "Among these, PI3Kα specific inhibitor alpelisib was approved by FDA for breast cancer and other α-isoform specific inhibitors such as inavolisib and serabelisib reached clinical trials. Moreover, correlated motions of all residues were generally higher for ATP except the H1047R mutation which exhibited a distinguishable reduction. The results presented here could be guiding for pre-clinical and clinical studies of personalized medicine where individual mutations are a strong consideration point."

Journal • Breast Cancer • Oncology • Solid Tumor • PIK3CA