gedatolisib (PF-05212384)

P1/2, N=54, Recruiting, Celcuity Inc | Not yet recruiting --> Recruiting

Gedatolisib plus palbociclib and endocrine therapy showed a promising objective response rate compared with the published results for standard-of-care therapies and had an acceptable safety profile.

P1/2, N=37, Active, not recruiting, Kari Wisinski | Trial completion date: Dec 2023 --> Mar 2024 | Trial primary completion date: Dec 2023 --> Mar 2024

P1, N=96, Recruiting, Dana-Farber Cancer Institute | Trial completion date: Jan 2025 --> Jan 2026 | Trial primary completion date: Jan 2024 --> Jan 2025

P1/2, N=54, Not yet recruiting, Celcuity Inc

Those with PIK3CA mutations will be assigned to Study 2 (n=350) and randomized to Arm D (geda, P, and F), Arm E (alpelisib and F), or Arm F (geda and F). Enrollment is ongoing. This trial abstract was previously presented at the 2022 San Antonio Breast Cancer Symposium, December 6-10, 2022.

Although this study did not meet its primary endpoint, there were 2 TNBC patients without a gBRCA1/2 mutation who achieved a partial response to this non-chemotherapy regimen. Future biomarker testing may help elucidate these findings and possible predictors of response.

P1/2, N=37, Active, not recruiting, Kari Wisinski | Recruiting --> Active, not recruiting

Studies have demonstrated the efficacy of Palbociclib (CDK 4/6 inhibitor), Gedatolisib (PI3K/mTOR dual inhibitor) and PD0325901 (MEK1/2 inhibitor) in colorectal cancer (CRC), however single agent therapeutics are often limited by the development of resistance. This study shows that the combination of Palbociclib and Gedatolisib has synergistic anti-proliferative effects in both wild-type and mutated CRC cell lines. Separately, the phosphorylation of S6rp may be a promising biomarker of responsiveness to this combination.

To date, three s-triazine derivatives, including altretamine, gedatolisib, and enasidenib, have already been approved for refractory ovarian cancer, metastatic breast cancer, and leukemia therapy, respectively, demonstrating that the s-triazine core is a useful scaffold for the discovery of novel anticancer drugs. The medicinal chemistry of s-triazine derivatives as anticancer agents was summarized, including discovery, structure optimization, and biological applications. This review will provide a reference to inspire new and original discoveries.

ConclusionThe current findings have shown a promising combinational therapy for triple negative breast cancer. Future work will assess Gedatolisib in combination with chemotherapy drugs in double and triple combinations in vitro and in vivo utilising both the chick embryo and Murine xenograft models as well as investigation of mechanisms underpinning toxicity

Compound 5f (LASSBio-2252) stood out as the most promising of the series, showing good aqueous solubility (42.38 μM (pH = 7.4); 39.33 μM (pH = 5.8)), good partition coefficient (cLogP = 2.96), cytotoxic activity on human leukemia cell lines (CCRF-CEM, K562 and MOLT-4) and an excellent metabolic stability profile in rat liver microsomes (t = 462 min; Clapp = 0.058 mL/min/g). The ability of 5f to exert its cytotoxic effect through modulation of the PI3K pathway was demonstrated by flow cytometry analysis in a comparative manner to gedatolisib.

Those with PIK3CA mutations will be assigned to Study 2 (n=350) and randomized to Arm D (geda, palbo, and FUL), Arm E (alpelisib and FUL), or Arm F (geda and FUL). The trial is open for enrollment. Clinical trial information: NCT05501886.

Currently, everolimus, an mTORC1 inhibitor, in combination with letrozole, an aromatase inhibitor, is one of the available hormonal therapy options for patients with advanced endometrioid EC...We hypothesized that gedatolisib, which potently inhibits all Class I PI3K isoforms, mTORC1, and mTORC2, can potentially be an effective and well tolerated therapy for patients with EC. A panel of endometrial, ovarian and cervical cancer cell lines with different PI3K pathway mutational status were assayed for their sensitivity to gedatolisib and other PAM inhibitors (PI3K-α: alpelisib, pan-PI3K: copanlisib; AKT: capivasertib; mTORC1: everolimus; pan-PI3K/mTOR: gedatolisib)... We demonstrated that, gedatolisib induces superior anti-proliferative activity compared to the other PAM pathway inhibitors, regardless of the PI3K pathway mutational status of the cancer cell lines evaluated. Gedatolisib as a single agent and in combination with other therapies has previously reported promising preliminary clinical efficacy and safety in various solid tumor types, including EC. In summary, nonclinical and preliminary clinical data supports the development of gedatolisib in combination with hormonal therapy for treatment of patients with EC.

Those with PIK3CA mutations will be assigned to Study 2 (n=350) and randomized to Arm D (geda, palbo, and FUL), Arm E (alpelisib and FUL), or Arm F (geda and FUL). The trial is open for enrollment. This trial abstract was previously presented at the 2022 San Antonio Breast Cancer Symposium, December 6-10, 2022.

This study revealed the molecular profiles of MPT that can lead to molecular classification and potential targeted therapy, and suggested that the MPT PDX model can be a useful tool for studying the pathogenesis of fibroepithelial neoplasms and for preclinical drug screening to find new therapeutic strategies for MPT.

A panel of PrC cell lines with different PI3K or PTEN status (wt: 22RV1, MDA-PCa-2b, DU145; null: LNCaP, PC3, C4-2) were assayed under different conditions for their sensitivity to gedatolisib and other PAM-I (PI3K: alpelisib, copanlisib; AKT: capivasertib, ipatasertib; mTOR: everolimus; pan-PI3K/mTOR: samotolisib, gedatolisib). We demonstrated that gedatolisib exerts superior activity regardless of PI3K or PTEN status in all PrC cell lines evaluated compared to the other PAM pathway inhibitors evaluated. Our results indicate potent and simultaneous blockade of all Class I PI3K isoforms, mTORC1, and mTORC2 could circumvent PTEN dependent resistance. Gedatolisib as a single agent and in combination with other therapies reported promising preliminary efficacy and safety in various solid tumor types.

P1, N=96, Recruiting, Dana-Farber Cancer Institute | Trial completion date: Jan 2024 --> Jan 2025 | Trial primary completion date: Jan 2023 --> Jan 2024

BPTF targeting with the bromodomain inhibitor bromosporine, alone or in combination with the PI3K pathway inhibitor gedatolisib, produced significant anti-tumor effects against TNBC cells in vitro and in vivo. These studies demonstrate BPTF activation in distinct breast cancer subtypes, identify pathways by which BPTF promotes breast cancer progression, and suggest BPTF as a rational target for breast cancer therapy.

P1/2, N=37, Recruiting, Kari Wisinski | N=54 --> 37 | Trial completion date: Dec 2023 --> Jun 2023 | Trial primary completion date: Dec 2022 --> Jun 2023

P3, N=701, Recruiting, Celcuity, Inc. | Not yet recruiting --> Recruiting

Background: Gedatolisib is a potent reversible dual inhibitor that selectively targets all Class I isoforms of phosphoinositide 3-kinase (PI3K) and mechanistic target of rapamycin (mTOR)...Study 2 will include up to 350 subjects randomized in a 3:3:1 ratio to Arm D (gedatolisib, palbociclib, and fulvestrant), Arm E (alpelisib plus fulvestrant), or Arm F (gedatolisib plus fulvestrant)...Secondary endpoints included overall survival (OS), safety and tolerability, ORR, duration of response, time to response, CBR, quality of life, and pharmacokinetics. This trial is open for enrollment.

To evaluate this hypothesis, we conducted a Phase Ib study of gedatolisib (G), a dual inhibitor of PI3K/mTOR, palbociclib (P) a CDK4/6i, and ET (with letrozole [LET] or fulvestrant [FUL]) in women with hormone receptor positive (HR+)/HER2- advanced breast cancer (ABC). These preliminary data demonstrate promising activity of G+P+ET combination in pts who were CDK4/6i-naïve and in those whose disease progressed on or after CDK4/6i therapy regardless of PIK3CA mutation status. Encouraging results in CDK4/6i treatment naïve patients warrant further evaluation of gedatolisib in combination with CDK4/6i treatment in the front-line setting. Arm D results provide a strong basis for the initiated Phase 3 study (VIKTORIA-1) in pts whose disease progressed on or after CDK4/6i therapy.

In vivo studies demonstrated an inhibition of tumor growth in the colorectal tumor model. According to the docking studies, the replacement of the triazine core in gedatolisib (8) by a quinazoline fragment, and incorporation of a (hetero)aromatic unit connected with the carbamide group via a flexible spacer, can result in more selective inhibition of the PI3Kα isoform.

P3, N=701, Not yet recruiting, Celcuity, Inc.

The combination of gedatolisib + cofetuzumab pelidotin was well tolerated and demonstrated promising clinical activity. Further investigation of this drug combination in metastatic TNBC is warranted.

P3, N=701, Recruiting, Celcuity, Inc.

The safety run-in indicated that this combination is safe and well tolerated with mostly grade 1-2 AEs. This combination therapy has moved into the phase II trial, with 2 cohorts. Cohort A includes BRCA-wildtype patients with TNBC and cohort 2 includes those with a BRCA mutation and HER2-negative disease.

The aim of our study was to investigate the efficacy of PI3K/AKT/mTOR pathway inhibitors (PI3Ki) (alpelisib, buparlisib and gedatolisib) and CDK4/6 inhibitors (CDKi) (palbociclib and ribociclib) in HPV-positive and -negative HNSCC cell lines. The efficacy of the inhibitors was assessed using MTT assays and changes in PI3K and Cyclin D1/CDK pathway protein expression were determined by Western blotting. PI3Ki and CDKi efficiently inhibit their respective pathways and HNSCC cell growth in vitro, the latter only in HPV-negative cell lines. Whereas PI3Ki especially show an effect on oxidative and glycolytic metabolism, CDKi particularly lead to cell cycle arrest. Further research should elucidate whether these inhibitors may be effective therapeutic agents in HNSCC patients.

P1b, N=141, Completed, Celcuity, Inc. | Active, not recruiting --> Completed | Trial completion date: Jun 2022 --> Jan 2022 | Trial primary completion date: Jun 2022 --> Jan 2022

P1, N=18, Active, not recruiting, Hoffman Oncology | Recruiting --> Active, not recruiting | Trial completion date: Sep 2020 --> Mar 2022 | Trial primary completion date: Sep 2020 --> Feb 2022

In this study, a series of diaryl urea derivatives has been designed and synthesized based on clinical candidate gedatolisib (6aa), and most of the newly synthesized derivatives showed kinase inhibitory and antiproliferative activities within nanomolar and submicromolar level, respectively...The safety investigations revealed that compound 6 ab exhibited more safer profiles in the selectivity of liver cells (selectivity index: >6.6 vs 1.85) and blood glucose regulation than 6aa. In addition, the in vitro stability assays also indicated our developed compound 6 ab possessed good metabolic stabilities.

P1/2, N=54, Recruiting, Kari Wisinski | Trial completion date: Dec 2022 --> Dec 2023 | Trial primary completion date: Dec 2021 --> Dec 2022

P1, N=96, Recruiting, Dana-Farber Cancer Institute | Trial completion date: Jan 2023 --> Jan 2024 | Trial primary completion date: Jan 2022 --> Jan 2023

P1/2, N=54, Recruiting, Kari Wisinski | Trial completion date: May 2022 --> Dec 2022 | Trial primary completion date: May 2021 --> Dec 2021

PI3K/mTOR inhibition plus PTX heightens response to ICI and may provide a viable therapeutic approach for treatment of metastatic BC.

This result held true whether analyzing Gedatolisib on its own (vs. vehicle treated animals), or in combination with dose dense doxorubicin and cyclophosphamide (vs. animals treated only with dose dense chemotherapies). These data suggest that PI3K is not the node downstream of integrin-β1 that confers chemotherapeutic resistance to DTCs. More broadly, they cast doubt on the strategy to target PI3K in order to eliminate DTCs and prevent breast cancer metastasis.

Dynamic live cell response to a GPCR agonist (LPA), a PI3K-α inhibitor (GDC-0077), a pan-PI3K inhibitor (copanlisib), a pan-PI3K/mTOR inhibitor (gedatolisib), and a BCL inhibitor (navitoclax) was measured using an xCELLigence impedance biosensor (Agilent Technologies). These findings suggest that a significant sub-group of BC patients have a RAS-involved oncogenic driver that is responsive ex vivo to pan-PI3K/mTOR and pan-PI3K/mTOR/BCL inhibitors. A clinical trial to evaluate treatment response of this patient sub-group to combined PI3K/mTOR or PI3K/mTOR/BCL inhibitors is warranted.

Dynamic live cell response to a GPCR agonist (LPA), a PI3K-α inhibitor (GDC-0077), a pan-PI3K inhibitor (copanlisib), a pan-PI3K/mTOR inhibitor (gedatolisib), and a BCL inhibitor (navitoclax) was measured using an xCELLigence impedance biosensor (Agilent Technologies). These findings suggest that a significant sub-group of OC patients have a RAS-involved oncogenic driver that is responsive ex vivo to pan-PI3K/mTOR and pan-PI3K/mTOR/BCL inhibitors. A clinical trial to evaluate treatment response of this patient sub-group to combined PI3K/mTOR or PI3K/mTOR/BCL inhibitors is warranted.