gedatolisib (PF-05212384) / Pfizer, Celcuity - LARVOL DELTA

Overall survival in patients with hormone receptor-positive, HER2-negative advanced breast cancer treated in a phase 1b trial evaluating gedatolisib in combination with palbociclib and endocrine therapy. (PubMed, Lancet Oncol) - No abstract available

Journal • P1 data • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • HER-2

Phase 1 Clinical Trial in mCRPC (GlobeNewswire) - P1/2 | N=54 | NCT06190899 | Sponsor: Celcuity Inc | "The preliminary efficacy and safety analyses for the combined arms showed: The six-month rPFS was 66%; No patients discontinued treatment due to a treatment-related AE and no dose reductions were required with gedatolisib or darolutamide; No Grade 3 hyperglycemia was reported; Grade 2-3 stomatitis was reported in four (10.5%) patients - three (7.9%) Grade 2 and one (2.6%) Grade 3. Additional preliminary results for the Phase 1 portion of the clinical trial will be presented at a medical conference later this year....In the amended Phase 1 portion of the clinical trial, up to six patients are planned to be enrolled in each of three arms and treated with different doses. Upon completion of Phase 1, up to an additional 40 patients will be randomly assigned to up to four Phase 1b cohorts....In the Phase 2 dose expansion study...up to 18 additional subjects will be enrolled to achieve a total of approximately 30 subjects..."

P1 data • Trial status • Castration-Resistant Prostate Cancer

Functional Analysis of the PI3K/AKT/mTOR Pathway Inhibitor, Gedatolisib, Plus Fulvestrant with and Without Palbociclib in Breast Cancer Models. (PubMed, Int J Mol Sci) - "The triplet combination was effective in treatment-naïve BC cell lines as well as in cell lines adapted to palbociclib and/or fulvestrant, regardless of PIK3CA/PTEN genetic alterations. Our findings provide a mechanistic rationale for conducting clinical studies evaluating gedatolisib in combination with CDK4/6 inhibitors and ET in HR+/HER2- ABC."

Journal • Preclinical • Breast Cancer • Endocrine Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2 • PIK3CA • PTEN

Discovery of Small-Molecule Inhibitors Against Norovirus 3CLpro Using Structure-Based Virtual Screening and FlipGFP Assay. (PubMed, Viruses) - "Among them, eight compounds demonstrated significant inhibitory activity against 3CLpro, with Gedatolisib showing the most potent effect (IC50 = 0.06 ± 0.01 μM). Molecular docking and molecular dynamics simulations were conducted to explore the binding mechanisms and structural stability of the inhibitor-3CLpro complexes. Our findings provide valuable insights into the development of antiviral drugs targeting Norovirus 3CLpro, offering potential therapeutic strategies to combat Norovirus infections."

Journal • Preclinical • Gastroenterology • Gastrointestinal Disorder • Infectious Disease

Gedatolisib Plus Fulvestrant With or Without Palbociclib vs Standard-of-Care for the Treatment of Patients With Advanced or Metastatic HR+/HER2- Breast Cancer (VIKTORIA-1) (clinicaltrials.gov) - P3 | N=701 | Recruiting | Sponsor: Celcuity Inc | Trial primary completion date: Mar 2025 ➔ Jun 2025

Trial primary completion date • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2 • PGR • PIK3CA

Phase 3 Study of Gedatolisib as First-Line Treatment for Patients With HR-Positive, HER2-Negative Advanced Breast Cancer (VIKTORIA-2) (clinicaltrials.gov) - P3 | N=674 | Recruiting | Sponsor: Celcuity Inc | Not yet recruiting ➔ Recruiting

Enrollment open • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor

RESOLVE: Abemaciclib + Letrozole +/- Metformin, Zotatifin, or Gedatolisib in Endometrial or Low-Grade Serous Ovarian Cancer (clinicaltrials.gov) - P2 | N=180 | Recruiting | Sponsor: Dana-Farber Cancer Institute | Active, not recruiting ➔ Recruiting | N=130 ➔ 180 | Trial completion date: Aug 2030 ➔ Aug 2031 | Trial primary completion date: Aug 2027 ➔ Aug 2028

Enrollment change • Enrollment open • P53WT • Trial completion date • Trial primary completion date • Endometrial Cancer • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Solid Tumor • ER

The novel diarylurea derivative HPT-15 for potential treatment of triple-negative breast cancer via dual inhibition of the mTOR and MAPK pathways. (PubMed, Cell Signal) - "Molecular docking and dynamics simulations confirmed that HPT-15 exhibited superior binding stability with mTOR as compared to the dual-target inhibitor PKI-587...In vivo experiments further confirmed that HPT-15 effectively suppressed tumor growth without apparent toxic side effects. These findings promote the potential of HPT-15 for treatment of TNBC."

Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • EIF4EBP1

Phase I/II trial investigating gedatolisib plus talazoparib in advanced triple negative or BRCA1/2 positive, HER2 negative breast cancers. (PubMed, Breast Cancer Res Treat) - P1/2 | "The combination of gedatolisib and talazoparib is safe but did not meet the prespecified efficacy threshold for objective response rate. Additional preclinical studies of these pathways are warranted prior to future clinical trials of the combination."

Journal • P1/2 data • Breast Cancer • Fatigue • Hematological Disorders • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Mucositis • Oncology • Solid Tumor • Stomatitis • Triple Negative Breast Cancer • BRCA1 • BRCA2 • HER-2 • HRD

Phase II study of trastuzumab-pkrb plus gedatolisib in patients with HER2-positive metastatic breast cancer who progressed after 2 or more HER2-directed chemotherapies (KM-10A/KCSG BR18-13). (ASCO 2025) - P2 | "In this phase II study, the combination of trastuzumab-pkrb and gedatolisib demonstrated a 43.2% response rate with manageable toxicity in patients with HER2 positive MBC and PIK3CA mutations. A translational research study focused on the analysis of cfDNA and PBMC is currently being planned."

Clinical • Metastases • P2 data • Breast Cancer • Diabetes • HER2 Breast Cancer • HER2 Positive Breast Cancer • Mucositis • Oncology • Palliative care • Solid Tumor • Stomatitis • PIK3CA • PTEN

[ASCO 2025]Will the era of ‘PI3K’ targeted therapy open in HER2-positive breast cancer treatment? (Korea Biomedical Review) - P2 | N=15 | NCT03698383 | "According to the results of a Korean investigator-led phase 2 clinical trial presented at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting (ASCO 2025) last Saturday (local time), the combination of trastuzumab biosimilar (Herzuma in trademark name) and PI3K/mTOR dual inhibitor gedatolisib showed significant antitumor effects in HER2-positive metastatic breast cancer patients with genetic abnormalities in the PI3K-AKT-mTOR pathway....Regarding genetic abnormalities, 26 patients reported PIK3CA kinase domain mutations, 11 PIK3CA helical domain mutations, one amplification, two PTEN deletions, and four other mutations. Of the 44 analyzable patients, two (4.5 percent) had a complete response (CR), and 17 (38.6 percent) had a partial response (PR), resulting in an objective response rate (ORR) of 43.2 percent and a disease control rate (DCR) of 86.4 percent."

P2 data • HER2 Positive Breast Cancer

Celcuity Inc. Reports First Quarter 2025 Financial Results and Provides Corporate Update (GlobeNewswire) - "The primary completion date of the PIK3CA wild-type cohort of the VIKTORIA-1 Phase 3 trial is expected in June 2025 and a topline data readout is anticipated in the third quarter of 2025...Enrollment is ongoing in the PIK3CA mutant cohort of the VIKTORIA-1 Phase 3 trial and a topline data readout is anticipated in the fourth quarter of 2025...VIKTORIA-2 Phase 3 trial remains on track to dose its first patient in the second quarter of 2025...Initiating a clinical trial collaboration with the Dana Farber Cancer Institute and Massachusetts General Hospital to evaluate gedatolisib in combination with abemaciclib and letrozole in patients with endometrial cancer"

New trial • P3 data: top line • Trial status • Castration-Resistant Prostate Cancer • Endometrial Cancer • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer

A randomized, open-label, phase 3 study of fulvestrant and CDK4/6 inhibitors with or without gedatolisib as first-line treatment in patients with HR+/HER2- advanced breast cancer (VIKTORIA-2) (AACR 2025) - P3 | "Background: For patients with HR+/HER2- advanced breast cancer (ABC), first-line treatment typically includes a CDK4/6 inhibitor (palbociclib, ribociclib, or abemaciclib) combined with endocrine therapy (ET)...Gedatolisib, a potent multi-node PAM inhibitor, has demonstrated superior potency and cytotoxicity in BC cell lines compared to approved single-node PAM inhibitors such as alpelisib, everolimus, and capivasertib (Rosetti S, et al...In a Phase 1b study, gedatolisib combined with palbociclib and letrozole as a 1L treatment for patients with endocrine sensitive HR+/HER2- ABC reported an overall response rate (ORR) of 85.2%, mPFS of 48.4 months, and a median OS of 77.3 months in treatment-naïve patients (Layman R, et al...Secondary endpoints will evaluate OS, safety, and tolerability between treatment arms. Enrollment is ongoing."

Clinical • Metastases • P3 data • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • HER-2 • PIK3CA

Co-targeting AR, mTOR, and PI3K inhibitors in DSRCT as a novel therapeutic approach (AACR 2025) - "Next, we explored the sensitivity of DSRCT cell lines to Enzalutamide and Darolutamide inhibitors; Temsirolimus (an mTOR inhibitor); Alpelisib (a PI3K inhibitor); and Gedatolisib (a dual mTOR and pan-PI3K inhibitor). We conclude that DSRCT cell lines are responsive to AR blocking and highly sensitive to PI3K/mTOR inhibitors. A co-targeting strategy that jointly inhibits the AR and PI3K/mTOR pathways is being investigated in murine models and might be considered for future studies if the regimens have non-overlapping toxicity profiles."

Genito-urinary Cancer • Oncology • Prostate Cancer • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • AR

Palbociclib in the Evolving Landscape of HR+ mBC Treatment : Real-World Data and Future Directions (GBCC 2025) - "Young-PEARL, the first study comparing CDK4/6 inhibitor plus ET and cytotoxic chemotherapy capecitabine focused on premenopausal women with HR+/HER2− mBC, reported that palbociclib plus exemestane and ovarian suppression significantly prolonged PFS compared with capecitabine...The INAVO120 trial demonstrated superior PFS when inavolisib was added to palbociclib and fulvestrant in patients with PIK3CA-mutated HR+/HER2− mBC. The AFT-38 PATINA trial showed that adding palbociclib to maintenance endocrine and first line trastuzumab and pertuzumab significantly extended PFS in patients with HR+/HER2+ mBC. Moreover, palbociclib is also being studied in combination with other PI3K/AKT pathway inhibitors, such as gedatolisib and capivasertib, or selective estrogen receptor degraders(SERDs) in order to explore potential synergistic effects in overcoming treatment resistance in HR+/HER2− mBC. Taken together, these findings suggest that palbociclib’s role in the treatment landscape..."

Clinical • Real-world • Real-world evidence • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2 • PIK3CA

Celcuity Inc. Reports Fourth Quarter and Full Year 2024 Financial Results and Provides Corporate Update (GlobeNewswire) - "The VIKTORIA-1 Phase 3 clinical trial evaluating gedatolisib in combination with fulvestrant with and without palbociclib in adults with HR+, HER2- advanced breast cancer who have received prior treatment with a CDK4/6 inhibitor is 100% enrolled for the PIK3CA wild-type cohort. We expect to provide topline data in Q2 2025: Enrollment for the PIK3CA mutant cohort remains on track and topline data is expected in Q4 of 2025; The VIKTORIA-2 Phase 3 open-label randomized study evaluating the efficacy and safety of gedatolisib in combination with fulvestrant plus a CDK4/6 inhibitor, either ribociclib or palbociclib, in comparison to fulvestrant plus a CDK4/6 inhibitor as a first-line treatment for patients with HR+/HER2- advanced breast cancer who are endocrine therapy resistant remains on track to enroll its first patient in Q2 2025."

Enrollment status • P3 data: top line • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer

Celcuity Inc. Reports Fourth Quarter and Full Year 2024 Financial Results and Provides Corporate Update (GlobeNewswire) - "The Phase 1b/2 clinical trial, evaluating gedatolisib in combination with darolutamide for the treatment of patients with metastatic castration resistant prostate cancer ('mCRPC'), is ongoing and remains on track to report preliminary data in late Q2 2025: The study is expected to enroll up to 54 patients with mCRPC whose disease progressed while on or after treatment with an androgen receptor signaling inhibitor."

Enrollment status • P1/2 data • Castration-Resistant Prostate Cancer

Fourth Quarter and Full Year 2024 Financial Results (GlobeNewswire) - "Research and development ('R&D') expenses were $33.5 million for the fourth quarter of 2024, compared to $18.1 million for the prior-year period. Of the approximately $15.4 million increase in R&D expenses, $9.9 million primarily related to costs supporting ongoing activities for the VIKTORIA-1 Phase 3 trial and the CELC-G-201 Phase 1b/2 trial, along with the commencement of the VIKTORIA-2 Phase 3 trial. The remaining $5.5 million primarily relates to increased employee and consulting expenses....R&D expenses for the full year 2024 were $104.2 million, compared to $60.6 million for the prior year. Of the approximately $43.6 million increase in R&D expenses, $30.7 million was related to costs supporting ongoing activities for the VIKTORIA-1 Phase 3 trial and the CELC-G-201 Phase 1b/2 clinical trial, along with the commencement of the VIKTORIA-2 Phase 3 trial. The remaining $12.9 million increase in R&D expenses was primarily related to increased employee and consulting expenses."

Commercial • Castration-Resistant Prostate Cancer • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer

Study of the CDK4/6 Inhibitor Palbociclib (PD-0332991) in Combination With the PI3K/mTOR Inhibitor Gedatolisib (PF-05212384) for Patients With Advanced Squamous Cell Lung, Pancreatic, Head & Neck and Other Solid Tumors (clinicaltrials.gov) - P1 | N=96 | Recruiting | Sponsor: Dana-Farber Cancer Institute | Trial primary completion date: Jan 2025 ➔ Sep 2025

Trial primary completion date • Endometrial Cancer • Head and Neck Cancer • Hepatology • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Oropharyngeal Cancer • Pancreatic Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • PIK3CA • PTEN

Bypassing cisplatin resistance in Nrf2 hyperactivated head and neck cancer through effective PI3Kinase targeting. (PubMed, bioRxiv) - "The PI3Ki gedatolisib inhibits cisplatin-resistant HNSCC proliferation, induces G2M arrest and potentiates cisplatin effectiveness through activation of autophagy, senescence and disruption of fatty acid metabolism. However, the development of effective systemic regimens for cisplatin-resistant HNSCC has not yet been successful. Here, we present, for the first time, a mechanistic, biomarker-informed strategy for effective targeting of the PI3Kinase pathway in cisplatin-resistant HNSCC with substantial anti-tumor activity in both orthotopic and metastatic models, which may be capable of bypassing or reversing cisplatin resistance in this disease."

Journal • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • NOTCH1

Exploring the antiproliferative effect of PI3K/Akt/mTOR pathway and CDK4/6 inhibitors in human papillomavirus‑positive and ‑negative head and neck squamous cell carcinoma cell lines. (PubMed, Int J Oncol) - "The present study aimed to investigate the efficacy of the CDK4/6 inhibitors (CDKi) palbociclib and ribociclib, and the PI3K/Akt/mTOR pathway inhibitors (PI3Ki) gedatolisib, buparlisib and alpelisib, in suppressing cell viability of HPV‑positive and ‑negative HNSCC cell lines. Whereas PI3Ki induced apoptosis and attenuated cellular metabolism, CDKi led to cell cycle arrest. Further research should be performed to elucidate whether (a combination of) these inhibitors may be effective therapeutic agents for patients with HNSCC."

Journal • Preclinical • Eye Cancer • Head and Neck Cancer • Oncology • Retinal Disorders • Retinoblastoma • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • ANXA5 • CCND1 • CDKN2A • PTEN

Phase 3 Study of Gedatolisib as First-Line Treatment for Patients With HR-Positive, HER2-Negative Advanced Breast Cancer (VIKTORIA-2) (clinicaltrials.gov) - P3 | N=674 | Not yet recruiting | Sponsor: Celcuity Inc

New P3 trial • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • PIK3CA

Design, synthesis, and pharmacological evaluation of triazine-based PI3K/mTOR inhibitors for the potential treatment of non-small cell lung cancer. (PubMed, Eur J Med Chem) - "Importantly, compared to the lead compound PKI-587, 5nh demonstrated significant inhibitory activity against non-small-cell lung cancer (NSCLC) cell lines, particularly HCC-827, with a 43-fold increase (3.5 nM vs 150 nM)...Importantly, the in vivo efficacy study demonstrated that orally treatment of 5nh led to significant tumor growth suppression, with a TGI value of 84.4 %. Collectively, our systematically medicinal chemistry campaigns suggested that 5nh, a novel oral available triazine derivative, held promise as a candidate for therapy of NSCLC by targeting the PI3K/AKT/mTOR cascade."

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

Different effects of gedatolisib versus single-node PI3K/AKT/mTOR pathway inhibitors on breast cancer cell metabolic functions (SABCS 2024) - "Background: Currently approved treatment options for patients with HR+/HER2- advanced breast cancer include single-node PI3K/AKT/mTOR (PAM) inhibitors, such as everolimus (mTORC1), capivasertib (AKT), and alpelisib (PI3Kα), in combination with hormonal therapy. By targeting multiple PAM pathway nodes, gedatolisib, inhibited cancer cell metabolic functions more effectively relative to more narrowly targeted PAM inhibitors. A more comprehensive inhibition of PAM-controlled functions, including critical metabolic functions required to sustain cancer cell proliferation, may explain the greater activity of gedatolisib relative to single node PAM inhibitors in breast cancer cells. Gedatolisib has previously demonstrated promising preliminary clinical efficacy and safety data in combination with hormonal therapy in advanced breast cancer."

Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • HER-2 • PIK3CA • PTEN

Gedatolisib Plus Fulvestrant With or Without Palbociclib vs Standard-of-Care for the Treatment of Patients With Advanced or Metastatic HR+/HER2- Breast Cancer (VIKTORIA-1) (clinicaltrials.gov) - P3 | N=701 | Recruiting | Sponsor: Celcuity Inc | Trial completion date: Sep 2026 ➔ Dec 2026 | Trial primary completion date: Sep 2024 ➔ Mar 2025

Metastases • Trial completion date • Trial primary completion date • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2 • PGR • PIK3CA