Gedatolisib

Shows activity

Also known as:

PKI-587 PF-05212384

Cancer types include:

breast cancer cervical cancer head and neck cancer ovarian cancer pancreas cancer

HealthScout AI Analysis

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Overview

Gedatolisib (PF-05212384; PKI‑587) is an investigational, intravenous dual inhibitor of class I PI3K isoforms and mTOR complexes 1/2 being developed primarily for hormone receptor–positive, HER2‑negative (HR+/HER2−) advanced breast cancer and other solid tumors. Early first‑in‑human work established a weekly dosing schedule with a manageable toxicity profile, and subsequent studies have explored combinations with endocrine therapy, CDK4/6 inhibitors, chemotherapy, PARP inhibitors, and other agents. (pubmed.ncbi.nlm.nih.gov)

Mechanism of action

Gedatolisib potently inhibits all four class I PI3K isoforms (p110α/β/γ/δ) and mTORC1/2, aiming to produce comprehensive blockade of PI3K/AKT/mTOR signaling and limit adaptive resistance seen with single‑node inhibitors. Preclinical work in breast cancer models showed greater anti‑proliferative and cytotoxic activity versus alpelisib (PI3Kα), capivasertib (AKT), or everolimus (mTORC1), irrespective of PAM‑pathway mutational status. (pubmed.ncbi.nlm.nih.gov)

Efficacy

First‑in‑human phase I (advanced solid tumors): Preliminary antitumor activity was observed with two confirmed partial responses and one unconfirmed PR; eight patients had stable disease >6 months. (pubmed.ncbi.nlm.nih.gov)
Phase I dose‑escalation with carboplatin/paclitaxel (advanced solid tumors; majority ovarian): ORR 65% overall and 80% in clear cell ovarian cancer; recommended phase II dose established. (pubmed.ncbi.nlm.nih.gov)
Phase 1b expansion in HR+/HER2− metastatic breast cancer (gedatolisib + palbociclib + endocrine therapy): Reported median PFS 12.9 months and ORR 63% after prior CDK4/6 inhibitor plus aromatase inhibitor; activity observed regardless of PIK3CA mutation status. (Abstract data.) (ascopubs.org)
Phase I combinations in breast cancer:
Gedatolisib + cofetuzumab pelidotin (metastatic TNBC/ER‑low): ORR 16.7%, clinical benefit at 18 weeks 27.8%, median PFS 2.0 months. (pubmed.ncbi.nlm.nih.gov)
Gedatolisib + talazoparib (advanced TNBC or BRCA1/2+, HER2−): ORR 12%, median PFS 2.5 months; did not meet prespecified efficacy threshold. (pubmed.ncbi.nlm.nih.gov)
Phase 3 (VIKTORIA‑1) topline, PIK3CA wild‑type cohort (HR+/HER2− ABC after CDK4/6i + AI):
Gedatolisib + palbociclib + fulvestrant: HR for progression or death 0.24 (95% CI 0.17–0.35), median PFS 9.3 vs 2.0 months vs fulvestrant.
Gedatolisib + fulvestrant: HR 0.33 (95% CI 0.24–0.48), median PFS 7.4 vs 2.0 months.
These are company‑reported topline results; full peer‑reviewed data are pending. (celcuity.com)

Ongoing/Planned phase 3: VIKTORIA‑2 (first‑line HR+/HER2− ABC, endocrine‑resistant) is randomizing fulvestrant + investigator’s‑choice CDK4/6 inhibitor with or without gedatolisib; first patient dosed July 24, 2025. (aacrjournals.org)

Safety

Class‑consistent adverse events observed across studies include stomatitis/mucositis, nausea, hyperglycemia, fatigue, decreased appetite, transaminase elevations, and myelosuppression when combined with chemotherapy. In the first‑in‑human study, the most common treatment‑related AEs were stomatitis (58%), nausea (43%), hyperglycemia (26%); grade 3 treatment‑related AEs occurred in 24% at the MTD (154 mg weekly), with no treatment‑related grade 4–5 events. (pubmed.ncbi.nlm.nih.gov)
With carboplatin/paclitaxel, frequent grade ≥3 events included neutropenia (35%), anemia (18%), and mucositis (12%); dose‑limiting toxicities informed the recommended phase II dose. (pubmed.ncbi.nlm.nih.gov)
In early HR+/HER2− breast cancer combinations, abstracted results describe a manageable profile with low discontinuation rates; company‑reported VIKTORIA‑1 topline notes lower discontinuations and lower rates of hyperglycemia and stomatitis versus earlier phase data, pending full disclosure. (ascopubs.org)

Additional notes

Pharmacokinetics: Weekly IV dosing shows biphasic PK with half‑life ~30–37 hours after multiple dosing. (pubmed.ncbi.nlm.nih.gov)
Potential resistance: Overexpression of efflux transporters (ABCB1/ABCG2) has been implicated in reduced cellular efficacy in preclinical models. (pubmed.ncbi.nlm.nih.gov)

Active trials using Gedatolisib

Found 4 active trials using this drug:

A Phase 1/2, Open-Label, Randomized, Dose Finding and Dose Expansion Study of Gedatolisib in Combination With Darolutamide in Metastatic Castration-Resistant Prostate Cancer (mCRPC)

Sponsor: Celcuity Inc (industry) Phase: 1/2 Start date: Jan. 1, 2024

HealthScout AI summary: Men with progressive metastatic castration‑resistant prostate adenocarcinoma after one next‑generation AR pathway inhibitor, ECOG 0–1, receive gedatolisib (investigational pan‑class I PI3K/mTORC1/2 inhibitor) plus darolutamide. Excludes prior PI3K/AKT/mTOR therapy or mCRPC chemo/radiopharmaceuticals; continued ADT required.

ClinicalTrials.gov ID: NCT06190899

Phase 3, Open-Label, Randomized, Study Comparing Gedatolisib Combined With Fulvestrant & With or Without Palbociclib to Standard-of-Care Therapies in Patients With HR-Positive, HER2-Negative Advanced Breast Cancer Previously Treated With a CDK4/6 Inhibitor in Combination w/Non-Steroidal Aromatase Inhibitor Therapy

Sponsor: Celcuity Inc (industry) Phase: 3 Start date: Dec. 8, 2022

HealthScout AI summary: This trial enrolls adults with HR-positive, HER2-negative advanced or metastatic breast cancer who have progressed on prior CDK4/6 inhibitor plus non-steroidal aromatase inhibitor therapy, excluding those with prior PI3K/AKT/mTOR inhibitor or chemotherapy for advanced disease. Patients are randomized to gedatolisib (a pan-PI3K/mTOR inhibitor) plus fulvestrant with or without palbociclib versus standard-of-care options (fulvestrant alone or alpelisib plus fulvestrant, depending on PIK3CA mutation status).

ClinicalTrials.gov ID: NCT05501886

RESOLVE: letRozole abEmaciclib combinationS in endOmetriaL and oVarian cancEr: A Multi-Cohort Phase 2 Study of Letrozole/Abemaciclib Alone and in Combination With Metformin, Zotatifin and Gedatolisib

Sponsor: Dana-Farber Cancer Institute (other) Phase: 2 Start date: Dec. 24, 2018

HealthScout AI summary: Adults with recurrent/metastatic or treatment‑resistant endometrial cancer (primarily ER+) or low‑grade serous ovarian/fallopian tube/peritoneal carcinoma (ER+ preferred; ER‑ allowed in LGSOC) receive abemaciclib with letrozole, alone or combined with agents targeting PI3K/mTOR/DNA‑PK (samotolisib/LY3023414), pan‑class I PI3K/mTORC1/2 (gedatolisib), translational control via eIF4A (zotatifin), or metabolic/AMPK pathways (metformin). Most cohorts require ECOG 0–1, measurable disease, adequate organ function, and endocrine sensitivity markers; one cohort allows prior CDK4/6 inhibitor exposure.

ClinicalTrials.gov ID: NCT03675893

Phase I 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

Sponsor: Dana-Farber Cancer Institute (other) Phase: 1 Start date: Feb. 28, 2017

HealthScout AI summary: Adults with metastatic or unresectable solid tumors, including expansion cohorts for squamous NSCLC, pancreatic cancer, head and neck SCC (non-oropharynx or HPV− oropharynx), or tumors with PI3K-pathway alterations (e.g., PIK3CA mutation/amplification or PTEN loss). Patients receive oral palbociclib (CDK4/6 inhibitor) D1–21 q28d plus weekly IV gedatolisib, a pan–class I PI3K and dual mTORC1/2 inhibitor.

ClinicalTrials.gov ID: NCT03065062