ly-2157299 and abemaciclib

Pancreatic ductal adenocarcinomas (PDAC) are characterized by frequent cell cycle pathways aberrations. This study evaluated safety and efficacy of abemaciclib, a cyclin-dependent kinase 4 and 6 inhibitor, as monotherapy or in combination with PI3K/mTOR dual inhibitor LY3023414 or TGFβ inhibitor galunisertib versus standard of care (SOC) chemotherapy in patients with pretreated metastatic PDAC.. This Phase 2 open-label study enrolled patients with metastatic PDAC who progressed after 1-2 prior therapies. Patients were enrolled in a safety lead-in (abemaciclib plus galunisertib) followed by a 2-stage randomized design. Stage 1 randomization was planned 1:1:1:1 for abemaciclib, abemaciclib plus LY3023414, abemaciclib plus galunisertib, or SOC gemcitabine or capecitabine. Advancing to Stage 2 required a disease control rate (DCR) difference ≥0 in abemaciclib-containing arms versus SOC. Primary objectives for Stages 1 and 2 were DCR and progression-free survival (PFS), respectively. Secondary objectives included response rate, overall survival, safety, and pharmacokinetics.. One hundred and six patients were enrolled. Abemaciclib plus galunisertib did not advance to Stage 1 for reasons unrelated to safety or efficacy. Stage 1 DCR was 15.2% with abemaciclib monotherapy, 12.1% with abemaciclib plus LY3023414, and 36.4% with SOC. Median PFS was 1.7 months (95% CI: 1.4-1.8), 1.8 months (95% CI: 1.3-1.9), and 3.3 months (95% CI: 1.1-5.7), respectively. No arms advanced to Stage 2. No new safety signals were identified.. In patients with pretreated metastatic PDAC, abemaciclib-based therapy did not improve DCRs or PFS compared with SOC chemotherapy. No treatment arms advanced to Stage 2. Abemaciclib remains investigational in patients with PDAC.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Humans; Pancreatic Neoplasms; Phosphatidylinositol 3-Kinases; Quinolones; TOR Serine-Threonine Kinases

Treatment effects were assessed using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay, western blot, cell viability, and cell cycle progression.. This study establishes the groundwork for the development of a combinatorial pharmacologic approach by using either LY2385219 or LY2157299 inhibitor plus O

Topics: Aminopyridines; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Astrocytes; Benzimidazoles; Brain Neoplasms; Cell Cycle; Cell Survival; Cells, Cultured; Cyclin D; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; DNA Modification Methylases; DNA Repair Enzymes; Drug Resistance, Neoplasm; G1 Phase Cell Cycle Checkpoints; Glioblastoma; Guanine; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Neurons; Phosphatidylinositol 3-Kinases; Pyrazoles; Quinolines; Receptor, Transforming Growth Factor-beta Type I; Smad Proteins; Temozolomide; Tumor Suppressor Proteins