A Phase II Study of Abemaciclib As a Monotherapy and in Combination with Other Agents in Patients with Previously Treated Metastatic Pancreatic Ductal Adenocarcinoma (PDAC).

TPS4150 Background: PDAC is a lethal tumor with unusual resistance to cytotoxic and targeted therapies, and pathogenesis frequently associated with hyperactive CDK 4&6 signaling. Pre-clinical models have demonstrated anti-proliferative activity with CDK 4&6 inhibitors alone, however, synergistic effects have been observed when combined with a PI3K/mTOR or TGF- βR1 inhibitor. Abemaciclib is a selective inhibitor of CDK 4&6 with an acceptable safety profile in clinical studies.This study will evaluate the safety and efficacy of abemaciclib alone or in combination with LY3023414, a PI3K/mTOR dual inhibitor, or galunisertib, a TGF-βR1 inhibitor, versus standard of care (SOC) in pateints (pts) with metastatic PDAC. Methods: Design: Study JPCJ is an adaptive, open-label, randomized, Phase 2 study in pts with previously treated metastatic PDAC. Pts will be stratified based on number of prior systemic therapies (1 or 2), and in Stage 1 (25 pts/arm) will be randomized in a 1:1:1:1 ratio to 4 treatment arms: abemaciclib; abemaciclib+LY3023414; abemaciclib + galunisertib; SOC treatment gemcitabine or capecitabine. Investigational arms demonstrating evidence of disease control rate (DCR) comparable to or better than the SOC will advance to Stage 2 (additional 50 pts/arm). Eligibility: Pts must have metastatic PDAC with disease progression following 1 or 2 prior lines of therapy, measurable disease, ECOG PS ≤1, no prior treatment with any CDK 4&6, TGF-β, or PI3K and/or mTOR inhibitors, no severe cardiac disorders, and must not have insulin-dependent diabetes. Objectives: The primary endpoint is to evaluate the DCR (Stage 1) and progression-free survival (PFS [Stage 2]). Secondary objectives include response rate, overall survival, safety, pharmacokinetics, biomarkers related to the CDK 4&6 pathway, and quality of life. Statistics: Assuming a hazard ratio of 0.65 in PFS (median PFS of 2.3 months in abemaciclib containing arms vs. 1.5 months in the SOC arm), the study has approximately 76% power to detect superiority of the abemaciclib-containing arm using a 2-sided log-rank test at 0.10 significance level. Accrual began on 01/12/2017. Clinical trial information: NCT02981342.