A Phase II trial of abiraterone in combination with PDMX1001 in enzalutamide-resistant prostate cancer

Project Abstract This SBIR Phase II proposal is based on our strong pre clinical data and SBIR phase I resultsand will support a Phase II clinical trial to examine the efficacy and toxicity of the combination of PDMXniclosamidewith abiraterone for the treatment of enzalutamide resistant Castration Resistant Prostate CancerCRPCand conduct molecular correlative studiesOur goal is to develop a novel treatment strategy for advanced prostate cancer by targeting both full length androgen receptorAR FLand androgen receptor variantAR VsignalingAbiraterone and enzalutamide are frequently used in treating CRPCHoweverthe response duration is usually shortand resistance to abiraterone and enzalutamide is the most common cause of treatment failureEven though both drugs are often effective initiallyafter CRPC develops resistance to one drugthe response rate to the other drug is aroundor lessConsiderable evidence from both clinical and experimental studies demonstrated that AR Vplays vital roles in induction of resistance to both drugsAR Vis not targeted by either abiraterone or enzalutamideThereforethere is urgent need to develop novel agents that target AR Vto overcome resistanceWe discovered PDMXas a potent inhibitor of AR Vand obtained extensive preclinical data showing that PDMXsynergizes abiraterone in treating CRPCBased on our previous pre clinical findingswe conducted a Phase Ib clinical trialNCTfunded by an SBIR Phase I grantRCAand confirmed that the PDMXand abiraterone combination treatment is safe and effective in CRPC patientsThe promising SBIR Phase I results lay foundation for this SBIR phase II study to conduct a single arm Phase II clinical trial to determine the efficacy and toxicity of the combination therapy of PDMXand abiraterone in enzalutamide resistant CRPC patientsWe will also conduct molecular correlative studies in these patientsThis projectif successfulis high yielding and will greatly benefit hundreds of thousands of prostate cancer patients every year Project Narrative Androgen receptor variantAR Vplays vital roles in resistance to abiraterone and enzalutamidePDMXniclosamideis a potent AR Vinhibitor and synergizes abiraterone in overcoming resistanceThis SBIR Phase II project is based on our strong pre clinical data and SBIR phase I resultsand will support a Phase II clinical trial to examine the efficacy and toxicity of the PDMXand abiraterone combination in the treatment of enzalutamide resistant CRPCand conduct molecular correlative studies