4-Demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN): A Phase II Clinica

DESCRIPTION (provided by applicant): The principal goal of this research project will be to evaluate 4-demethyl-4- cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN), a polychlorinated cholesterol carbonate as anticancer therapy for patients with advanced cancer in a Phase II clinical trial. During pre-clinical studies DM-CHOC-PEN produced complete remissions with long term survival vs. intracranially (IC) implanted human gliomas and breast cancer xenograft and melanoma murine models in mice. In the recentlycompleted Phase I clinical trial (that included patients with CNS involvement), the drug proved to be non-neurotoxic. Several patients - sarcoma, GBM, breast cancer (CNS lesions) have demonstrated PFS gt 6-18 mos. and one (sarcoma spread to the sine) has NED x 12+ mos. Renal, pulmonary and hematological side effects were not observed; dose limiting effect was hepatic - elevated bilirubin. Complete pharmacokinetic studies/parameters are reviewed. The clinical product is an emulsion with stability under refrigeration - 1.5 yrs. The package has been reviewed by IRBs and FDA - IND 68,876. The aims will include: 1) Initiate a Phase II trial with DM-CHOC-PEN administered IV to patients with advanced or recurrent cancer (+/- CNS involvement acceptable) and verify that the proposed dose is acceptable, monitor pharmacodynamics and toxicities. 2) Monitor tumor responses to DM-CHOC-PEN per imaging/examinations using RECIST guidelines. 3) Electronically store/analyze clinical data for toxicity, responses and tumor-organrelationships. 4) Continue to bank tumor tissue from pre- and post-treated patients when possible and assay tumor - drug/metabolite content and bio-markers; store blood samples for future studies, i.e. Caris Target Now, etc. 5) Prepare a FDA presentation for subsequent Phase II (binary drug) or III (single drug) trials with DM-CHOC-PEN in patients with specific tumor types. PUBLIC HEALTH RELEVANCE PUBLIC HEALTH RELEVANCE: DM-CHOC-PEN is a novel polychlorinated pyridine carbonate that was designedat DEKK-TEC to cross the blood brain barrier and penetrate intracranially growing cancer. The drug demonstrated impressive abilities to cross the BBB and produced CR and LTS in intracranially implanted U251 and D54 human glioblastomas and MX-1breast cancer xenograft models. The drug has now completed Phase I clinical trial studies in advanced cancer with CNS involvement. The limiting toxicity was hepatic - elevated bilirubin. No hematological, renal, pulmonary or neuro-toxicity was noted. Seventeen patients were treated and three (3) patients with CNS/PNS involvement had gt PFS6 - up to 18+ months. One (1) patient with advanced spinal sarcoma is now NED x 18+ months. The drug is to begin Phase II enrollment. The treating dose in Phase II will be 85.8 mg/m2,the MTD from Phase I and sixty (60) patients with advanced cancer (+/- CNS) will be enrolled and treated.