A Phase I Clinical Trial: Binary Therapy with DM-CHOC-PEN and WBRT in Adults with Cancer Involving the CNS

The goal of this Phase I clinical trial will be to document safety and potential usefulness ofdemethylcholesteryloxycarbonylpenclomedineDM CHOC PENin combination with de escalating doses of whole brain radiation therapyWBRTas binary therapy in subjects with advanced cancer involving the CNSa Phase I clinical trialDM CHOC PEN is a polychlorinated pyridyl cholesteryloxycarbonatewhich has completed Phase I II clinical trials in adults with advanced cancer involving the CNSObjective responsesimproved PFS OS and acceptable toxicities have been observed primarily in lung and breast cancersmelanoma and sarcoma malignancies involving the CNSThe incidence of metastatic cancer involving the CNS was rtcases in the US alone inrttimes the incidence of high grade GBMThe four most common tumor types to develop CNS metastases were lung rt breast rt melanoma rt renal cellwith median survival worse than those reported for primary CNS malignanciesmonths vsmonths for GBMRadiationRTis still the main stay of treatment in the manage of CNS metastases since the presentation is often multi focalsurgery is not attempted and most chemotherapeutic agents do not cross the blood brain barrierBBBHoweverresponses to whole brain radiationWBRTand stereotactic radiosurgerySRSstandard of careare of a short interval and associated with CNS side effectsTodatethe responsestolerance and safety observed in those subjects with cancers involving the CNS that were treated with the drugsupport the use of the proposed combinationDM CHOCPENan alkylating agent may also prevent DNA repair plus sensitize micrometasteses to radiationFivesubjectsNSCLC andsarcoma involving the CNS from the Phase I II trials received radiationRTpost DM CHOC PEN therapy without toxicitysubjectNSCLCwas treated twice and now a CRall have had excellent long term responsesPlussupport is presented that the drug accumulates in cancers involving the CNSas well as potentiates radiation effects in human lung cancerA critical component in designing an agent to cross the protective BBB is selecting one that will be readily transported intracerebrallydoes not produce local irritation and is not rejected back into the general circulationDM CHOC PEN satisfies these requirespenetrates the BBBplus is not a substrate for the transporter protein P glycoproteinP gpand not recycled out of the CNSNo neuropsycho performance alterations or neuro adverse events have been attributed to the drug in either the animal studiesor in any of the adult subjects treatedDM CHOC PEN s MOA is via bis alkylation of DNAforms adducts with Nguanine and Ncytosinewith no hematological renal toxicities observedthus the combination should be compatiblehowever will be monitored closelyThe specific objectives of the Phase I study will be toConduct a Phase I clinical trial with the binary combinationDM CHOC PEN plus de escalatingdoses of WBRTin adults with advanced cancer involving the CNS to document safetytoxicitiesdefine acceptable minimal effective dosesMEDfor the WBRTStudy the pharmacokinetic dynamic profiles for DM CHOC PEN and metabolites in the presence of WBRT in adults with advanced NSCLC adenocarcinoma involving the CNSMonitor and document any anticancer activity for the binary therapyanalyze data and prepare a binary Phase II clinical trial in subjects with cancers involving the CNSINDDrsT MahmoodP FriedlanderRS WeinerM BarnhillMH HaymanML WareE Zakris and M Mehta will be the coop clinical trial center directorsThey are well established clinical investigatorsa combination of medicalradiation and neuro oncologistsmost of whom were involved in the Phase I IItrials with DM CHOC PEN and are well qualified to co direct this binary trialConsultants are identified in the Relevant Experience SectionPlusthe FDA supports the proposed Phase I binary study