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Principal Investigator: William H. Gmeiner
Organization: DEEP CREEK PHARMA, LLC
Fiscal Year: 2024
Award: $1,018,545
Funding agency: National Cancer Institute
PROJECT SUMMARY
Decades of modulating the anti-cancer activity of fluoropyrimidine drugs (FPs) thru schedule optimization,
biochemical modulation, and drug combinations have provided a significant, but limited, survival advantage for
treating colorectal cancer (CRC) patients with locally advanced or metastatic disease (mCRC). However,
outcomes remain poor for patients with mCRC and since targeted therapies and immunotherapies provide only
a limited benefit to a sub-set of CRC patients, new approaches are urgently needed. Deep Creek Pharma
together academic partner Wake Forest School of Medicine (WFSM) is developing CF10, the first DNA-based
FP polymer, as an improved treatment for CRC. In pre-clinical studies through Phase 1 STTR support, we have
demonstrated that CF10 is much more potent than 5-FU to CRC cells and demonstrated improved survival
relative to 5-FU in multiple colon tumor models in rodents. Further, CF10 displayed reduced systemic toxicities
relative to 5-FU making it a strong candidate for clinical development. We have also established CF10 displays
distinct pharmacological and mechanistic properties relative to conventional FP drugs. Based on these findings,
DeepCreek Pharma and WFSM/Gmeiner Lab propose to jointly investigate CF10 as a candidate for clinical
development.
A major unmet need is treatment of mCRC that is refractory to FOLFOX (5-FU, Leucovorin (LV), oxaliplatin), and
other front-line therapies for mCRC. The proposed research in phase II will therefore focus on (Aim 1) Developing
CF10 lipid nanoparticles (LNPs) and testing for improved activity, including in a therapy-resistant CRC liver
metastasis model. LNP formulation has proven to be a robust delivery strategy for multiple nucleic acid drugs,
and identifying a preferred LNP formulation will promote CF10 clinical development. In Aim 2 of the Phase II
studies we will perform safety pharmacology studies of CF10 and CF10:LNPs in rodents while in Aim 3 we will
evaluate pharmacokinetics (PK) and biodistribution in non-human primates (NHPs). Studies in NHPs accurately
reflect human physiology and metabolism and are particularly important for regulatory apprval. Collectively, our
Phase II STTR studies will provide critical data for to advance CF10 into clinical trials and ultimately its
commercialization.
Terms: <1-OHP><5-FU><5-Fluracil><5FU><Animal Model><Animal Models and Related Studies><Award><BNT 162b2><BNT162b2><Biochemical><Biodistribution><Cancer Model><CancerModel><Clinical><Clinical Research><Clinical Study><Clinical Trials><Clinical Trials Design><Collaborations><Colon Cancer><Colon Carcinoma><Colon Neoplasms><Colon Tumor><Colon or Rectum><Colonic Mass><Colonic Neoplasms><Colonic Tumor><Colorectal><Colorectal Cancer><Common Rat Strains><DNA><Data><Death Rate><Deoxyribonucleic Acid><Disease><Disorder><Dose><Drug Combinations><Drug Kinetics><Drugs><FDA approved><Fluoro Uracil><Fluorouracil><Fluoruracil><Fluouracil><Folinic Acid><Folinic Acid-SF><Formulation><Foundations><GI cancers><GI malignancies><GI tract cancers><Gastrointestinal Cancer><Gastrointestinal Tract Cancer><Generations><Genetic><Hepatic Neoplasm Secondary><Hepatic metastasis><Human><Immune mediated therapy><Immunologically Directed Therapy><Immunotherapy><Intermediary Metabolism><L-Leucovorin><Laboratories><Leucovorin><Leukovorum><Levofolinic acid><Levoleucovorin><Liver secondaries><Liver secondary cancer><Lung><Lung Respiratory System><Malignant Cell><Malignant Gastrointestinal Neoplasm><Malignant neoplasm of gastrointestinal tract><Medication><Metabolic Processes><Metabolism><Metastatic Neoplasm to the Liver><Metastatic Tumor to the Liver><Metastatic malignant neoplasm to liver><Mice><Mice Mammals><Modeling><Modern Man><Murine><Mus><Nucleic Acids><Outcome><Patients><Pfizer covid19 vaccine><Pfizer-BioNTech COVID-19 vaccine><Pfizer-BioNTech coronavirus disease 2019 vaccine><Pfizer/BioNTech vaccine><Pharmaceutical Agent><Pharmaceutical Preparations><Pharmaceuticals><Pharmacokinetics><Pharmacologic Substance><Pharmacological Study><Pharmacological Substance><Pharmacology><Pharmacology Study><Pharmacology and Toxicology><Phase><Physiologic><Physiological><Physiology><Polymers><Pre-clinical Drug Testing/Development><Preclinical Drug Development><Preclinical Drug Testing/Development><Preclinical Testing><Property><Rat><Rats Mammals><Rattus><Refractory><Regimen><Research><Rodent><Rodent Model><Rodentia><Rodents Mammals><STTR><Safety><Saline><Saline Solution><Schedule><Small Business Technology Transfer Research><Sterility><Testing><Therapeutic><Toxic effect><Toxicities><Toxicity Testing><Toxicity Tests><Toxicology><Translating><anticancer activity><cancer cell><cancer in the colon><chemotherapy><citrovorum><clinical candidate><clinical development><colon cancer patients><colon neoplasia><colorectal cancer patients><colorectal cancer therapy><colorectal cancer treatment><colorectum><commercialization><design><designing><disease model><disorder model><drug/agent><efficacy testing><fluoropyrimidine><gastrointestinal malignancies><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapies><immune-based treatments><immuno therapy><improved><innovate><innovation><innovative><lipid based nanoparticle><lipid nanoparticle><liver metastases><malignant liver neoplasm, specified as secondary><medical college><medical schools><metastasis in the liver><metastasis to the liver><metastasize to the liver><metastatic cancer to liver><metastatic colo-rectal><metastatic colo-rectal cancer><metastatic colo-rectal carcinoma><metastatic colon cancer><metastatic colorectal><metastatic colorectal cancer><metastatic colorectal carcinoma><metastatic liver><metastatic liver neoplasm><model of animal><mortality rate><mortality ratio><mouse model><murine model><new approaches><non-human primate><nonhuman primate><novel approaches><novel strategies><novel strategy><oxaliplatin><oxaliplatine><pharmaceutical><pharmacokinetic model><pharmacologic><phase 2 study><phase II study><polymer><polymeric><pre-clinical drug development><pre-clinical study><pre-clinical testing><preclinical study><pulmonary><resistance to therapy><resistant to therapy><school of medicine><secondary liver malignancy><secondary malignant liver neoplasm><standard of care><sterile><systemic toxicity><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic resistance><therapy resistant><treatment resistance><tumor>