NCI-CTEP-sponsored trials have always comprised a significant component of the tri-institutional Harvard Phase 1 Program, led by Drs. Donald Kufe and Bruce Chabner. The first grant under a U01 mechanism to support these trials was awarded in 1993, with Dr. Kufe as the Harvard Principal Investigator. Three subsequent renewals carried the U01 through 2013, with a mandate to support NCI-CTEP-sponsored Phase 1 studies. At DFCI, MGH and BIDMC, this grant also supported a limited number of Phase 2 studies.
Under the U01 grant, DF/HCC led and contributed substantially to trials of agents targeting signal transduction, angiogenesis, cell cycle, epigenetic targets, anti-apoptotic proteins and immune checkpoints. Below is a sampling of studies conducted under the U01:
- Signal Transduction: Cetuximb/Pertuzumab in colorectal cancer; ARQ197 (cMETi) in triple negative breast cancer; Vemurfanib/Cabozantinib in Melanoma; MK2206 (AKTi) in endometrial, ovarian and HER2+ breast cancer; Selumetinib (MEKi) in BRAF mutant tumors.
- Angiogenesis: Bevacizumab pharmacodynamic study; Bevacizumab + chemoradiation in rectal cancer; cediranib monotherapy in high-grade serous ovarian cancer, glioblastoma, hepatocellular cancer, head and neck cancer; Biomarker study of sorafenib in soft tissue sarcoma
- Cell Cycle: Flavopiridol trials pre-dated current agents and allowed development of pharmacodynamics markers that were used for currently approved agents; CDK2 inhibition in melanoma; trials of KSP (mitotic kinase) inhibitors
- Epigenetics: Early work on HDACs with p21Waf1/Cip1 as a biomarker
- Anti-apoptotic proteins: Early work on obataclax in CLL
- Immuno-Oncology: Trials demonstrating the utility of combining GVAX and ipilimumab in melanoma
In 2013, CTEP announced plans to establish the Experimental Therapeutics Clinical Trials Network (ETCTN) and launched a national competition for ETCTN membership. DF/HCC competed via a UM1 mechanism to become a Lead Academic Organization (LAO) within the ETCTN, and was one of 12 LAOs chosen for the conduct of NCI-CTEP early phase trials (primarily Phase 1).
Since the original 2013 award, DF/HCC has received UM1 supplements facilitating (1) expansion of the portfolio to Phase 2 trials; (2) funding of genomic analyses (targeted NextGen sequencing, whole-exome sequencing and RNA-seq) performed at the BWH Center for Advanced Molecular Diagnostics and the DFCI/Broad Institute Center for Cancer Precision Medicine; (3) collection of blood samples to be used for CTC isolation and generation of patient-derived xenograft models; and (4) development of biomarkers for DNA repair and immuno-oncology studies, as well as liquid biopsies from patients harboring EGFR mutant NSCLC.
DF/HCC has led and participated in multiple Drug Development Project Teams and routinely leads 15-20 active trials within the ETCTN, while participating in an additional 25-30 trials led by other ETCTN sites.