An estimated 15% of solid tumors, including some non-small cell lung (NSCLC), esophageal, bladder, liver, kidney and colon cancers, have a genetic alteration that causes them to lack expression of the enzyme methylthioadenosine phosphorylase (MTAP).
Under the leadership of investigator Guru Sonpavde, MD, AdventHealth’s Clinical Research Unit (CRU), a collaborative between the AdventHealth Cancer Institute and AdventHealth Research Institute, is participating in a new Phase I clinical trial to evaluate the safety, pharmacokinetics (PK), pharmacodynamics (PD) and anti-tumor activity of a novel therapy called IDE397 to treat MTAP-deficient tumors.
The study will evaluate the therapy both as a single agent and in combination with docetaxel, paclitaxel, gemcitabine/nab-paclitaxel and pemetrexed in adult patients with selected advanced or metastatic MTAP-deleted advanced solid tumors who are unresponsive to standard of care therapy or for whom no curative therapy is available.
Several studies have demonstrated that some kinds of cancers demonstrate abnormal expressions of MAT2A, a metabolic enzyme responsible for the production of S-adenosyl-L-methionine (SAM), a primary donor of methyl groups in cellular transmethylation reactions that regulate gene expression, cell growth and differentiation. Researchers believe inhibition of MAT2A may impede proliferation in MTAP-deleted cancers that rely heavily on SAM synthesis. Taken orally, IDE397 is designed to target, bind to and inhibit the activity of MAT2A.
“With this new trial, we are taking a targeted, precision medicine approach to fighting the cancer,” explains Dr. Sonpavde. “Similar to how PARP inhibitors can control cancers harboring BRCA1 and BRCA2 gene variants in breast, ovarian, pancreatic and prostate cancers, we know from laboratory studies that MTAP-deficient tumors have a specific mutation that may make the cancer cells more sensitive to IDE397 without harming normal, healthy cells.
This increase in vulnerability to specific therapies in the presence of certain gene alterations is termed ‘synthetic lethality.’ The MTAP alteration is identified on tumor tissue using next generation sequencing (NGS) genomics testing. Full inclusion and exclusion criteria for the IDE397 clinical trial can be viewed here.
Additional CRU Phase I trials are also currently open or opening soon that advance new treatments across many different cancers using the principles of precision medicine. Examples include the following:
- A new FGFR3 targeting drug (LOXO-435 [LY3866288]) for those with FGFR3 mutations or amplifications in the cancer
- An antibody drug conjugate (CPO301) targeting EGFR (epidermal growth factor receptor) in adult patients with advanced or metastatic solid tumors
- An antibody drug conjugate (SGB B7H4V) to target cancers known to over-express the B7H4 protein
- A SMARCA2 degrader PROTAC class of agent (PRT3789) for those with SMARCA4 alterations in the cancer
- A new Nectin-4 targeting peptide-toxin complex (BT8009) for those with Nectin4 expressing cancers
- A second-generation PARP1 inhibitor (IMP1734) to target cancers with BRCA1, BRCA2, PALB2 and RAD51 mutations
Established in the fall of 2020 and located on the campus of AdventHealth Celebration, the CRU continues to grow, providing patients with advanced cancers access to Phase I clinical trials of novel treatment options, including immunotherapies, targeted therapies, therapeutic oncolytic viruses and antibody drug conjugates. While Phase I trials are primarily designed to test the safety and observe preliminary evidence of efficacy of new cancer treatments which require confirmation in future Phase II and III trials, early signs of efficacy can benefit some patients on Phase I trials. The CRU treated a patient diagnosed with colon cancer with rapid progression, including liver and lung metastases, after chemotherapy and anti-angiogenic therapy. He consented to participate in a Phase I trial investigating a novel inhibitor of a tumor environment protein and a PD1 inhibitor immunotherapy.
“The patient exhibited significant tumor response with a more than 60% decrease in size and is continuing to receive and benefit from therapy for over 18 months,” shares Dr. Sonpavde. “Indeed, almost all the current FDA-approved treatments for cancers were evaluated initially in Phase I trials. Participation in these trials expedites new drug discovery and should be considered a standard of care, perhaps even a preferred standard of care for eligible patients.”
Dr. Sonpavde or Lindley Mosqueda, APRN, can rapidly screen patients for eligibility to any CRU clinical trials and provide prompt appointments, including televisits if necessary, for patient convenience.