New targeted therapy and immunotherapy approaches: Phase I clinical trial developments at ESMO Virtual Congress 2020
Clayton Boldt, Ph.D.
Studying new cancer therapies through clinical trials is essential for progress in cancer care. Phase I clinical trials are designed to evaluate the safety of new medicines and determine the most appropriate treatment dose. They also provide insight into how effective the treatment may be. The advances and insights gained through Phase I clinical trials plays a vital role in helping us bring the newest cancer treatments to more patients.
New drug designed to kill cancer cells and stimulate an anti-tumor immune response (Abstract 1026MO)
A Phase Ib clinical trial led by Daniel Karp, M.D., is evaluating a new therapy called PT-112 in combination with avelumab, an immune checkpoint inhibitor that blocks the PD-L1 checkpoint protein. PT-112 is a type of drug called a phosphaplatin, which works by causing a process known as immunogenic cell death.
Through this process, PT-112 kills cancer cells in such a way that causes the release of proteins that act as signals to the immune system. Those signals redirect the immune system to attack the cancer, leading to an increased anti-tumor response. By combining PT-112 with immunotherapy, the researchers hope to further stimulate the immune system and promote anti-tumor response.
Of 12 patients included in this analysis, eight had stable disease, and two patients with metastatic prostate cancer had tumor shrinkage and other positive responses.
“In a group of patients that had many previous treatments, this combination was well tolerated and showed some early signals of activity,” says Karp. “These results warrant further investigation of this regimen, which we are now studying in a Phase II trial.”
Targeted therapy improves progression-free survival in patients with gastrointestinal stromal tumors (Abstract 1623MO)
Treatment for gastrointestinal stromal tumors typically includes surgery and/or targeted therapies, particularly imatinib. However, imatinib may not be effective if the tumors have certain mutations in the KIT and/or PDGFRA genes. Ripretinib specifically blocks the activity of KIT and PDGFRA even in situations when other inhibitors are ineffective, and it was approved by the Food and Drug Administration (FDA) to treat patients with advanced gastrointestinal stromal tumors that have received more than two previous targeted therapies.
This study evaluated whether patients would benefit from increasing dosage from once to twice daily. Participating patients had at least one prior targeted therapy treatment. Each patient started by receiving once-daily therapy and were given the option to move to twice-daily therapy when their cancer progressed.
“In each trial cohort, patients received an additional progression-free survival benefit from twice-daily ripretinib with similar side effects reported,” says Janku. “Based on these encouraging results, we continue to evaluate ripretinib as a therapy for GISTs, where we have a great unmet need.”
Second-generation BRAF inhibitor shows activity in advanced cancers with BRAF mutations (Abstract 529MO)
Janku and postdoctoral fellow Mohamed Gouda, M.D., led a Phase I/II clinical trial for a new targeted therapy, PLX8394, which blocks the activity of mutant BRAF. Mutations in the BRAF gene are common in a variety of cancers, including melanoma and colorectal cancer. First-generation drugs targeting BRAF have proven effective in treating patients with BRAF mutations but can also activate other cancer-related signaling pathways in some cases. This is known as paradoxical activation.
PLX8394 has been shown not to cause this paradoxical activation and can broadly target multiple forms of mutant BRAF. The current clinical trial was designed to evaluate PLX8394 with or without a drug called cobicistat, which was given to enhance the exposure to PLX8394.
The clinical trial enrolled 69 patients with advanced cancers with BRAF mutations. Patients receiving cobicistat saw an increase in exposure to PLX8394, with corresponding improvements in response. Partial responses, or tumor shrinkage, lasting up to 56 months were seen in 10 patients.
The researchers also monitored tumor DNA found circulating in the blood, or ctDNA, during the course of treatment. The levels of ctDNA in the blood were found to be predictive of clinical outcomes: patients with detectable ctDNA had shorter periods without disease progression.
“This new generation of BRAF inhibitor has a favorable safety profile and showed encouraging activity in this early clinical trial,” says Gouda. “We hope to continue studying this approach to provide new treatment options for patients with BRAF-mutant cancers.”