Trial and Error: Researchers Publish Findings From First UC Phase I Trial

Researchers at the University of Cincinnati College of Medicine recently published a study—their inaugural study in the Phase I Experimental Therapeutics Program first formed in 2010—which did not have favorable outcomes, but that opens the possibility for future studies which could be applicable to patient treatment one day.

"It was our first investigator-sponsored trial, but it just didn’t work out the way we hoped. However, the results of our study do highlight the critical need for consideration of biopharmaceutical properties in designing investigational agents targeting molecular pathways and drug delivery approaches to find therapeutically relevant drug combinations,” says John Morris, MD, study co-author and director of the UC Phase I Experimental Therapeutics Program.

The study, published in the journal Targeted Oncology, found that the combination of two targeted therapies which showed promise in preclinical models (human tumor samples and animal models) were not beneficial and caused a number of side effects in patients enrolled in the study.

"The development of molecularly targeted agents, small molecules or antibodies directed against specific cancer-causing targets, has transformed cancer therapy, leading to improved disease control and extended survival,” says Morris, co-leader of the UC Cancer Institute's Comprehensive Lung Cancer Program, member within the Cincinnati Cancer Consortium, professor in the division of hematology oncology and UC Health medical oncologist. "However, only a few of these agents have been successful as single agents, likely because many tumors develop alternate signaling pathways or harbor additional genetic alterations and are not driven by a single mutation. Therefore, these tumors require targeting of multiple key signaling regulators, warranting combination therapy.”

Morris says a pathway known as PI3K/AKT/mTOR has been identified as a central pathway in cell survival and proliferation in cancer, and its abnormal activation has been associated with poor patient outcomes. 

"The mTOR-stopping compound everolimus is FDA approved for the treatment of a number of cancers including kidney, pancreatic and breast, among others; however, achieving clinical responses with only everolimus is challenging, perhaps due to self-preserving processes that take effect at the molecular level,” he says. "Preclinical studies in animal and human tumor models have shown that the drug compound BEZ235 effectively inhibits growth of tumors, including glioblastoma, breast, lung, pancreatic, and prostate cancer, so we tested a combination of the two, in escalating doses for efficacy, in a Phase I trial.”

The UC Phase I program, the only program of its kind locally, offers cancer treatment options only available in an experimental clinical trial setting. These clinical research trials are the first step in moving tested scientific concepts from the laboratory bench into the clinic and are intended to evaluate safe dosages, method of administration (oral or injection) and frequency of drug administration. 

Trials typically include less than 30 people and therapy is administered in a closely-monitored setting where the patient can be observed and followed by the attending physicians and support staff.

BEZ235 was orally administered daily in escalating doses of 200, 400 and 800 mg along with everolimus at 2.5 mg daily in 28-day cycles. Nineteen patients were enrolled in the study, and adverse events and tumor responses were evaluated regularly.

Morris says unfortunately, participants experienced fatigue, diarrhea, nausea, mucositis (painful inflammation of the mouth) or elevated liver enzymes, and tumors didn’t shrink. 

Once the issues were observed, patients were put on standard therapies. 

"Sadly, this trial was not favorable for patients, but in knowing what doesn’t work, we can now try other combinations that could be beneficial. In having the Phase I program at UC, we can house trials that could be—and many which have proven to be—beneficial for patients,” he says. "There will hopefully be many more that will help treat patients living with cancer.”