‘First in Human’ Trial Defines Safe Dosage for Small Molecule Drug ONC201 for Solid Cancer Tumors

Research from Rutgers Cancer Institute of New Jersey examines oral drug that targets cancer cells and spares healthy tissue
March 22, 2017

Mark Stein, MDNew Brunswick, N.J. – A ‘first in human’ clinical trial examining the small molecule drug ONC201 in cancer patients with advanced solid tumors shows that this investigational drug is well tolerated at the recommended phase II dose. That’s according to Rutgers Cancer Institute of New Jersey investigators and colleagues whose research also showed early signs of clinical benefit in patients with advanced prostate and endometrial cancers. The work appears in the ‘OnlineFirst’ section of Clinical Cancer Research (DOI: 10.1158/1078-0432.CCR-16-2658).

At focus is the investigational drug ONC201 that targets a dopamine receptor, a member of the G protein-coupled receptor superfamily residing on the surface of cancer cells, to cause their destruction. ONC201 is the first of a new family of therapeutic compounds called imipridones. Previous research on the study drug conducted by Rutgers Cancer Institute and Oncoceutics, Inc. – which is also supporting this trial – suggests that ONC201 may be capable of turning off proteins that maintain tumor growth and and may help kill cancer cells while sparing normal ones.  Pre-clinical study demonstrated ONC201 was effective in laboratory models against a number of solid tumors including colon cancer, brain cancer, triple-negative breast cancer and non-small cell lung cancer. 

In this phase I dose-escalation study, 10 patients over age 18 with advanced solid tumors that were resistant to standard therapies were enrolled through Rutgers Cancer Institute between January and July 2015. Participants received a starting dose of 125mg of the study drug, which was taken orally via capsule every 21 days (one cycle). The dosage for this cohort was increased incrementally up to a maximum dose of 625mg, which is five-fold above the dose that was effective in laboratory models. An additional 18 patients were enrolled in an expansion phase between August 2015 and February 2016 and treated at the recommended phase II dose of 625mg in order to collect additional safety, pharmacokinetic and pharmacodynamic information.

There were no drug-related adverse events over Grade 1 in either the dose escalation phase or the expansion phase. The few low grade events that were recorded (nausea, fever) were resolved quickly, note the authors.  While the study achieved the aim of identifying the recommended phase II dose of the drug, findings also showed tumor regression in patients with metastatic disease. Results also demonstrated prolonged stable disease following more than nine cycles (27 weeks) of treatment – particularly in prostate and endometrial cancer patients that had lymph node, bone and lung lesion involvement. Out of the 28 participants, 10 completed at least four cycles of treatment with two patients receiving at least nine cycles. The authors note while a 90-year old prostate cancer patient saw his primary tumor and metastatic bone lesion shrink by about 25 percent after taking two 625mg doses of ONC201, a 72-year old patient with advanced clear cell endometrial cancer had a mixed response after two doses, with multiple nodes decreasing by more than 30 percent but experiencing the development of new nodes.   

“By exploring a novel agent that targets the cancer but leaves non-cancerous tissue untouched, we have an opportunity to not only provide a new treatment option for patients who have exhausted standard forms of therapy without the typical toxicities associated with anticancer treatment, but to also offer them a therapeutic that may result in a better quality of life since healthy cells are not impacted,” notes Rutgers Cancer Institute medical oncologist Mark Stein, MD, who is an associate professor of medicine at Rutgers Robert Wood Johnson Medical School and lead investigator of the work. “While meaningful to confirm the safety profile of this dosage for ONC201, it is noteworthy that our findings also showed some evidence of clinical benefit to some patients.”

Along with Dr. Stein, other investigators include Janice M. Mehnert, Howard L. Kaufman, and Tina M. Mayer, Rutgers Cancer Institute of New Jersey and Rutgers Robert Wood Johnson Medical School; Rebecca Anne Moss, Bristol-Myers Squibb; Ann W. Silk, Nancy Chan, Lorna Rodriguez and Bruce G. Haffty, Rutgers Cancer Institute of New Jersey and Rutgers Robert Wood Johnson Medical School; Robert S. DiPaola, University of Kentucky; Tracie Saunders, Yasmeen Beckett and Ling Zheng, Rutgers Cancer of New Jersey; Wafik S. El-Deiry, Fox Chase Cancer Center; Joshua E. Allen, Martin Stogniew and Wolfgang Oster, Oncoceutics; and Joseph Bertino, Rutgers Cancer Institute of New Jersey and Rutgers Robert Wood Johnson Medical School.  

About Rutgers Cancer Institute of New Jersey
Rutgers Cancer Institute of New Jersey (www.cinj.org) is the state’s first and only National Cancer Institute-designated Comprehensive Cancer Center. As part of Rutgers, The State University of New Jersey, Rutgers Cancer Institute is dedicated to improving the detection, treatment and care of patients with cancer, and to serving as an education resource for cancer prevention both at its flagship New Brunswick location and at its Newark campus at Rutgers Cancer Institute of New Jersey at University Hospital. Physician-scientists across Rutgers Cancer Institute also engage in translational research, transforming their laboratory discoveries into clinical practice that supports patients on both campuses. To make a tax-deductible gift to support the Cancer Institute of New Jersey, call 848-932-8013 or visit www.cinj.org/giving. Follow us on Facebook at www.facebook.com/TheCINJ.

 

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