For patients with pheochromocytoma-paraganglioma and desmoplastic small round cell tumors, there are a few treatment options, including targeted and non-targeted, systemic chemotherapies for tumors that are unresectable or have metastasized. But most of the drugs used come with high risk of side effects and other toxicities. A new drug, ONC201, may be a better option. It's an imipridone heterocyclic small molecule that is a dopamine-like receptor (DRD2) antagonist/caseinolytic protease P agonist.
Data from The Cancer Genome Atlas shows that pheochromocytoma-paragangliomas have the highest expression of DRD2 by far compared with other cancers, explained researcher Peter Anderson, MD, PhD, Professor and Pediatric Oncologist at Cleveland Clinic Children's. So Anderson's group designed a clinical trial to evaluate whether the new drug helped patients with these rare tumors, as well as for patients with desmoplastic small round cell tumors and some other neuroendocrine tumors.
The data, published online in the journal Clinical Cancer Research, revealed the drug was well-tolerated with a low toxicity profile and improved outcomes for patients with both types of neuroendocrine tumors (2022; doi: 10.1158/1078-0432.CCR-21-4030).
"What patients want and need is a drug that works with very little side effects," Anderson, the principal investigator for the trial, told Oncology Times in an interview. "And that's what we showed in this study."
Study Details
The investigator-initiated Phase II clinical trial included 30 patients with recurrent and/or metastatic neuroendocrine tumors, including pheochromocytoma-paraganglioma, desmoplastic small round cell tumors, and other neuroendocrine tumors with a catecholamine or dopamine biomarker or paracrine dependence on dopamine, including medullary thyroid carcinoma, clear cell sarcoma, neuroblastoma, cholangiocarcinoma, and adrenocortical carcinoma.
There were other inclusion criteria for normal organ function, including hemoglobin count, neutrophil count, and platelet count, among a few others. The trial was originally only for patients 18 years old and older, but was expanded to patients who were 14 years or older when additional data became available for people in that age group.
Patients were either given 625 mg orally of ONC201 once a week (cohort A included only patients with pheochromocytoma-paraganglioma and cohort B included patients with other neuroendocrine tumors, or the same dose for 2 consecutive days weekly in cohort C).
The primary endpoint of the Phase II trial of ONC201 was radiographic response using RECIST criteria. Secondary endpoints included progression-free survival, overall survival, and safety. The data revealed that five of the 10 patients in cohort A had a partial response to the drug and two of the patients had stable disease after 3 months. Five patients continued the drug for over a year (median duration of continuation of the drug for cohort A was 9 months).
Cohort B included 12 patients. One patient had a partial response and two patients had stable disease for longer than 3 months. Median duration of therapy for patients in cohort B was 3 months. For cohort C (eight patients), one patient had a partial response and seven had stable disease for more than 10 months. Average duration of therapy for the cohort was longer than 10 months.
Over the course of the trial, no dose modification due to treatment-related adverse events was needed. Side effects of ONC201 were mild and infrequent. Almost all patients reported minimal if any difference in activity or function on the day of ONC201 dosing for both the schedules that included once per week and the 2 consecutive days per week.
Compared to other drugs used to treat these tumors, Anderson noted that the difference in side effect profiles is "night and day." Patients on the drug could go to school, work, and on vacations. They didn't experience low blood cell counts, they didn't require blood transfusions, and they didn't experience neutropenia. Compared to mTOR inhibitors, which are sometimes used for these tumors, there was no mucositis. Compared to VEGF inhbitors, there were no gastrointestinal symptoms, like diarrhea, abdominal discomfort, or weight loss.
Because of the low toxicity profile, Anderson said the drug may be a good one to consider using in combination therapy regimens. Used in combination, the treatment might yield even better results for the patient than either drug used alone, he noted. "Most of our most effective regimens are indeed combination regimens. It's just painfully hard and long to get there."
Testing ONC201
The next steps for ONC201 and determining its best use for patients with rare neuroendocrine therapy will be testing the drug in patients earlier in the course of their disease, rather than using it as third-, fourth-, or fifth-line treatment, Anderson noted. It will likely be important to determine the best surrogate endpoints to better evaluate the drug for these patients, he said, as overall survival and even disease-free survival can take a long time to evaluate. Looking at things like circulating DNA in blood or using dotatate PET/CT imaging may prove useful.
Anderson hopes patient groups hear and organize around this drug. As with any rare tumor or disease, accruing enough patients on clinical trials will be a challenge. But if enough patients hear about the drug and the ongoing trials, that will help. When patients and patient advocacy groups are involved from the beginning, that can also help with designing these trials in ways that are more acceptable to the patients, he concluded.
Sarah DiGiulio is a contributing writer.
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