Originally published Oct. 28.
NEW YORK (GenomeWeb) – Arno Therapeutics recently presented data from an ongoing Phase I/II dosing trial involving its lead compound onapristone in men with advanced castration-resistant prostate cancer (CRPC).
In CRPC, Arno is conducting a randomized Phase I/II open label trial looking at five doses (10 mg to 50 mg twice daily) of onapristone. The hormone blocker is Arno's lead product and is designed to block activation of the progesterone receptor that many tumors depend on to grow and advance.
The first stage of the Phase I/II study will focus on dose selection and the second will enroll an expanded cohort into the selected Phase II dose to establish the safety and gauge initial efficacy profile of the drug. In the first stage, researchers are studying the progesterone receptor expression of tumor biopsies from patients at baseline, and Arno presented preliminary data in this regard at the annual Prostate Cancer Scientific Retreat in California last week. Out of 45 CRPC specimens tested at baseline, nearly 29 percent had PR expression, while 4 percent had "strong PR expression," Arno reported.
Arno is hoping to use PR expression as a way to gauge best responders to onapristone. "As PR expression in prostate cancer has been reported to increase in CRPC specimens, the transcriptionally activated PR offers a potential biomarker target in advanced CRPC," the company said in a statement. The company has licensed from the University of Minnesota technology related to a gene signature that will enable it to detect activated progesterone and develop a companion test for gauging best responders to onapristone.
Out of 14 patients screened as part of the study to date, 11 have been enrolled in the trial and are receiving onapristone. Researchers have not identified any dose limiting toxicities or liver function test abnormalities at the first two dose levels of 10 mg or 20 mg twice a day.
Patients experienced adverse events such as fatigue, constipation, and low sodium levels; one patient displayed aggressive behavior and another had grade 4 central retinal artery occlusion 14 days after stopping treatment. Arno researchers believe these AEs to be "unrelated to onapristone." There were six patients who reported drug related AEs but all were grade 1 (not serious).
Based on this, an independent data review committee has given Arno the green light to move on to the escalation portion of the study and investigate the next three doses of onapristone, at 30 mg, 40 mg, and 50 mg twice a day. Additionally, Arno said it is refining the companion diagnostic that will gauge activated PR levels and the firm is hoping the test will be able to identify 75 percent of patients at the Phase II recommended dose as biomarker positive.
In a separate announcement, Arno said that the onapristone program in progesterone receptor-expressing tumors in women has advanced from Phase I and now the company will begin enrolling patients – primarily women with gynecologic tumors – at the recommended Phase II dose of 50 mg extended release twice daily.
The company to date has enrolled 48 heavily pretreated patients in the Phase I study, 28 with gynecologic malignancies and 19 with breast cancer. The data so far suggest the drug is well tolerated in these patients. Although three patients experienced grade 3 liver toxicities, these adverse events weren't drug related an independent safety review committee has determined.
Now, 15 patients from the dose escalation portion of the trial are still receiving onapristone; five patients have been on the study for less than eight weeks and haven't yet had their first disease assessment evaluations. Out of 43 evaluated patients, one with serous ovarian cancer on the 10 mg twice daily dose of the extended release formulation experienced a durable and ongoing partial response of 24 weeks. Additionally, five patients with gynecologic tumors and two with breast tumors have had stable disease for more than 16 weeks.