An open-label phase II clinical trial of the RXR agonist IRX4204 in taxane-resistant, castration-resistant metastatic prostate cancer (CRPC).

Abstract

169 Background: IRX4204 is a potent, selective, oral small compound agonist of retinoid X receptor (RXR) nuclear receptor pathways. In preclinical studies IRX4204 synergizes with insulin-like growth factor binding protein-3, to induce apoptosis in human prostate cancer cells and was effective in reducing human prostate tumor burden in a murine xenograft model. The only prostate cancer patient in a phase I trial of IRX4204 trial manifested a sustained greater than 90% prostate-specific antigen (PSA) reduction and a PR lasting over seven months. These findings led to the current open label phase II trial of IRX4204 to evaluate safety and activity or futility, for treatment of advanced castration-resistant metastatic prostate cancer (CRPC). Methods: The trial enrolled 23 men with metastatic CRPC, who had failed a taxane or declined chemotherapy, with ECOG 0-2 with evidence of biochemical or radiographic progression on bone scan, CT and/or MRI. Patients continued with androgen blockade and had to have adequate organ function. Patients were deemed to have demonstrated benefit of IRX4204 treatment if they had PFS greater than 56 days, and/or a 50% PSA decrease, and/or PR or CR by RECIST. Futility defined as four or fewer patients demonstrating benefit in the planned enrollment of 37 patients. Patients received IRX4204 (20 mg/orally daily). PSA was checked Q4 weeks and radiographic assessments Q8 weeks. Radiographic, not PSA progression, was used to determine progression. Results: IRX4204 was well tolerated for up to 11 months. No drug related serious adverse events (SAE) have occurred. Manageable decreases in the thyroid-stimulating hormone (TSH) and increases in triglycerides, both known adverse effects of RXR agonists, have been observed. Protocol defined patient benefit was observed in 13 out of 23 (57%) patients. Progression-free survival (PFS) more than 56 days observed in 13 out of 23 (57%). PFS more than 112 days observed in 9 out of 23 (39%), range 113 to 330 days. PSA 50% response occurred in 3 out of 23 (13%), including one additional PSA 90% response. No objective responses have occurred. Conclusions: This study demonstrates that IRX4204 treatment of taxane-resistant CRPC is well tolerated, and provides an activity signal warranting further evaluation of IRX4204 as a treatment for chemo-refractory CRPC. Funding: Supported by Io Therapeutics, Inc. 1805 East Garry Ave., Suite 110, Santa Ana, 92705. Clinical trial information: NCT01540071.

Targeting nuclear hormone receptors for the prevention of breast cancer

“…Similarly, the fourth generation rexinoid IRX4204 was shown to prevent mammary carcinogenesis in the ER-negative MMTV-neu mouse model with demonstrated effects on the activity of RAW264.7 macrophage-like cells ( 159 ). Neither LG100268 or IRX4204 have been explored in clinical trials for breast cancer treatment or prevention but IRX4204 has been tested for the treatment of taxane-resistant, castration-resistant metastatic prostate cancer with no reported serious adverse events ( 160 ).…”

Promoting remyelination in multiple sclerosis: Current drugs and future prospects

“…48 As the molecule has already been studied in prostate cancer patients without serious adverse effects, an open-label phase II clinical trial of IRX4204 in taxaneresistant, castration-resistant metastatic prostate cancer (CRPC) is currently in preparation. 49 Olesoxime Yet another potential candidate with promise for use as a remyelination therapy is olesoxime (cholest-4-en-3-one, oxime; TRO19622), a cholesterol-like small-molecule compound. Initially, olesoxime was discovered to play a role in promoting motor neuron survival in an animal model of amyotrophic lateral sclerosis (ALS).…”