Rare Disease Report

Treatment for Ultra-Rare Neuroendocrine Cancers Shows Efficacy in Phase 2 Trial

JUNE 05, 2018
Krista Rossi
At the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting, Progenics Pharmaceuticals, Inc presented updated overall survival data from the company’s pivotal Phase 2 trial of its targeted, high-specific-activity radiotherapeutic candidate, iobenguane I 131 (AZEDRA), in patients with malignant, recurrent, or unresectable pheochromocytoma and paraganglioma (pheo/para).

The data was presented by the trial’s lead investigator Dr Daniel Pryma, associate professor of Radiology & Radiation Oncology and chief of the division of Nuclear Medicine & Clinical Molecular Imaging at the Perelman School of Medicine at the University of Pennsylvania.

Iobenguane I 131 is a high-specific-activity radiotherapeutic. It is a substrate for norepinephrine reuptake transporter, whichis highly expressed on the cell surfaces of neuroendocrine tumors. Pheochromocytoma and paraganglioma are rare neuroendocrine tumors that originate from autonomic nervous system cells.

“This pivotal study, the largest prospective clinical trial in pheochromocytoma and paraganglioma to date, has demonstrated multiple clinical benefits of AZEDRA treatment, which has translated into impressive overall survival data in this highly pre-treated and advanced patient population,” commented Dr Pryma, in a recent statement. "The primary cause of death in pheo/para patients is tumor progression. In this study, 98% of patients who received two doses experienced stable disease or better as measured by Response Evaluation Criteria In Solid Tumors (RECIST).” 

“In addition, 30% of pheo/para patients die from complications due to catecholamine-associated hypertension, while patients treated with iobenguane I 131 were able to achieve control of catecholamine-associated hypertension and a sustained reduction of antihypertensive medications,” he added. “These benefits were correlated with a robust tumor biomarker response. With no approved therapies in the United States for pheo and para, iobenguane I 131 has the potential to offer a meaningful treatment option for patients with these life-threatening tumors.”

Under a Special Protocol Assessment (SPA) with the US Food and Drug Administration (FDA), the pivotal phase 2 open-label, multi-center trial was conducted. The study’s primary endpoint-evaluating the proportion of pheochromocytoma and paraganglioma patients who achieved a 50% or greater reduction of all antihypertensive medication for at least 6 months served as the primary endpoint—was met. The key secondary endpoints consisted of evaluating the proportion of patients with overall tumor response as measured by RECIST; results were favorable here as well.

Partial response or stable disease was achieved by 92.2% of patients treated with at least one therapeutic dose of iobenguane I 131 achieved a confirmed partial response or stable disease by 12 months. Furthermore, iobenguane I 131 was found to be safe and well-tolerated.

As of December 4, 2017, the median overall survival time was 37 months from the first iobenguane I 131 therapeutic dosing in the study population as a whole, and 44 months among patients who were administered 2 therapeutic doses as compared with 18 months among patients who were only administered 1 therapeutic dose.

Additionally, the potential for iobenguane I 131 to extend survival in patients with liver or lung metastasis, which is generally considered in the literature to be less than 24 months, was implied in the study’s data. A similarity in the median survival time was also observed in patients with lung or liver metastasis compared with those without (43 vs. 41 months).

“These data, which are the basis of our New Drug Application, show that AZEDRA has the potential to address the dual goals of therapy in pheo and para – to reduce the cardiovascular symptoms associated with the excess hormone production, and to produce favorable tumor responses,” Mark Baker, chief executive officer of Progenics said in a recent statement. “We are eagerly anticipating the FDA’s decision on AZEDRA, as we believe it has the potential to be a breakthrough treatment option for patients with these deadly, ultra-rare neuroendocrine cancers.”

Long-term follow-up of the participants will continue.

Previous to these findings, the FDA granted Orphan Drug designation, Fast Track status, and Breakthrough Therapy designation to iobenguane I 131. A phase 2 pivotal study has been completed in patients with malignant, recurrent, or unresectable pheochromocytoma and paraganglioma under a Sales and Purchase (SPA) agreement with the FDA. 

The FDA has also granted Priority Review of the submitted New Drug Application and has set an action date of July 30, 2018 under the Prescription Drug User Fee Act.

Currently, there are no FDA-approved therapies for pheochromocytoma and paraganglioma.

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