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Bone Toxicity of Ipafricept Outweighed Potential Efficacy for Platinum-Sensitive Ovarian Cancer

August 26, 2019

“Overall there was a signal that ipafricept could be efficacious, but toxicities limited us from developing the drug further in Phase II or III trials,” Mantia-Smaldone said. “The Wnt pathway is still a worthwhile target for future therapy, and even this drug could be developed further if we can come up with safer dosing or a different formulation.”“Overall there was a signal that ipafricept could be efficacious, but toxicities limited us from developing the drug further in Phase II or III trials,” Mantia-Smaldone said. “The Wnt pathway is still a worthwhile target for future therapy, and even this drug could be developed further if we can come up with safer dosing or a different formulation.” PHILADELPHIA (August 26, 2019) – Ipafricept, a potentially promising drug for platinum-sensitive ovarian cancer, will not be studied further after an early clinical trial revealed increased likelihood for bone toxicity at its most efficacious doses.

Ipafricept blocks signaling of the Wnt pathway, an important oncologic driver of epithelial ovarian cancer, said Gina M. Mantia-Smaldone, MD, assistant professor of surgical oncology in the Division of Gynecologic Oncology at Fox Chase Cancer Center.

“The Wnt pathway is thought to be related to a stem cell pathway in ovarian cancer,” said Mantia-Smaldone, one of the study’s authors. “The idea with this therapy was to see if it would potentially attack the stem cell for the cancer, prevent recurrence of the disease, and lead to longer survival.”

The Phase I study of ipafricept was designed to establish a safe dose that could be evaluated in Phase II and III trials. During Phase I trials, researchers determine the maximum tolerated dose, look at toxicities associated with the drug, and obtain preliminary results regarding response rates and survival.

Mantia-Smaldone’s was a dose escalation study where each subsequent group of patients received an increase in the dose of ipafricept, given in combination with taxane and platinum therapy.

“During the early course of this study, there was also a very similar drug being studied in a different disease site,” Mantia-Smaldone said. “For both drugs, there was an unanticipated increased risk for bone fractures, some of which were very severe and impacted patients’ day-to-day lives.”

The maximum administered dose in this study was originally 10 mg/kg every three weeks. However, this was revised as part of a bone safety plan to 6 mg/kg every three weeks, with the taxane and platinum therapy given subsequently instead of concurrently. Of the 37 patients in the study, 30 were treated with the revised protocol.

Common ipafricept treatment-emergent adverse events included fatigue, nausea, diarrhea, decreased appetite, vomiting, and taste distortions.

Overall, about 75 percent of patients responded to treatment. The median progression-free survival was 10.3 months and the median overall survival was almost three years.

“Overall there was a signal that ipafricept could be efficacious, but toxicities limited us from developing the drug further in Phase II or III trials,” Mantia-Smaldone said. “The Wnt pathway is still a worthwhile target for future therapy, and even this drug could be developed further if we can come up with safer dosing or a different formulation.”

The paper, “A Phase 1b Dose Escalation Study of Ipafricept (OMP—54F28) in Combination With Paclitaxel and Carboplatin in Patients With Recurrent Platinum-sensitive Ovarian Cancer,” was published in Gynecologic Oncology.

The work was supported by the National Institutes of Health/National Cancer Institute Support Grant P30 CA008748.

       

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