A phase 1 study of oral ridaforolimus in pediatric patients with advanced solid tumors

Area of Science:

• Pediatric Oncology
• Pharmacology
• Clinical Trials

Background:

• Ridaforolimus is a potent, selective mTOR inhibitor investigated for cancer treatment.
• Advanced solid tumors in children present significant therapeutic challenges.
• Understanding the optimal dosing and safety of novel agents in pediatric populations is crucial.

Purpose of the Study:

• To determine the recommended phase 2 dose (RP2D) of oral ridaforolimus in pediatric patients.
• To evaluate the safety, pharmacokinetics, and antitumor activity of ridaforolimus in children with advanced solid tumors.
• To establish the maximum tolerated dose (MTD) for oral ridaforolimus in this population.

Main Methods:

• A phase 1, multicenter, open-label study involving children aged 6 to <18 years with advanced solid tumors.
• Oral ridaforolimus administered at escalating doses (22, 28, 33 mg/m2) for 5 days/week in 28-day cycles.
• Dose escalation followed by expansion at the determined RP2D, with safety and pharmacokinetic assessments.

Main Results:

• Twenty patients were treated; 18 were evaluable for dose-limiting toxicities.
• The most frequent treatment-related adverse events included stomatitis, thrombocytopenia, and fatigue, generally manageable.
• The recommended phase 2 dose (RP2D) was established at 33 mg/m2, with ridaforolimus exposure exceeding adult levels at higher doses.
• Two patients with pineoblastoma and diffuse intrinsic pontine glioma achieved stable disease for extended periods.

Conclusions:

• Oral ridaforolimus is orally bioavailable and demonstrates a favorable safety profile in children with advanced solid tumors.
• The pediatric RP2D of 33 mg/m2 is higher than the adult RP2D, suggesting potential for effective dosing in children.
• The pharmacokinetic and toxicity profiles support ridaforolimus as a potential agent for combination therapy in pediatric malignancies.