10026 Background: Insulin-like growth factor signaling plays an important role in several pediatric cancers. Dalotuzumab is a highly specific, humanized IgG1 monoclonal antibody against IGF-1R. This multicenter phase 1 study explored the safety and pharmacokinetics (PK) of dalotuzumab in pediatric patients with advanced solid tumors. Methods: Dalotuzumab was administered intravenously every 3 weeks. Dose-escalation was performed according to a modified Toxicity Probability Interval (mTPI) design starting at 900 mg/m2. The PK profile of dalotuzumab was evaluated with the primary goal of confirming that the Day 22 mean serum trough concentration exceeded 25 μg/mL. Results: 24 patients were enrolled and 20 treated (median age, 10.5 years; range, 3–17 years). Six patients had recurrent Ewing sarcoma. Patients received a median of 2 cycles (range, 1-10). No dose-limiting toxicity was observed in any of the three dose levels explored (900, 1200 and 1500 mg/m2). Main treatment-related toxicities were Grade 3 elevated transaminases. PK data showed dose dependent increases in AUC0-∞ (105,000, 164,000 and 281,000 hr*mg/mL, for the 900, 1200 and 1500 mg/m2 dose levels, respectively), Ctrough (65.2, 71.6, 148 mg/mL) and Cmax (559, 643, 888 mg/mL). The mean half-life was 247, 394 and 376 hours respectively. The Cmax exhibited mild variability (4.8-35% Coefficient of Variation), whereas variability was moderate to high on the Ctrough (39-200%), apparent t1/2 (28-154%), AUC0-∞ (29-106%) and clearance (52-161%). Except for one patient at the 1200 mg/m2 dose level, all patients met the PK target, a Ctrough of 25 μg/mL, suggesting 900 mg/m2as the recommended phase 2 dose (RP2D). One patient with Ewing sarcoma had a confirmed partial response; 2 patients with Ewing sarcoma and one with nephroblastoma had stable disease for at least 7, 5 and 6 months, respectively. Conclusions: Dalotuzumab is well tolerated in pediatric patients with advanced malignancies. The RP2D of 900 mg/m2 was chosen based on tolerability and PK parameters. Preliminary data confirm prior reports suggesting activity in Ewing sarcoma. Clinical trial information: NCT01431547.
Phase I Clinical Trial of Ipilimumab in Pediatric Patients with Advanced Solid Tumors