An investigator-initiated registration-directed phase I/II clinical trial of irinotecan hydrochroride for refractory pediatric solid tumors.

Abstract

9547 Background: Although irinotecan hydrochloride (CPT-11) is a promising chemotherapeutic agent to treat refractory pediatric solid tumors, this indication and effect is not labeled in US, EU, and Japan. Therefore, we conducted the phase I/II trial of CPT-11 monotherapy in a registration-directed setting. Methods: Patients (Pt) aged 2 to 18 years with pediatric solid tumors refractory to, or relapsed after treatment with standard chemotherapies are eligible. This multi-center phase I/II trial consists of phase I part (PI), in which dose-escalation from level 1 (40 mg/m2/day) to estimate the maximum tolerating dose (MTD) was planned, followed by phase II part (PII), in which the recommended dose (RD) at one level lower than the MTD was adopted. CPT-11 was administered intravenously on days 1, 2, 3 and 8, 9, 10, repeated every 21-day cycle up to 8 cycles. Primary endpoints are the dose limiting toxicity (DLT) in PI, and response rate per RECIST criteria including patients entered in PI and PII. Pharmacokinetic study was planned in selected Pt. Results: Seventeen Pt (11 in PI and 6 in PII) received CPT-11. Because DLTs were observed in 1 Pt (diarrhea) in level 1 and 3 Pt (diarrhea, febrile neutropenia, and elevated serum amylase) in level 2 (45 mg/m2/day), the level 2 was regarded as the MTD and the RD was determined to be 40 mg/m2/day. Tumor responses included one confirmed PR in poorly-differentiated sarcoma, one unconfirmed PR in neuroblastoma, two SD continued more than 24 weeks in rhabdomyosarcoma and Ewing/PNET, respectively. The response rate was 5.9%, which was lower than expected. Pharmacokinetic parameters in 11 Pt showed a similar pattern to results of the past pediatric reports. Conclusions: The RD of CPT-11 in this treatment schedule is 40 mg/m2/day. CPT-11 monotherapy is not active enough to expect tumor shrinkage but possibly active to stabilize disease even in refractory pediatric solid tumors. Nontheless, the clinical data from this registration-directed clinical trial is not enough to obtain approval for pediatric solid tumors. Further investigations including possible combination chemotherapy are warranted. No significant financial relationships to disclose.