Phase 1/2 Study of Crizotinib in Children With Relapsed/Refractory ALK-Positive Anaplastic Large Cell Lymphoma or Neuroblastoma in Japan

Clinical development of crizotinib in children with ALK-positive anaplastic large cell lymphoma (ALCL) was advanced in the US but not in Japan. The objectives of phase 1 part of a clinical study in Japan were to assess the safety and pharmacokinetics and determine the recommended phase 2 dose (RP2D) of crizotinib in children with relapsed/refractory (R/R) ALK-positive ALCL or neuroblastoma (NB). Two dose levels (165 and 280 mg/m² twice daily (BID)) were planned to be evaluated. The aim of phase 2 part of the study was to assess the antitumor activity of crizotinib at the RP2D in children with R/R ALK-positive ALCL. Seven patients were eligible for phase 1 part, 5 with ALCL and 2 with NB. All 7 patients received crizotinib at a starting dose of 165 mg/m² BID, with 1 dose-limiting toxicity observed (grade 3 gamma-glutamyltransferase increased). The most common grade 3 or 4 adverse event was neutropenia (71%). The steady-state C_max and AUC_tau of crizotinib at 165 mg/m² BID were higher than expected. Considering the risk of a greater incidence of severe neutropenia, we decided that the 165 mg/m² BID be the RP2D without evaluation at 280 mg/m² BID. A total of 11 patients with ALK-positive ALCL were enrolled in the phase 2 part. The objective response rate was 72.7% (90% CI, 43.6%–92.1%). One patient permanently discontinued crizotinib due to disease progression. Crizotinib at 165 mg/m² BID was well tolerated and showed favorable antitumor activity in children with R/R ALK-positive ALCL. Trial Registration: UMIN-CTR: UMIN000028075.