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The second-generation ALK inhibitor ceritinib (Zykadia) demonstrated encouraging antitumor activity in pediatric patients with ALK-positive refractory or recurrent malignancies, according to a multicenter phase I study.

The recommended dose for expansion (RDE) of ceritinib was established at 510 mg/m² in a fasted state or 500 mg/m² in a fed state, which was given to 55 patients, reported Johannes Schulte, MD, of Charité-Universitätsmedizin Berlin in Germany, and colleagues.

Overall response rates with ceritinib were 75% in patients with anaplastic large cell lymphoma (ALCL; six of eight patients), 70% in those with inflammatory myofibroblastic tumor (IMT; seven of 10), 20% in those with neuroblastoma (six of 30), and 14% in those with other tumors (one of seven), they noted in .

The drug's safety profile was consistent with that seen in adult patients, the authors added.

"Our data support the notion that ALK inhibitors should be considered in therapeutic strategies for pediatric patients with malignancies with genetic ALK alterations," Schulte and team wrote.

"These next-generation ALK inhibitors with a higher therapeutic index than the first-generation inhibitors will hopefully overcome resistance in neuroblastoma and destroy quiescent residual neoplastic cells, reducing the risk of relapse after treatment discontinuation," wrote Laurence Brugieres, MD, of Gustave Roussy Cancer Center in Villejuif, France, and colleagues, in an .

The trial was conducted at 23 academic sites in 10 countries, and included patients ages 1 to 18 years diagnosed with an advanced or metastatic ALK-positive malignancy that had progressed despite standard therapy, or for which there is no effective standard therapy.

Of the 83 patients in the study (median age 8 years), 67 had metastatic disease at study entry. Forty patients were included in the dose-escalation group, and 43 were included in the dose-expansion group. All had received at least one previous regimen of antineoplastic therapy (55% had received one or two, while 35% had received at least three), 63% had undergone surgery, and 43% had received radiotherapy.

The primary outcome of this study was to establish the maximum tolerated dose, or RDE, of ceritinib in fasted and fed states. Secondary outcomes included overall response rate, disease control rate, duration of response, progression-free survival, and safety.

Disease control rates were 53% for patients with neuroblastoma, 80% for those with IMT, 88% for those with ALCL, and 43% for those with other tumors.

The median duration of response in the six patients with neuroblastoma who had a confirmed complete or partial response treated at the fasted or fed RDE was 15 months, and was not reached in the six responding patients with ALCL, the seven patients with IMT, or the one patient with another tumor type.

Fifty percent of patients with neuroblastoma had ongoing responses at 12 months, as did 80% of patients with IMT, and 67% with ALCL.

Among responders, disease progression was reported in three patients with neuroblastoma and one each with IMT and ALCL.

The drug's safety in the pediatric population "was consistent with the known safety profile established in adult patients, comprising mainly gastrointestinal toxicity and increased aminotransferases," Schulte and colleagues reported.

The most common adverse events (AEs) of any grade were vomiting (87% of patients), diarrhea (78%), increased alanine aminotransferase (65%), increased aspartate aminotransferase (59%), nausea (57%), and abdominal pain (51%). Grade 3 or 4 AEs were reported in 81% of patients, mainly increases in alanine aminotransferase (46%) and aspartate aminotransferase (33%).

There were 14 deaths during the study, 12 of which occurred on treatment: 10 were due to disease progression (neuroblastoma), one was due to sepsis, and one was due to intractable hypotension.

"Although ALK inhibitors are generally tolerated by children, ongoing and future trials need to assess the appropriate length of therapy needed to treat these diseases, and to test whether ALK inhibitors are associated with any long-term toxic effects in children," the editorialists concluded.

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