Final analysis of phase I study of ceritinib in pediatric patients with malignancies harboring activated anaplastic lymphoma kinase (ALK).

Abstract

10505 Background: Activation of anaplastic lymphoma kinase has been detected in several pediatric malignancies, including anaplastic large-cell lymphoma (ALCL), inflammatory myofibroblastic tumor (IMT), neuroblastoma and others. Preliminary findings from this phase 1, multicenter, dose-escalation study (NCT01742286) indicated a Maximum Tolerated Dose (MTD)/Recommended Dose for Expansion (RDE) of the potent oral ALK inhibitor ceritinib to be 510 mg/m2 (fasted) and 500 mg/m2 (fed) in pediatric patients (pts). Here, we report final safety, pharmacokinetics (PK) and efficacy results. Methods: Children aged ≥1 to <18 years with advanced, mostly pretreated, ALK-aberrant malignancies were enrolled in this study. Dose escalation was conducted to determine the MTD/RDE of ceritinib (primary objective), in both fasted and fed states, following which pts entered an expansion phase to evaluate safety, tolerability, and efficacy at the MTD/RDE. Secondary objectives were evaluation of safety, PK, and efficacy (overall response rate [ORR], duration of response [DOR] and progression-free survival [PFS]). Results: A total of 83 pts (median age, 8 years) with ALK-aberrant malignancies were enrolled into dose-escalation (n = 40) and expansion (n = 43) study periods. Of these, 55 pts (neuroblastoma, n = 30; IMT, n = 10; ALCL, n = 8; others, n = 7) were treated with ceritinib at MTD/RDE (510 mg/m2 [fasted], n = 13; 500 mg/m2 [fed], n = 42). Systemic exposure of ceritinib between the two doses was comparable, so data were pooled for efficacy assessment. The ORRs (95% CI) were 75% (34.9-96.8) for pts with ALCL, 70% (34.8-93.3) for IMT and 20% (7.7-38.6) for neuroblastoma. The median DOR was 15 months (95% CI: 5.8, 22.2) for the 6/30 pts with neuroblastoma who had confirmed CR or PR treated at fasted/fed MTD/RDE. Median DOR was not reached for those with ALCL and IMT. Most common adverse events (AEs) (N = 83; all-grades, all-causality, ≥50% of pts): vomiting (86.7%), diarrhea (78.3%), increased ALT (65.1%), increased AST (59.0%), nausea (56.6%), and abdominal pain (50.6%). Grade 3/4 AEs were observed in 80.7% of pts (mostly transaminase elevations) and were manageable. Six pts (7.2%) were discontinued from ceritinib due to a grade 3/4 AE (mostly transaminase elevation). Conclusions: Substantial activity was observed with ceritinib at the RDE in pts with IMT, ALCL and heavily pretreated neuroblastoma. The toxicity profile of ceritinib in children was manageable and similar to that previously reported in adults. Clinical trial information: NCT01742286.

Recent progress in the treatment of cancer in children

“…In a phase 1/2 study of pediatric patients with ALK‐positive R/R ALCL treated with the ALK inhibitor crizotinib, >80% of patients achieved a CR 78 . Similarly, a very high response rate has been reported with the second‐generation ALK inhibitor ceritinib 79 . The CD30‐targeting ADC brentuximab vedotin demonstrated a 53% ORR, including 41% CRs, in a multicenter phase 1/2 study of patients with R/R ALCL 78 .…”

“…78 Similarly, a very high response rate has been reported with the second-generation ALK inhibitor ceritinib. 79 The CD30-targeting ADC brentuximab vedotin demonstrated a 53% ORR, including 41% CRs, in a multicenter phase 1/2 study of patients with R/R ALCL. 78 On the basis of the positive response rates of these 2 agents in relapsed ALCL, an ongoing frontline clinical trial is randomizing pediatric patients with newly diagnosed ALCL to receive either crizotinib or brentuximab vedotin in combination with chemotherapy (ClinicalTrials.gov identifier NCT01979536).…”

“…147 It is notable that, other than BRAF V600E, the highest response rates have been observed in patients with tumors harboring kinase fusions, suggesting that these fusions may be a particularly susceptible cancer vulnerability (Table 1). 78,79,152,154,[161][162][163][164][165][166] Critically, given the small number of patients who have tumors with each of these individual mutations, development of these molecularly targeted agents for children has been an international endeavor, with trials spanning multiple countries and often multiple continents.…”

“…Patients whose tumors had ALK mutations had statistically significant worse EFS and OS, demonstrating the need for added therapies for these patients 97 . Several ALK inhibitors have been tested in phase 1 studies of children with neuroblastoma 79,98 . On the basis of early results, the addition of crizotinib to upfront therapy for children with high‐risk neuroblastoma harboring an ALK mutation is now being studied (ClinicalTrials.gov identifier NCT03126916).…”

Pursuing Precision: Receptor Tyrosine Kinase Inhibitors for Treatment of Pediatric Solid Tumors

“…Other strategies to address resistance include the development of second-generation and third-generation ALK inhibitors such as alectinib, ceritinib, lorlatinib, and ensartinib. Preclinical testing of these drugs has demonstrated activity in cell lines or xenograft models that harbor ALK mutations resistant to crizotinib [ 69 , 70 , 71 , 72 ] and anecdotal reports and early phase I trials showing clinical activity are now starting to appear [ 70 , 73 , 74 , 75 ]. Another drug, entrectinib, is a multi-targeted RTK inhibitor with action not only against ALK but also the TRK-B receptor, which is expressed in over half of high-risk neuroblastoma tumors and associated with a poor prognosis [ 76 ].…”