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Phase I Study of Ceritinib (LDK378) in Japanese Patients with Advanced, Anaplastic Lymphoma Kinase-Rearranged
Makoto Nishio1, Haruyasu Murakami, Atsushi Horiike
1*The Cancer Institute Hospital of JFCR, Tokyo, Japan; †Shizuoka Cancer Center, Shizuoka, Japan; ‡National Kyushu Cancer Center, Fukuoka, Japan; §Novartis Pharma K.K., Tokyo, Japan; ¶Novartis Pharmaceuticals Corporation, East Hanover, New Jersey; and ‖Novartis Institutes for Biomedical Research, Cambridge, Massachusetts.
Introduction:
Anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung cancer (NSCLC) is sensitive to ALK inhibitors, but resistance develops. This study assessed the maximum-tolerated dose, safety, pharmacokinetics (PK), and antitumor activity of ceritinib, a novel ALK inhibitor (ALKi), in Japanese patients with ALK-rearranged malignancies.
Methods:
This phase I, multicenter, open-label study (NCT01634763) enrolled adult patients with ALK-rearranged (by fluorescence in situ hybridization and/or immunohistochemistry) locally advanced/metastatic malignancy that had progressed despite standard therapy. The study comprised two parts: dose escalation and dose expansion. Ceritinib (single-dose) was administered orally in the 3-day PK run-in period, then once daily, in 21-day cycles. Adaptive dose escalations were guided by a Bayesian model.
Results:
Twenty patients (80% with ALKi treatment history [ALKi-pretreated]; 19 NSCLC; one inflammatory myofibroblastic tumor) received ceritinib 300 to 750 mg (19 during dose escalation, one in dose expansion). Two dose-limiting toxicities occurred: grade 3 lipase increase (600 mg); grade 3 drug-induced liver injury (750 mg). The most common adverse events were gastrointestinal (nausea: 95%; diarrhea, vomiting: 75%). Ceritinib PK profile was dose proportional across 300 to 750 mg dosages; steady state was reached by day 15. Overall response rate was 55% (11 of 20 patients). Among patients with NSCLC, partial response was observed in two of four ALKi-naive patients, five of nine crizotinib-pretreated patients, two of four alectinib-pretreated patients, and one of two crizotinib and alectinib/ASP3026 pretreated patients. The ASP3026-pretreated inflammatory myofibroblastic tumor patient achieved partial response.
Conclusions:
Ceritinib maximum-tolerated dose was 750 mg once daily in Japanese patients. Antitumor activity was observed irrespective of prior ALKi treatment history. Dose expansion, examining the activity of ceritinib in alectinib-resistant patients, is ongoing.
Insights
Ceritinib showed antitumor activity in Japanese patients with ALK-rearranged cancers, with a maximum tolerated dose of 750 mg daily. This novel ALK inhibitor (ALKi) demonstrated efficacy regardless of prior treatment history.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- Anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung cancer (NSCLC) often develops resistance to ALK inhibitors.
- Assessing novel ALK inhibitors is crucial for managing treatment resistance.
Purpose of the Study:
- To determine the maximum-tolerated dose (MTD) of ceritinib in Japanese patients.
- To evaluate the safety, pharmacokinetics (PK), and antitumor activity of ceritinib.
- To assess ceritinib's efficacy in patients with ALK-rearranged malignancies, including those with prior ALK inhibitor (ALKi) exposure.
Main Methods:
- Phase I, multicenter, open-label study in adult Japanese patients with advanced/metastatic ALK-rearranged malignancies.
- Dose escalation and expansion phases, with ceritinib administered orally once daily.
- Bayesian modeling guided adaptive dose escalation.
Main Results:
- The MTD of ceritinib was determined to be 750 mg once daily.
- Common adverse events included gastrointestinal issues (nausea, diarrhea, vomiting).
- An overall response rate of 55% was observed, with activity seen in ALK inhibitor-naïve and pretreated patients.
Conclusions:
- Ceritinib is a potential treatment option for Japanese patients with ALK-rearranged malignancies.
- Antitumor activity was observed irrespective of prior ALK inhibitor treatment.
- Further investigation in alectinib-resistant patients is ongoing.
