Phase Ib/II study of ceritinib in combination with ribociclib in patients with ALK-rearranged non-small cell lung cancer.

BACKGROUND: Preclinical data show that the combination of an ALK inhibitor (ALKi) with a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) may act synergistically to overcome drug resistance mechanisms. Here, we assessed the safety, tolerability, and preliminary clinical activity of ceritinib, an ALKi in combination with ribociclib, a CDK4/6i, in patients with ALK-rearranged non-small cell lung cancer (NSCLC). METHODS: This was a multicenter, open-label, phase Ib/II dose-escalation study to determine the maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D) for ceritinib plus ribociclib therapy. RESULTS: Twenty-seven adult patients with ALK-rearranged advanced NSCLC with an ECOG PS ≤ 2 were enrolled into five cohorts to receive various dose combinations of ceritinib (range, 300-450 mg/day) and ribociclib (range, 100-300 mg/day). Median age of patients was 57 years. MTDs were not reached in this study. Enrollment into phase Ib was terminated early and phase II was not opened due to changes in the ALK-rearranged NSCLC treatment landscape. Ceritinib 300 mg/day and ribociclib 200 mg/day (3-weeks-on/1-week-off schedule) was identified as the RP2D. Among the 27 evaluable patients, the overall response rate (ORR) was 37.0% (95% CI, 19.4-57.6) and median progression-free survival (mPFS) was 21.5 months (95% CI, 5.5-25.0). At RP2D, the ORR was 50.0%, disease control rate was 75%, and mPFS was 24.8 months (95% CI, 5.5-25.1). Safety profile of the combination therapy was consistent with single-agent safety data. CONCLUSION: Combination of ceritinib and ribociclib showed clinical activity with a manageable safety profile in patients with advanced ALK-rearranged NSCLC.

A Phase 1 Study of a CDH6-Targeting Antibody-Drug Conjugate in Patients with Advanced Solid Tumors with Evaluation of Inflammatory and Neurological Adverse Events.

PURPOSE: This first-in-human study (NCT02947152) evaluated the safety, tolerability, pharmacokinetics, and preliminary efficacy of HKT288, a first-in-class CDH6-targeting antibody-drug conjugate (ADC). EXPERIMENTAL DESIGN: HKT288 was administered intravenously (IV) every 3 weeks until patients experienced unacceptable toxicity or progressive disease (PD). The starting dose of 0.3 mg/kg was determined based on the highest nonseverely toxic dose in monkeys, which was 2 mg/kg IV weekly. Based on preclinical toxicology, skin, eyes, bone marrow, and liver were expected targets of toxicity. RESULTS: Nine patients were enrolled: 5 with renal cell carcinoma and 4 with epithelial ovarian cancer. The best overall response on the 0.3 mg/kg cohort in patients with measurable disease was RECIST v1.1 stable disease in 3 patients and PD in 2 patients. The most frequent adverse events (AEs) regardless of causality were pyrexia (44.4%), constipation (44.4%), fatigue (33.3%), and vomiting (33.3%). Three suspected-related neurologic AEs (Grade 2) were reported on the 0.75 mg/kg cohort: seizure in 1 patient and another patient with aphasia and encephalopathy. Further studies were unable to identify the underlying mechanism of the neurologic AEs, and the study was terminated early. CONCLUSIONS: Preclinical toxicology did not predict the neurotoxicity observed with HKT288, and a comprehensive assessment performed post hoc did not identify the mechanism of toxicity. The development of further CDH6-targeting ADCs should be pursued with caution.

Methotrexate Elimination When Coadministered With Levetiracetam.

BACKGROUND: Delayed elimination of methotrexate was previously reported in 2 patients receiving concomitant levetiracetam. OBJECTIVE: To explore the potential interaction between methotrexate and levetiracetam in patients receiving high-dose methotrexate. METHODS: This retrospective study reviewed the records of 81 adults receiving 280 cycles of methotrexate to determine the effects of levetiracetam on methotrexate elimination. Institutional review board approval was obtained. RESULTS: Levetiracetam was administered in 33 (12%) cycles of methotrexate. Patients receiving levetiracetam had significantly lower 24-hour methotrexate concentrations compared with those not receiving levetiracetam (2.91 vs 7.37 µmol/L, P = 0.005). Despite this difference, concentrations at 48 and 72 hours were similar between groups. Times to nontoxic methotrexate concentration (<0.1 µmol/L) were the same regardless of the presence of levetiracetam. The frequency of delayed elimination at 24, 48, and 72 hours was similar in both groups as was the frequency of delayed elimination at any time point. Cox regression demonstrated that levetiracetam was not a significant predictor of time to nontoxic methotrexate concentration (P = 0.796; HR = 1.058; 95% CI = 0.692-1.617), and logistic regression demonstrated that levetiracetam was not a significant predictor of delayed elimination at any time point. Levetiracetam use was similar between groups when comparing patients experiencing delayed elimination at any time point with those without delayed elimination (13% vs 10%, respectively, P = 0.527). CONCLUSION: This study does not support the previous reports of a significant interaction between levetiracetam and methotrexate. A clinically significant interaction is unlikely in those without additional risk factors for delayed elimination.