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H. Loong

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    P1.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 206)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 1
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      P1.01-085 - A Multicenter Phase 1B Study of Ceritinib plus Nivolumab in Patients with ALK+ NSCLC (ID 1323)

      09:30 - 17:00  |  Author(s): H. Loong

      • Abstract

      Ceritinib is a novel, highly selective, orally active and potent tyrosine kinase inhibitor of anaplastic lymphoma kinase (ALK), and has demonstrated clinical efficacy in ALK-rearranged (ALK+) non-small cell lung cancer (NSCLC) (ASCEND-1; NCT01283516). Nivolumab is a fully human, immunoglobulin G4 programmed cell death protein-1 (PD-1) immune checkpoint inhibitor antibody that selectively prevents interaction with PD-1 ligands (PD-L1 and PD-L2), thereby promoting antitumor T-cell function, and is approved by the United States Food and Drug Administration for treatment of squamous NSCLC patients with progression following platinum doublet (Checkmate-017; NCT01642004). Nivolumab in combination with chemotherapy, other immune modulators and molecular targeted therapy has shown promising preliminary results in Stage IIIB/IV NSCLC patients (CheckMate-012; NCT01454102). The demonstrated efficacy of ceritinib in ALK+ NSCLC, and nivolumab in Stage IIIB/IV NSCLC, provides a rationale to study ceritinib in combination with nivolumab in patients with ALK+ NSCLC.

      In this prospective, open-label, multicenter phase 1B study (CLDK378A2120C; NCT02393625), the primary objectives are to determine the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE) and to evaluate the preliminary efficacy, based on overall response rate of ceritinib in combination with a fixed dose of nivolumab in adult stage IIIB/IV ALK+ NSCLC patients. Secondary objectives include evaluating duration of response, disease control rate, time to response, progression-free survival, overall intracranial response rate for patients with baseline measurable brain metastases, overall survival, and safety profile. In dose escalation phase, patients may have had ≥ 1 prior ALK inhibitors (except ceritinib) or prior chemotherapy regimens. In expansion phase, there will be 2 arms: 1) ALK-inhibitor pre-treated patients with 0 or 1 prior chemotherapies; 2) ALK-inhibitor naïve patients with 0 or 1 prior chemotherapies. Other key inclusion criteria are: presence of ≥ 1 measurable lesion as defined by Response Evaluation Criteria In Solid Tumors (RECIST) 1.1, and a World Health Organization performance status 0-1. Patients with asymptomatic, untreated brain metastases at baseline are allowed. Dose-escalation phase will consist of successive cohorts of patients (3 to 6) receiving increasing doses of ceritinib (starting dose: 450 mg/d with a low-fat meal; 28-day cycles) plus nivolumab (3 mg/kg Q2W) and will enroll a minimum of 12 patients. In expansion phase, approximately 60 patients will be allocated to arms 1 and 2 (30 in each arm) and treated with ceritinib at MTD/RDE plus nivolumab (3 mg/kg Q2W). Material required for central assessment of ALK rearrangement must be either archival tissue or, preferably, a fresh biopsy. Apart from ALK rearrangement, potential predictive markers of PD-L1 and PD-L2 expression and/or additional immunological biomarkers will also be assessed. Patients may continue treatment until unacceptable toxicity, disease progression, discontinuation at the discretion of the investigator, or consent withdrawal. MTD and/or RDE estimation will be based on the probability of dose-limiting toxicities using an adaptive Bayesian logistic regression model guided by the escalation with overdose control principle and an overall assessment of safety and tolerability data. Tumor responses will be assessed per RECIST v1.1 by investigator assessment.

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