A phase Ib, open label, multi-center study to characterize the safety, tolerability and preliminary efficacy of EGF816 in combination with selected targeted agents in EGFRmutant NSCLC
This is a Phase Ib, open label, non-randomized dose escalation study of EGF816 in combination with ribociclib, trametinib, or LXH254, followed by dose expansion of EGF816 in combination with ribociclib, trametinib, LXH254, INC280, or gefitinib in adult patients with advanced EGFR-mutant NSCLC. Patients must be either treatment-naïve in the advanced setting and harbor a sensitizing mutation in EGFR (ex19del or L858R) or have progressed on a 1st or 2nd generation EGFR TKI (e.g., erlotinib, gefitinib, afatinib) and harbor an EGFR T790M mutation within the tumor. Patients should not have previously received a 3rd generation EGFR TKI (e.g., osimertinib, rociletinib, ASP8273).
The primary objective is to characterize the safety and tolerability of EGF816 + ribociclib, EGF816 + trametinib, and EGF816 + LXH254, in patients with advanced EGFR-Mutant NSCLC in 1st line or ≥ 2nd line T790M+, 3rd gen EGFR TKI-naive and identify are commended dose and regimen.
The primary objective is to estimate the preliminary anti-tumor activity of the addition of ribociclib, trametinib, LXH254, gefitinib, or INC280 to EGF816 in advanced EGFR-Mutant NSCLC in 1st line or 2nd line and beyond EGFR T790M+, 3rd generation EGFR TKI-naïve patients.
In- and exclusion Criteria
• Patients must have histologically or cytologically confirmed locally advanced (stage IIIB) or metastatic (stage IV) EGFR mutant (ex19del, L858R) NSCLC.
• Requirements of EGFR mutation status and prior lines of treatment:
- Treatment naive patients, who have locally advanced or metastatic NSCLC with EGFR sensitizing mutation (e.g., L858R and/or ex19del), have not received any systemic antineoplastic therapy for advanced NSCLC and are eligible to receive EGFR TKI treatment. Patients with EGFR exon 20 insertion/duplication are not eligible. Note: patients who have received only one cycle of chemotherapy in the advanced setting are allowed.
- Patients who have locally advanced or metastatic NSCLC with EGFR sensitizing mutation AND an acquired T790M mutation (e.g., L858R and/or ex19del, T790M+) following progression on prior treatment with a 1st-generation EGFR TKI (e.g. erlotinib, gefitinib or icotinib) or 2nd-generation EGFR TKI (e.g., afatinib or dacomitinib). These patients may not have received more than 4 prior lines of antineoplastic therapy in the advanced setting, including EGFR TKI, and may not have received any agent targeting EGFR T790M mutation (i.e., 3rd-generation EGFR TKI).
• Patients who have locally advanced or metastatic NSCLC with EGFR sensitizing mutation and a "de novo" T790M mutation (i.e., no prior treatment with any agent known to inhibit EGFR including EGFR TKI). These patients may not have received more than 3 prior lines of antineoplastic therapy in the advanced setting, and may not have received any prior 3rd generation EGFR TKI.
• Left ventricular ejection fraction (LVEF) < 50% or below• Patients with uncontrolled hypertension defined as a Systolic Blood Pressure (SBP) 140 mm Hg and/or Diastolic Blood Pressure (DBP) > 90 mm Hg, with or without anti-hypertensive medication. Initiation or adjustment of antihypertensive medication(s) is allowed prior to screening.
• Ventricular arrhythmias
• Supraventricular and nodal arrhythmias not controlled with medication
• Other cardiac arrhythmia not controlled with medication
• History or current evidence of retinal vein occlusion (RVO) or current risk factors for RVO (e.g., uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability syndromes)
• Patients who have been treated with EGFR TKI in the adjuvant setting within 6 months, unless acquired EGFR T790M is present in a tumor or blood sample obtained since the discontinuation of the EGFR TKI
• Patients who have been treated with prior EGFR TKI targeting T790M (3rd generation, e.g. osimertinib, CO-1686/rociletinib, ASP8273, HM61713/BI 1482694/olmutinib)
• Patients who have been treated with systemic anti-neoplastic therapy within:
≤ 2 weeks for fluoropyrimidine monotherapy
≤6 weeks for nitrosoureas and mitomycin
≤4 weeks or ≤ 5 half-lives (whichever is shorter) for biological therapy (including
monoclonal antibodies) and continuous or intermittent small molecule
therapeutics or any other investigational agent
A phase Ib, open label, multi-center study to characterize the safety, tolerability and preliminary efficacy of EGF816in combination with selected targeted agents in EGFRmutant NSCLC
Novartis Pharma GmbH
University Hospital of Cologne
Dep. I of Internal Medicine
Phone: +49 221 478 87008
Fax: +49 221 478 87010
Prof. Dr. J. Wolf
Last Update: 2. July 2018