Study of EGF816 in Combination With Selected Targeted Agents in EGFR-mutant NSCLC

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 EGFR Mutant NSCLC

The study purpose is to evaluate the safety, tolerability, and preliminary efficacy of the addition of INC280, trametinib, ribociclib, gefitinib, or LXH254 to EGF816 in adult patients with advanced EGFR-mutant NSCLC.

Study Overview

• Status: Active, not recruiting
• Conditions: EGFR-mutant Non-small Cell Lung Cancer
• Intervention / Treatment: Drug: EGF816; Drug: trametinib; Drug: ribociclib; Drug: LXH254; Drug: INC280; Drug: gefitinib

Detailed Description

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.

During the dose escalation part, patients will be assigned to the addition of trametinib, ribociclib, or LXH254 to EGF816.

Following determination of the recommended dose for the combination of EGF816 + trametinib, EGF816 + ribociclib, and EGF816 + LXH254, patients may be enrolled to the dose expansion arms of each of these combinations. Patients may also be assigned to EGF816 + INC280 or EGF816 + gefitinib in dose expansion.

Efficacy assessments will be performed at baseline and every 2 cycles during treatment.

• Study Type: Interventional
• Enrollment (Actual): 105
• Phase: Phase 1

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 2M9
      • Novartis Investigative Site
• Germany
  • Essen, Germany, 45147
    • Novartis Investigative Site
  • Koeln, Germany, 50937
    • Novartis Investigative Site
• Hong Kong
  • Shatin New Territories, Hong Kong
    • Novartis Investigative Site
• Italy
  • AN
    • Ancona, AN, Italy, 60126
      • Novartis Investigative Site
  • MI
    • Milano, MI, Italy, 20162
      • Novartis Investigative Site
    • Rozzano, MI, Italy, 20089
      • Novartis Investigative Site
• Singapore
  • Singapore, Singapore, 119228
    • Novartis Investigative Site
  • Singapore, Singapore, 168583
    • Novartis Investigative Site
• Taiwan
  • Tainan, Taiwan, 70403
    • Novartis Investigative Site
  • Taipei, Taiwan, 10002
    • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion 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 or 2nd-generation EGFR TKI. 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.
• Patients must have a site of disease amenable to biopsy, and be a candidate for tumor biopsy according to the treating institution's guidelines. Patients must be willing to undergo a new tumor biopsy during therapy on this study, and at screening if an archival tumor sample obtained since the diagnosis of advanced disease (1L patients) or since last treatment failure (2L+ patients) is not available.

Exclusion Criteria:

• Patients with a history or presence of interstitial lung disease or interstitial pneumonitis, including clinically significant radiation pneumonitis.
• Patients with unstable brain metastases.
• Patients with a history of another malignancy.
• Patients with a known history of human immunodeficiency virus (HIV) seropositivity.
• Patients with clinically significant, uncontrolled heart disease.
• Patients participating in additional parallel investigational drug or medical device studies.
• Prior therapies:
• 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).

• 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

10

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm 1; EGF816+ trametinib in escalation phase	Drug: EGF816; Study Drug; Drug: trametinib; Study Drug
Experimental: Arm 2; EGF816 + ribociclib in escalation phase	Drug: EGF816; Study Drug; Drug: ribociclib; Study Drug
Experimental: Arm 3; EGF816 + LXH254 in escalation phase	Drug: EGF816; Study Drug; Drug: LXH254; Study Drug
Experimental: Arm A; EGF816 + INC280 in expansion phase (patients with no known resistance mechanism)	Drug: EGF816; Study Drug; Drug: INC280; Study Drug
Experimental: Arm B; EGF816 + trametinib in expansion phase	Drug: EGF816; Study Drug; Drug: trametinib; Study Drug
Experimental: Arm C; EGF816 + ribociclib in expansion phase	Drug: EGF816; Study Drug; Drug: ribociclib; Study Drug
Experimental: Arm D; EGF816 + LXH254 in expansion phase (patients with no known resistance mechanism)	Drug: EGF816; Study Drug; Drug: LXH254; Study Drug
Experimental: Arm E; EGF816 + LXH254 in expansion phase (patients with known resistance mechanism)	Drug: EGF816; Study Drug; Drug: LXH254; Study Drug
Experimental: Arm F; EGF816 + gefitinib in expansion phase	Drug: EGF816; Study Drug; Drug: gefitinib; Study Drug
Experimental: Arm G; EGF816 + INC280 in expansion phase (patients with known resistance mechanism)	Drug: EGF816; Study Drug; Drug: INC280; Study Drug

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of patients with adverse events and serious adverse events	Assess safety and tolerability including incidence of dose limiting toxicities, adverse events, and serious adverse events.	Every day until study end, approximately 4 years
ORR2	Modified objective response rate (ORR2) per RECIST v1.1 (taking as baseline the most recent assessment prior to initiating combination)	Every 8-12 weeks until study ends, approximately 4 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
ORR	Overall response rate (ORR) per RECIST v1.1	Every 8-12 weeks until study ends, approximately 4 years
PFS	Time from the date of first dose of study treatment to the date of first documented disease progression (per RECIST v1.1) or death due to any cause	Every 8-12 weeks until study ends, approximately 4 years
DCR	Proportion of patients with best overall response of CR, PR, or SD	Every 8-12 weeks until study ends, approximately 4 years
DOR	Time from first documented response (PR or CR) to the date of first documented disease progression or death due to any cause	Every 8-12 weeks until study ends, approximately 4 years
Time to response		Every 8-12 weeks until study ends, approximately 4 years

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals
• Investigators: Study Chair: Novartis Pharmaceuticals, Novartis

Study record dates

Study Major Dates

• Study Start (Actual): January 29, 2018
• Primary Completion (Estimated): December 16, 2024
• Study Completion (Estimated): December 16, 2024

Study Registration Dates

• First Submitted: October 31, 2017
• First Submitted That Met QC Criteria: November 2, 2017
• First Posted (Actual): November 6, 2017

Study Record Updates

• Last Update Posted (Estimated): February 2, 2024
• Last Update Submitted That Met QC Criteria: February 1, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: EGFR-mutant NSCLC; EGF816; LXH254; INC280; ribociclib; trametinib; gefitinib; EGFR T790M; BRAF mutation; BRAF fusion; BRAF rearrangement; MET amplification
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Gefitinib; Trametinib; Nazartinib; Naporafenib
• Other Study ID Numbers: CEGF816X2102; 2017-002496-25 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No