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

NCT03333343 | Active Not Recruiting Phase 1

• 2 other identifiers: CEGF816X21022024-511757-21-00
• Study Type: interventional
• Target: 105
• Locations: 6 countries
• Sites: 11

Brief Summary

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 Epidermal growth factor receptor- mutant (EGFR-mutant) non-small cell lung cancer (NSCLC).

Conditions

EGFR-mutant Non-small Cell Lung Cancer

Keywords

EGFR-mutant NSCLC; EGF816; LXH254; INC280; ribociclib; trametinib; gefitinib; EGFR T790M; BRAF mutation; BRAF fusion; BRAF rearrangement; MET amplification

Outcome Measures

Primary Outcomes (5)

• 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

• Number of participants with DLTs in the first cycle of combination (Dose escalation only)

  A Dose-Limiting Toxicity (DLT) is defined as an adverse event or abnormal laboratory value of Common Terminology Criteria for Adverse Events (CTCAE) grade ≥ 3 assessed as unrelated to disease, disease progression, inter-current illness or concomitant medications that occurs within the first 28 days of combination treatment during the dose escalation part of the study. Other clinically significant toxicities may be considered to be DLTs, even if not CTCAE grade 3 or higher.

  28 days

• Number of participants with dose interruptions and reductions

  Assessment of tolerability. For patients who do not tolerate the protocol-specified dosing schedule, dose adjustments may be permitted in order to allow patients to continue the study treatment.

  From first dose until study ends, approximately 4 years

• Dose intensity of study drugs

  Dose intensity is computed as the ratio of actual cumulative dose received to actual duration of exposure.

  From first dose until study ends, 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 Outcomes (7)

• ORR

  Every 8-12 weeks until study ends, approximately 4 years

• PFS

  Every 8-12 weeks until study ends, approximately 4 years

• DCR

  Every 8-12 weeks until study ends, approximately 4 years

• DOR

  Every 8-12 weeks until study ends, approximately 4 years

• Time to response

  Every 8-12 weeks until study ends, approximately 4 years

Study Arms (10)

Arm 1

EXPERIMENTAL

EGF816+ trametinib in escalation phase

Drug: EGF816; Drug: trametinib

Arm 2

EXPERIMENTAL

EGF816 + ribociclib in escalation phase

Drug: EGF816; Drug: ribociclib

Arm 3

EXPERIMENTAL

EGF816 + LXH254 in escalation phase

Drug: EGF816; Drug: LXH254

Arm A

EXPERIMENTAL

EGF816 + INC280 in expansion phase (patients with no known resistance mechanism)

Drug: EGF816; Drug: INC280

Arm B

EXPERIMENTAL

EGF816 + trametinib in expansion phase

Drug: EGF816; Drug: trametinib

Arm C

EXPERIMENTAL

EGF816 + ribociclib in expansion phase

Drug: EGF816; Drug: ribociclib

Arm D

EXPERIMENTAL

EGF816 + LXH254 in expansion phase (patients with no known resistance mechanism)

Drug: EGF816; Drug: LXH254

Arm E

EXPERIMENTAL

EGF816 + LXH254 in expansion phase (patients with known resistance mechanism)

Drug: EGF816; Drug: LXH254

Arm F

EXPERIMENTAL

EGF816 + gefitinib in expansion phase

Drug: EGF816; Drug: gefitinib

Arm G

EXPERIMENTAL

EGF816 + INC280 in expansion phase (patients with known resistance mechanism)

Drug: EGF816; Drug: INC280

Interventions

EGF816 DRUG

Study Drug

Arm 1; Arm 2; Arm 3; Arm A; Arm B; Arm C; Arm D; Arm E; Arm F; Arm G

trametinib DRUG

Study Drug

Arm 1; Arm B

ribociclib DRUG

Study Drug

Arm 2; Arm C

LXH254 DRUG

Study Drug

Arm 3; Arm D; Arm E

INC280 DRUG

Study Drug

Arm A; Arm G

gefitinib DRUG

Study Drug

Arm F

Eligibility Criteria

• Age: 18 Years - 100 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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:
• weeks for fluoropyrimidine monotherapy
• weeks for nitrosoureas and mitomycin
• 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

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (11)

Novartis Investigative Site

Toronto, Ontario, M5G 2M9, Canada

Location

Novartis Investigative Site

Cologne, North Rhine-Westphalia, 50937, Germany

Location

Novartis Investigative Site

Essen, 45147, Germany

Location

Novartis Investigative Site

Hong Kong, 999077, Hong Kong

Location

Novartis Investigative Site

Ancona, AN, 60126, Italy

Location

Novartis Investigative Site

Milan, MI, 20162, Italy

Location

Novartis Investigative Site

Rozzano, MI, 20089, Italy

Location

Novartis Investigative Site

Singapore, 119074, Singapore

Location

Novartis Investigative Site

Singapore, 168583, Singapore

Location

Novartis Investigative Site

Tainan, 704302, Taiwan

Location

Novartis Investigative Site

Taipei, 10002, Taiwan

Location

MeSH Terms

Interventions

nazartinib; trametinib; ribociclib; naporafenib; capmatinib; Gefitinib

Intervention Hierarchy (Ancestors)

Quinazolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Novartis Pharmaceuticals

  Novartis

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 31, 2017
• First Posted: November 6, 2017
• Study Start: January 29, 2018
• Primary Completion (Estimated): October 5, 2026
• Study Completion (Estimated): October 5, 2026
• Last Updated: January 16, 2026

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will not share

Locations

TW (2); HK (1); IT (3); CA (1); DE (2); SG (2)