EGF816 and Trametinib in Patients With Non-small Cell Lung Cancer Harboring Activating EGFR Mutations

NCT03516214 | Completed Phase 1 DMC FDA Drug

• 3 other identifiers: Uni-Koeln-17842016-003944-35AIO-TRK-0216
• Study Type: interventional
• Target: 18
• Locations: 2 countries
• Sites: 7

Brief Summary

The aim of this trial is to identify the maximum tolerated dose (MTD)/recommended phase II dose (RP2D), to define pharmacokinetic (PK) parameters and the preliminary efficacy of a continuous treatment with EGF816 and trametinib in locally advanced or metastatic (stage IIIB or IV) lung cancer patients with activating mutations in the epithelial growth factor receptor (EGFR).

Conditions

Bronchial Neoplasms

Keywords

acquired resistance; EGFR p.T790M-positive; osimertinib resistance; EGFR p.T790M-negative

Outcome Measures

Primary Outcomes (1)

• Incidence of dose-limiting-toxicities (DLT) of the combination of EGF816 and trametinib to assess the maximum tolerated dose (MTD)/recommended phase II dose (RP2D)

  Incidence of dose-limiting-toxicities (DLT) that occur during the DLT period (i.e. first 4 weeks of treatment) of each patient in the dose-escalation part (N=18)

  Approximately one and a half years (from FPFV until the end of the DLT period of the last patient included into the trial or until death of the last patient, whichever occurs first)

Secondary Outcomes (9)

• Number of participants with treatment-related adverse events as assessed by CTCAE v4.03

  Approximately four years (from FPFV until the completion of the clinical trial)

• Number of patients who experienced dose interruptions or reductions

  Approximately four years (from FPFV until the end-of-treatment visit of the last patient or until death of the last patient, whichever occurs first)

• Objective response rate (ORR) according to RECIST 1.1

  Approximately 4 years (from FPFV until the progression of the last patient treated within the trial or until death of the last patient, whichever occurs first)

• Disease control rate (DCR) according to RECIST 1.1

  Approximately 4 years (from FPFV until the progression of the last patient treated within the trial or until death of the last patient, whichever occurs first)

• Progression-free survival (PFS) according to RECIST 1.1

  Approximately 4 years (from FPFV until the progression of the last patient treated within the trial or until death of the last patient, whichever occurs first)

Other Outcomes (4)

• Massively parallel sequencing (MPS), FISH and phospho-immunoblots of pre-treatment tumour samples in order to assess potential predictive markers for response and resistance

  Approximately one and a half years (from FPFV until the inclusion of the last patient)

• Massively parallel sequencing (MPS), FISH and phospho-immunoblots of post-treatment tumour samples in order to assess potential predictive markers for response and resistance

  Approximately four years (from the first progressing patient until the last progressing patient or death of the last patient, whichever occurs first)

• MPS of cell-free DNA (cfDNA) at baseline, during treatment and at progression to assess the value of cell-free plasma DNA (cfDNA) for assessment of predictive molecular markers of response and resistance and for monitoring patients under therapy

  Approximately four years (from FPFV until the progression of the last patient or death of the last patient, whichever occurs first)

Study Arms (1)

EGF816 (nazartinib) and trametinib

EXPERIMENTAL

Patients will receive oral EGF816 (nazartinib) and trametinib at escalating dose levels. Intra-patient dose-escalation will not be allowed.

Drug: EGF816; Drug: Trametinib

Interventions

EGF816 DRUG

Continuous oral treatment (once daily) with the 3rd generation EGFR inhibitor EGF816.

Also known as: Nazartinib

EGF816 (nazartinib) and trametinib

Trametinib DRUG

Continuous oral treatment (once daily) with the MEK inhibitor trametinib.

Also known as: Mekinist

EGF816 (nazartinib) and trametinib

Eligibility Criteria

• Age: 18 Years - 99 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Written informed consent must have been obtained prior to any screening procedures.
• Patients (male or female) ≥ 18 years of age.
• Histologically documented, locally advanced or recurrent (stage IIIB who are not eligible for combined modality treatment) or metastatic (stage IV) non-small cell lung cancer.
• Presence of at least one measurable lesion according to RECIST v.1.1.
• ECOG performance status ≤ 2
• Patients must have NSCLC harbouring EGFR p.L858R or EGFR del19 as assessed by local testing.
• Patients must be EGFR TKI treatment naïve (prior chemotherapy treatment is allowed) or must have progressed while on continuous treatment with a first- or second-generation EGFR TKI (EGFR p.T790M-negative or -positive) or must have progressed while on continuous treatment with osimertinib (EGFR p.T790M-negative or -positive)
• In patients who have received no prior EGFR TKI treatment, an archival biopsy sample, defined as a sample being obtained prior to any anti-cancer treatment is mandatory. If an archival biopsy fulfilling this criterion is not available, patients must be suitable and willing to undergo baseline biopsy according to the local institution's guidelines (newly obtained biopsy).
• Patients who have received prior osimertinib treatment, may only be eligible if no standard treatment approach outside this trial is available or feasible (e.g. chemotherapy)
• Patients who have progressed while on continuous treatment with a first- or second-generation EGFR inhibitor and whose tumour has been tested EGFR p.T790M-negative may only be eligible if no standard treatment approach outside this trial is available or feasible (e.g. chemotherapy).
• In patients who have received prior EGFR TKI treatment, progression of disease according to RECIST v1.1 while on continuous treatment with an EGFR TKI (e.g. erlotinib, gefitinib, afatinib or osimertinib) must be documented.

You may not qualify if:

• History of allergic reactions or hypersensitivity to one of the study drugs or to any component of the study drugs
• Prior treatment with any investigational agent known to inhibit EGFR (mutant or wild-type)
• Prior treatment with any agent known to inhibit MEK/ERK or other mediators of RAS pathway.
• Patients with high level MET amplification in the archival or newly obtained biopsy sample as determined by local testing. High-level MET amplification is defined as: a) a MET/CEN7 ratio ≥2.0 and/or b) an average MET gene copy number per cell of ≥6.0 \[modified Schildhaus et al., 2015\].
• Patients with EGFR mutations other than EGFR del19, p.L858R or p.T790M.
• Patients with brain metastases. However, if radiation therapy and/or surgery has been completed at least 4 weeks prior to screening for the trial and evaluation by CT (with contrast enhancement) or MRI at study baseline demonstrates the disease to be stable and if the patient remains asymptomatic and off steroids, then patients with brain metastases may be enrolled.
• Patients with presence or history of carcinomatous meningitis.
• Any acute or chronic medical, mental or psychological condition, which in the opinion of the investigator would not permit the patient to participate or complete the study or understand the patient information
• History of hepatitis B (HBV) or hepatitis C (HCV) or positive result in mandatory testing for acute or chronic hepatitis B or hepatitis C
• Known HIV infection or history of HIV infection independent from the cellular immune status
• Patients who receive any continuous, long term immunosuppressive treatment, including long term treatment with steroids at immunosuppressive doses at the time of study entry
• Patients who underwent bone marrow or solid organ transplantation, including patients who do not receive any immunosuppressive treatment.
• Presence or history of any other primary malignancy other than NSCLC within 5 years prior to enrolment into the trial. Except from this: Adequately treated basal or squamous cell carcinoma of the skin or any adequately treated in situ carcinoma
• Any of the following within 6 months prior to first trial drug administration: Myocardial infarction (NSTEMI or STEMI), severe/unstable angina pectoris, symptomatic congestive heart failure (\> NYHA II), uncontrolled hypertension, coronary/peripheral artery bypass graft, cerebrovascular accident or transient ischemic attack, atrial fibrillation of CTCAE Grade ≥ 2, ongoing cardiac dysrhythmias of CTCAE Grade ≥ 2, including corrected QTcF prolongation of \> 480 ms,
• Aortic valve stenosis with mean gradient ≥ 25 mmHg and aortic valve area of ≤ 1.5 cm2

Sponsors & Collaborators

• University of Cologne: lead

Study Sites (7)

University Hospital of Cologne

Cologne, Germany

Location

University Hospital Dresden

Dresden, Germany

Location

University Hospital Essen

Essen, Germany

Location

University Hospital Frankfurt

Frankfurt, Germany

Location

University Hospital Würzburg

Würzburg, Germany

Location

Instituto Oncológico Dr. Rosell

Barcelona, 08028, Spain

Location

Vall d'Hebron University Hospital

Barcelona, Spain

Location

MeSH Terms

Conditions

Bronchial Neoplasms

Interventions

nazartinib; trametinib

Condition Hierarchy (Ancestors)

Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Bronchial Diseases; Respiratory Tract Diseases

Study Officials

• Jürgen Wolf, Prof. Dr.

  University Hospital of Cologne

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Prof. Dr.

Study Record Dates

• First Submitted: March 29, 2018
• First Posted: May 4, 2018
• Study Start: April 25, 2018
• Primary Completion: September 30, 2022
• Study Completion: November 27, 2023
• Last Updated: February 15, 2024

Record last verified: 2024-02

Locations

DE (5); ES (2)