A Phase I/II, Multicenter, Open-label Study of EGFRmut-TKI EGF816, Administered Orally in Adult Patients With EGFRmut Solid Malignancies

• ClinicalTrials.gov Identifier: NCT02108964
• Recruitment Status: Completed
• First Posted: April 9, 2014
• Results First Posted: October 26, 2020
• Last Update Posted: September 7, 2023
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Tracking Information

• First Submitted Date: April 7, 2014
• First Posted Date: April 9, 2014
• Results First Submitted Date: October 1, 2020
• Results First Posted Date: October 26, 2020
• Last Update Posted Date: September 7, 2023
• Actual Study Start Date: June 6, 2014
• Actual Primary Completion Date: March 22, 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 1, 2020)

• Number of Participants With Dose Limiting Toxicities (DLTs) (Phase I Part) [ Time Frame: First 28 days of dosing ]
  Number of participants with DLTs during the first 28 days of therapy. A DLT is defined as an adverse event or abnormal laboratory value assessed as unrelated to disease, disease progression, inter-current illness, or concomitant medications that occurs within the first cycle of treatment with EGF816 and meets any of the criteria described in the protocol. A participant with multiple occurrences of DLTs under one treatment is counted only once.
• Overall Response Rate (ORR) by Blinded Independent Review Committee (BIRC) (Phase II Part) [ Time Frame: From baseline up to 64 weeks ]
  ORR is defined as the proportion of patients with a best overall response of complete response (CR) or partial response (PR) determined by BIRC assessment in accordance to Response Evaluation Criteria in Solid Tumors (RECIST 1.1).

Original Primary Outcome Measures (submitted: April 7, 2014)

• Phase I Part: Incidence of dose limiting toxicity (DLT) [ Time Frame: first 28 days of dosing ]
  Maximum tolerated dose/Recommended dose for expansion (MTD)/RDE)
• Phase II Part: Overall response rate (ORR) [ Time Frame: baseline, every 8 weeks until disease progression, consent withdraw or death up to 3 years ]
  ORR (Overall respnse rate ). Overall respnse rate is the proportion of patients with a best overall response of complete response (CR) or partial respose (PR) according to RECIST 1.1 criteria

Current Secondary Outcome Measures (submitted: October 1, 2020)

• Progression-free Survival (PFS) by Investigator Assessment (Phase I & Phase II Parts) [ Time Frame: At least 24 weeks ]
  PFS is defined as time from date of first dose of study treatment to date of first documented disease progression or death due to any cause determined by Investigator assessment in accordance to RECIST 1.1
• Duration of Response (DOR) by Investigator Assessment (Phase I & II Parts) [ Time Frame: At least 24 weeks ]
  DOR is defined as the time from first documented response (PR or CR) to the date of first documented disease progression or death due to any cause determined by Investigator assessment in accordance to RECIST 1.1
• Observed Maximum Plasma Concentration (Cmax) of EGF816 and Metabolite LMI258 (Phase I & Phase II Part) [ Time Frame: Cycle (C) 1 Day (D) 1 (pre-dose and 0.5,1,2,3,4,6,8,12 and 24 hours (hrs) post-dose), C1D15 (pre-dose and 0.5,1,2,3,4,6,8,12 and 24 hrs post-dose) (for Phase I part only) and C2D1 (pre-dose and 0.5,1,2,3,4,6,8,12 and 24 hrs post-dose). ]
  To characterize the PK properties of EGF816 and metabolite LMI258, Cmax will be calculated (Phase I & II parts)
• Time to Maximum Plasma Concentration (Tmax) of EGF816 and Metabolite LMI258 (Phase I & Phase II Part) [ Time Frame: Cycle (C) 1 Day (D) 1 (pre-dose and 0.5,1,2,3,4,6,8,12 and 24 hours (hrs) post-dose), C1D15 (pre-dose and 0.5,1,2,3,4,6,8,12 and 24 hrs post-dose) (for Phase I part only) and C2D1 (pre-dose and 0.5,1,2,3,4,6,8,12 and 24 hrs post-dose). ]
  To characterize the PK properties of EGF816 and metabolite LMI258, Tmax will be calculated (Phase I & II parts)
• Area Under the Serum Concentration-time Curve From Time Zero to the End of the Dosing Interval Tau (AUCtau) of EGF816 and Metabolite LMI258 (Phase I & Phase II Part) [ Time Frame: Cycle (C) 1 Day (D) 1 (pre-dose and 0.5,1,2,3,4,6,8,12 and 24 hours (hrs) post-dose), C1D15 (pre-dose and 0.5,1,2,3,4,6,8,12 and 24 hrs post-dose) (for Phase I part only) and C2D1 (pre-dose and 0.5,1,2,3,4,6,8,12 and 24 hrs post-dose). ]
  To characterize the PK properties of EGF816 and metabolite LMI258, AUCtau will be calculated (Phase I & II parts)
• Change From Baseline in H-score for Immunohistochemistry (IHC) Biomarkers From Tumor Tissue Samples (Phase I Part) [ Time Frame: Baseline and Cycle 1 Day 15 ]
  Changes in EGFR signaling pathway of newly obtained tumor samples following EGF816 treatment will be evaluated by IHC of three pharmacodynamics (PD) biomarkers: p-EGFR, p-AKT and p-ERK. The assigned H-score semi-quantitatively assesses the expression level of these protein markers and their phosphorylated forms.
• Overall Response Rate (ORR) by Investigator Assessment (Phase I & II Parts) [ Time Frame: At least 24 weeks ]
  ORR is defined as proportion of patients with best overall response of PR+CR determined by Investigator assessment in accordance to RECIST 1.1
• Disease Control Rate (DCR) by Investigator Assessment (Phase I & II Parts) [ Time Frame: At least 24 weeks ]
  DCR is defined as the proportion of patients with best overall response of CR, PR, or SD determined by Investigator assessment in accordance to RECIST 1.1
• Time to Response (TTR) by Investigator Assessment (Phase I & II Parts) [ Time Frame: At least 24 weeks ]
  TTR is defined as the time from the date of the first dose to the date of first documented response (CR or PR) determined by Investigator assessment in accordance to RECIST 1.1
• Number of Participants With Dose Interruptions and Dose Reductions (Phase I & II Parts) [ Time Frame: At least 24 weeks ]
  Assessment of the tolerability of EGF816 will be performed continuously during the treatment phase
• Duration of Response (DOR) by BIRC (Phase II Part) [ Time Frame: At least 24 weeks ]
  DOR is defined as the time from first documented response (PR or CR) to the date of first documented disease progression or death due to any cause determined by BIRC in accordance to RECIST 1.1
• Disease Control Rate (DCR) by BIRC (Phase II Part) [ Time Frame: At least 24 weeks ]
  DCR is defined as the proportion of patients with best overall response of CR, PR, or SD determined by BIRC in accordance to RECIST 1.1
• Progression-Free Survival (PFS) by BIRC (Phase II Part) [ Time Frame: At least 24 weeks ]
  PFS is defined as time from date of first dose of study treatment to date of first documented disease progression or death due to any cause determined by BIRC in accordance to RECIST 1.1
• Time to Response (TTR) by BIRC (Phase II Part) [ Time Frame: At least 24 weeks ]
  TTR is defined as as the time from the date of first dose of study treatment to the date of first documented response (CR or PR) determined by by BIRC in accordance to RECIST 1.1
• Overall Survival (OS) (Phase II Part) [ Time Frame: At least 24 weeks ]
  OS is defined as the time from first dose of the study treatment to the date of death due to any cause.

Original Secondary Outcome Measures (submitted: April 7, 2014)

• Best overall response [ Time Frame: baseline, every 8 weeks until disease progression, consent withdraw or death up to 3 years ]
  Best overall response (BOR). BOR is the best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for PD the smallest measurements recorded since the treatment started).
• Progression-free survival [ Time Frame: baseline, every 8 weeks until disease progression, consent withdraw or death up to 3 years ]
  Progression-free survival (PFS). PFS is the time from date of randomization/start of treatment to the date of event defined as the first documented progression or death due to any cause according to RECIST 1.1 criteria
• Duration of response [ Time Frame: baseline, every 8 weeks until disease progression, consent withdraw or death up to 3 years ]
  Duration of response (DOR). For patients with a CR or PR (which may have to be confirmed the start date is the date of first documented response (CR or PR) and the end date and censoring is defined the same as that for time to progression.
• Frequency/severity of adverse events (AEs) [ Time Frame: continuously during study until 30 days after safety follow up ]
  To characterize EGF816 as a measure of safety
• Pharmacokinetics properties of EGF816 and metabolite LMI258 [ Time Frame: cycle 1 day 1,2,8, 15; cycle 2 day 1, 2; cycle 3 day 1; cycle 4 day 1 ]
  Plasma concentration vs. time profiles, plasma PK parameters
• the tumor EGFR signaling inhibition by EGF816 [ Time Frame: baseline and cycle 1 day 15 ]
  Pre- and post- treatment immunohistochemistry of EGFR pathway molecules
• Number of Dose interruptions and reductions [ Time Frame: continuously throughout the study until 30 days after safety follow up ]
  To characterize the EGF816 as a measure of tolerability.
• Frequency/severity of serious adverse events (SAEs) [ Time Frame: continuously during study until 30 days after safety follow up ]
  To characterize EGF816 as a measure of safety

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Phase I/II, Multicenter, Open-label Study of EGFRmut-TKI EGF816, Administered Orally in Adult Patients With EGFRmut Solid Malignancies
• Official Title: A Phase I/II, Multicenter, Open-label Study of EGFRmut-TKI EGF816, Administered Orally in Adult Patients With EGFRmut Solid Malignancies

Brief Summary

This is a Phase I/II, multi-center, open-label study, composed with a Phase I part (dose-escalation phase) followed by a Phase II part (expansion phase).

The dose escalation phase was designed to determine as primary objective the maximum tolerated dose (MTD) or recommended Phase II dose (RP2D) of EGF816 monotherapy in adult subjects with locally advanced (stage IIIB) or metastatic (stage IV) NSCLC harboring specific EGFR mutations. Patients may have or not have received prior lines of antineoplastic therapy. An adaptive Bayesian Logistic Regression Model (BLRM) employing the escalation with overdose control (EWOC) principle will be used during the dose escalation part for dose level selection and MTD recommendation. The primary objective of the Phase II part is to estimate antitumor activity of EGF816 as measured by overall response rate (ORR) determined by Blinded Independent Review Committee (BIRC) assessment in accordance to RECIST 1.1.

• Detailed Description: Following completion of screening procedures and confirmation of patient eligibility, the participants are enrolled in the study. The study treatment begin on Cycle 1, Day 1 with the first administration of EGF816. A treatment cycle is defined as 28 days. Oral EGF816 is administered once daily on a continuous schedule until patient experiences unacceptable toxicity, progressive disease (PD), and/or treatment is discontinued at the discretion of the investigator, patient withdrawal of consent, or due to any other reasons. Treatment with EGF816 may be continued beyond RECIST 1.1 defined PD, if, in the judgment of the investigator, there is evidence of clinical benefit and the patient wishes to continue with the study treatment.
• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Advanced Non-small Cell Lung Cancer

Intervention

Drug: EGF816

EGF816 will be dosed once daily. On the first day of each treatment cycle, the patient receives an adequate drug supply for self-administration at home. The investigator will instruct the patient to take EGF816 exactly as prescribed.

Other Name: Nazartinib

Study Arms

• Experimental: Phase I part
  Participants with locally advanced or metastatic NSCLC harboring specific EGFR mutations will be administered escalated doses of EGF816 orally once a day as continuous daily dosing in each cycle (of 28 days) during Phase I part of the study. The starting dose for the Phase I part first cohort of patients will be 75 mg once per day capsule.
  Intervention: Drug: EGF816
• Experimental: Phase II part
  Treatment naïve participants with locally advanced or metastatic NSCLC harboring EGFR mutations will be administered with EGF816 at RP2D during Phase II part of the study.
  Intervention: Drug: EGF816

Publications *

• Tan DSW, Kim SW, Ponce Aix S, Sequist LV, Smit EF, Yang JCH, Hida T, Toyozawa R, Felip E, Wolf J, Grohe C, Leighl NB, Riely G, Cui X, Zou M, Ghebremariam S, O'Sullivan-Djentuh L, Belli R, Giovannini M, Kim DW. Nazartinib for treatment-naive EGFR-mutant non-small cell lung cancer: Results of a phase 2, single-arm, open-label study. Eur J Cancer. 2022 Sep;172:276-286. doi: 10.1016/j.ejca.2022.05.023. Epub 2022 Jul 7.
• Tan DS, Leighl NB, Riely GJ, Yang JC, Sequist LV, Wolf J, Seto T, Felip E, Aix SP, Jonnaert M, Pan C, Tan EY, Ko J, Moody SE, Kim DW. Safety and efficacy of nazartinib (EGF816) in adults with EGFR-mutant non-small-cell lung carcinoma: a multicentre, open-label, phase 1 study. Lancet Respir Med. 2020 Jun;8(6):561-572. doi: 10.1016/S2213-2600(19)30267-X. Epub 2020 Jan 15.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: October 1, 2020): 225
• Original Estimated Enrollment (submitted: April 7, 2014): 211
• Actual Study Completion Date: August 15, 2023
• Actual Primary Completion Date: March 22, 2018 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria: (For all patients unless otherwise specified)

• Histologically or cytologically confirmed locally advanced (stage IIIB not amenable to definitive multi-modality therapy including surgery) or metastatic (stage IV) EGFR mutant NSCLC.
• Patients with controlled brain metastases
• ECOG performance status: Phase I part: 0, 1, or 2; Phase II part: 0 or 1
• Presence of at least one measurable lesion according to RECIST 1.1 per investigator assessment
• Patients who are either Hepatitis B surface antigen (HBsAg) positive or hepatitis B virus (HBV)-DNA positive must be willing and able to take antiviral therapy 1-2 weeks prior to 1st dose of EGF816 treatment and continue on antiviral therapy for at least 4 weeks after the last dose of EGF816
• Patients must have negative hepatitis C antibody (HCV-Ab) or positive HCV-Ab but undetectable level of HCV-RNA. Note: patients with detectable HCV-RNA are not eligible for the study.
• For Phase I: patients must have failed no more than 3 lines of any systemic antineoplastic therapy for advanced NSCLC, including EGFR-TKI
• For Phase II: patients must be naïve from any systemic antineoplastic therapy in the advanced setting. Patients who have failed no more than 1 cycle of systemic antineoplastic therapy in the advanced setting are allowed.

Exclusion criteria: (For all patients unless otherwise specified)

• Patients with a history or presence of interstitial lung disease (ILD) or interstitial pneumonitis, including clinically significant radiation pneumonitis (i.e. affecting activities of daily living or requiring therapeutic intervention)
• Presence or history of another malignancy
• Undergone a bone marrow or solid organ transplant
• Known history of human immunodeficiency virus (HIV) seropositivity
• Patients receiving concomitant immunosuppressive agents or chronic corticosteroids use at the time of study entry except for control of brain metastases, topical applications, inhaled sprays, eye drops or local injections
• Patients with clinically significant, uncontrolled heart disease
• Any prior therapies ≤ 4 weeks prior to the first dose of study treatment
• Patients who are receiving treatment with medications that are known to be strong inhibitors or inducers of CYP3A4/5 and cannot be discontinued 1 week prior to the start of EGF816 treatment and for the duration of the study.
• Patients who have impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of EGF816
• Patients who are receiving treatment with any enzyme-inducing anticonvulsant that cannot be discontinued at least 1 week before first dose of study treatment, and for the duration of the study
• Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception
• Sexually active males unless they use a condom during intercourse while taking drug and for 3 months after stopping treatment

Other protocol-defined inclusion and exclusion criteria may apply.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Canada, Germany, Japan, Korea, Republic of, Netherlands, Singapore, Spain, Taiwan, United States
• Removed Location Countries: Belgium, China, France, Italy

Administrative Information

• NCT Number: NCT02108964
• Other Study ID Numbers: CEGF816X2101; 2013-004482-14 ( EudraCT Number )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes

Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)

• Current Responsible Party: Novartis ( Novartis Pharmaceuticals )
• Original Responsible Party: Same as current
• Current Study Sponsor: Novartis Pharmaceuticals
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Novartis Pharmaceuticals; Novartis Pharmaceuticals

• PRS Account: Novartis
• Verification Date: September 2023