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

NCT02108964 | Completed Phase 1 Results FDA Drug

• 2 other identifiers: CEGF816X21012013-004482-14
• Study Type: interventional
• Target: 225
• Locations: 9 countries
• Sites: 14

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.

Conditions

Advanced Non-small Cell Lung Cancer

Keywords

NSCLC; Non-small Cell Lung Cancer EGFRmut; EGFR TKIs (EGF816); acquired T790M mutation; de novo T790M mutation; EGFR TKI activating mutation (i.e. L858R or ex19del); Treatment naive advanced NSCLC with EGFR activating mutations; Locally advanced NSCLC (Stage IIIB NSCLC not amenable to definitive multi-modality therapy including surgery); Metastatic NSCLC refers to Stage IV NSCLC; 1st line

Outcome Measures

Primary Outcomes (2)

• Number of Participants With Dose Limiting Toxicities (DLTs) (Phase I Part)

  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.

  First 28 days of dosing

• Overall Response Rate (ORR) by Blinded Independent Review Committee (BIRC) (Phase II Part)

  ORR is defined as the percentage 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).

  From baseline up to 64 weeks

Secondary Outcomes (15)

• Progression-free Survival (PFS) by Investigator Assessment (Phase I & Phase II Parts)

  At least 24 weeks up to approx. 9 years

• Duration of Response (DOR) by Investigator Assessment (Phase I & II Parts)

  At least 24 weeks up to approx. 9 years

• Observed Maximum Plasma Concentration (Cmax) of EGF816 and Metabolite LMI258 (Phase I & Phase II Part)

  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).

• Time to Maximum Plasma Concentration (Tmax) of EGF816 and Metabolite LMI258 (Phase I & Phase II Part). Tmax is the Time to Reach Maximum (Peak) Plasma Drug Concentration (Time).

  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).

• 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)

  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).

Study Arms (2)

Phase I part

EXPERIMENTAL

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.

Drug: EGF816

Phase II part

EXPERIMENTAL

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.

Drug: EGF816

Interventions

EGF816 DRUG

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.

Also known as: Nazartinib

Phase I part; Phase II part

Eligibility Criteria

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

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (14)

Massachusetts General Hospital Mass General

Boston, Massachusetts, 02114, United States

Location

Memorial Sloan Kettering Oncology Department

New York, New York, 10017, United States

Location

Novartis Investigative Site

Toronto, Ontario, M5G 2M9, Canada

Location

Novartis Investigative Site

Berlin, 13125, Germany

Location

Novartis Investigative Site

Cologne, 50937, Germany

Location

Novartis Investigative Site

Nagoya, Aichi-ken, 464 8681, Japan

Location

Novartis Investigative Site

Fukuoka, Fukuoka, 811-1395, Japan

Location

Novartis Investigative Site

Zoetermeer, NL-2722 EP, Netherlands

Location

Novartis Investigative Site

Singapore, 168583, Singapore

Location

Novartis Investigative Site

Seoul, 03080, South Korea

Location

Novartis Investigative Site

Seoul, 05505, South Korea

Location

Novartis Investigative Site

Barcelona, Catalonia, 08035, Spain

Location

Novartis Investigative Site

Madrid, 28041, Spain

Location

Novartis Investigative Site

Taipei, 10002, Taiwan

Location

Related Publications (2)

• 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.

  PMID: 35810553 DERIVED

• 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.

  PMID: 31954624 DERIVED

MeSH Terms

Interventions

nazartinib

Results Point of Contact

• Title: Study Director
• Organization: Novartis Pharmaceuticals

Novartis.email@novartis.com

862-778-8300

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

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

Study Record Dates

• First Submitted: April 7, 2014
• First Posted: April 9, 2014
• Study Start: June 6, 2014
• Primary Completion: March 22, 2018
• Study Completion: August 15, 2023
• Last Updated: December 11, 2024
• Results First Posted: October 26, 2020

Record last verified: 2024-12

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP

Locations

CA (1); ES (2); SG (1); JP (2); TW (1); US (2); KR (2); NL (1); DE (2)