A Phase I/II, Multicenter, Open-label Study of EGFRmut-TKI EGF816, Administered Orally in Adult Patients With EGFRmut Solid Malignancies
- Registration Number
- NCT02108964
- Lead Sponsor
- Novartis Pharmaceuticals
- 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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 225
(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.
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Phase I part EGF816 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. Phase II part EGF816 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.
- Primary Outcome Measures
Name Time Method Number of Participants With Dose Limiting Toxicities (DLTs) (Phase I Part) 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) From baseline up to 64 weeks 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).
- Secondary Outcome Measures
Name Time Method Progression-free Survival (PFS) by Investigator Assessment (Phase I & Phase II Parts) At least 24 weeks up to approx. 9 years 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) At least 24 weeks up to approx. 9 years 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) 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).
Cmax is maximum (peak) observed plasma drug concentration (mass x volume-1).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). To characterize the PK properties of EGF816 and metabolite LMI258, Tmax will be calculated (Phase I \& II parts). Tmax is the time to reach maximum (peak) plasma drug concentration (time).
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). To characterize the PK properties of EGF816 and metabolite LMI258, AUCtau will be calculated (Phase I \& II parts). AUCtau is the AUC calculated to the end of a dosing interval (tau) (amount x time x volume-1).
Percentage Change From Baseline in H-score for Immunohistochemistry (IHC) Biomarkers From Tumor Tissue Samples (Phase I Part) Baseline and Cycle 1 Day 15 Changes in EGFR signaling pathway of newly obtained tumor samples following EGF816 treatment were evaluated by IHC of three pharmacodynamics (PD) biomarkers: p-EGFR, p-AKT and p-ERK. The assigned H-score semi-quantitatively assessed the expression level of these protein markers and their phosphorylated forms.
Overall Response Rate (ORR) by Investigator Assessment (Phase I & II Parts) At least 24 weeks up to approx. 4 years ORR is defined as percentage of patients with best overall response of partial response (PR)+ complete response (CR) determined by Investigator assessment in accordance to RECIST 1.1
Disease Control Rate (DCR) by Investigator Assessment (Phase I & II Parts) At least 24 weeks up to approx. 4 years 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) At least 24 weeks up to approx. 9 years 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) At least 24 weeks up to approx. 9 years Assessment of the tolerability of EGF816 will be performed continuously during the treatment phase
Duration of Response (DOR) by BIRC (Phase II Part) At least 24 weeks up to approx. 9 years 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) At least 24 weeks up to approx. 9 years DCR is defined as the percentage 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) At least 24 weeks up to approx. 9 years 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) At least 24 weeks up to approx. 9 years 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) At least 24 weeks up to approx. 9 years OS is defined as the time from first dose of the study treatment to the date of death due to any cause.
Trial Locations
- Locations (3)
Massachusetts General Hospital Mass General
🇺🇸Boston, Massachusetts, United States
Memorial Sloan Kettering Oncology Department
🇺🇸New York, New York, United States
Novartis Investigative Site
🇨🇳Taipei, Taiwan