Advanced Non-small Cell Lung Cancer
Conditions
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
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.
Interventions
DRUGEGF816
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.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| 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 |
| 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. |
| 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 |
| 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 |
Countries
Canada, Germany, Japan, Netherlands, Singapore, South Korea, Spain, Taiwan, United States
Participant flow
Recruitment details
This is a 2-part study conducted in 14 investigative sites in 9 countries: Phase I part (dose-escalation) and Phase II part (dose expansion)
Pre-assignment details
370 subjects were screened for eligibility during the 28 days prior to starting study treatment on Cycle 1 Day 1 (C1D1). The eligibility assessments were performed and ensured that all inclusion and exclusion criteria were satisfied
Participants by arm
| Arm | Count |
|---|---|
| EGF816 75 mg (Phase I Part) Participants with locally advanced or metastatic NSCLC harboring specific EGFR mutations were administered with EGF816 75 mg orally once a day as continuous daily dosing in each cycle (of 28 days) during Phase I part of the study. | 17 |
| EGF816 100 mg (Phase I Part) Participants with locally advanced or metastatic NSCLC harboring specific EGFR mutations were administered with EGF816 100 mg orally once a day as continuous daily dosing in each cycle (of 28 days) during Phase I part of the study. | 38 |
| EGF816 150 mg (Phase I Part) Participants with locally advanced or metastatic NSCLC harboring specific EGFR mutations were administered with EGF816 150 mg orally once a day as continuous daily dosing in each cycle (of 28 days) during Phase I part of the study. | 73 |
| EGF816 200 mg (Phase I Part) Participants with locally advanced or metastatic NSCLC harboring specific EGFR mutations were administered with EGF816 200 mg orally once a day as continuous daily dosing in each cycle (of 28 days) during Phase I part of the study. | 8 |
| EGF816 225 mg (Phase I Part) Participants with locally advanced or metastatic NSCLC harboring specific EGFR mutations were administered with EGF816 225 mg orally once a day as continuous daily dosing in each cycle (of 28 days) during Phase I part of the study. | 28 |
| EGF816 300 mg (Phase I Part) Participants with locally advanced or metastatic NSCLC harboring specific EGFR mutations were administered with EGF816 300 mg orally once a day as continuous daily dosing in each cycle (of 28 days) during Phase I part of the study. | 5 |
| EGF816 350 mg (Phase I Part) Participants with locally advanced or metastatic NSCLC harboring specific EGFR mutations were administered with EGF816 350 mg orally once a day as continuous daily dosing in each cycle (of 28 days) during Phase I part of the study. | 11 |
| EGF816 150 mg (Phase II Part) Treatment naïve participants with locally advanced or metastatic NSCLC harboring EGFR mutations were administered with 150 mg orally once a day as continuous daily dosing in each cycle (of 28 days) during Phase II part of the study. | 45 |
| Total | 225 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 |
|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 4 | 0 | 1 | 0 | 3 | 2 |
| Overall Study | Death | 1 | 1 | 4 | 0 | 3 | 0 | 0 | 2 |
| Overall Study | Physician Decision | 1 | 5 | 7 | 1 | 2 | 1 | 1 | 3 |
| Overall Study | Progressive disease | 15 | 31 | 54 | 7 | 20 | 4 | 6 | 33 |
| Overall Study | Study terminated by Sponsor: remaining participants benefiting from drug were transitioned to PSDS | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 3 |
| Overall Study | Subject/Guardian decision | 0 | 1 | 4 | 0 | 2 | 0 | 1 | 2 |
Baseline characteristics
| Characteristic | Total | EGF816 100 mg (Phase I Part) | EGF816 75 mg (Phase I Part) | EGF816 150 mg (Phase I Part) | EGF816 200 mg (Phase I Part) | EGF816 225 mg (Phase I Part) | EGF816 300 mg (Phase I Part) | EGF816 350 mg (Phase I Part) | EGF816 150 mg (Phase II Part) |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 92 Participants | 15 Participants | 7 Participants | 26 Participants | 2 Participants | 13 Participants | 3 Participants | 4 Participants | 22 Participants |
| Age, Categorical Between 18 and 65 years | 133 Participants | 23 Participants | 10 Participants | 47 Participants | 6 Participants | 15 Participants | 2 Participants | 7 Participants | 23 Participants |
| Race/Ethnicity, Customized Asian | 147 Participants | 22 Participants | 13 Participants | 44 Participants | 6 Participants | 21 Participants | 4 Participants | 9 Participants | 28 Participants |
| Race/Ethnicity, Customized Black | 2 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Caucasian | 69 Participants | 14 Participants | 2 Participants | 24 Participants | 2 Participants | 7 Participants | 1 Participants | 2 Participants | 17 Participants |
| Race/Ethnicity, Customized Unknown | 7 Participants | 2 Participants | 2 Participants | 3 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 143 Participants | 23 Participants | 13 Participants | 50 Participants | 7 Participants | 13 Participants | 3 Participants | 7 Participants | 27 Participants |
| Sex: Female, Male Male | 82 Participants | 15 Participants | 4 Participants | 23 Participants | 1 Participants | 15 Participants | 2 Participants | 4 Participants | 18 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 3 / 17 | 1 / 38 | 13 / 73 | 0 / 8 | 7 / 28 | 0 / 5 | 1 / 11 | 6 / 45 | 31 / 225 |
| other Total, other adverse events | 17 / 17 | 36 / 38 | 73 / 73 | 8 / 8 | 28 / 28 | 5 / 5 | 11 / 11 | 42 / 45 | 220 / 225 |
| serious Total, serious adverse events | 7 / 17 | 11 / 38 | 40 / 73 | 2 / 8 | 16 / 28 | 4 / 5 | 5 / 11 | 22 / 45 | 107 / 225 |
Outcome results
Primary
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.
Time frame: First 28 days of dosing
Population: Dose-determining set (DDS) including all patients who received at least one dose of EGF816 in the dose escalation phase who had met the minimum safety evaluation requirements (observed for ≥ 28 days following the first dose) and the minimum exposure criterion (at least 75% of the planned doses of EGF816) or discontinue earlier due to DLTs
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| EGF816 75 mg (Phase I Part) | Number of Participants With Dose Limiting Toxicities (DLTs) (Phase I Part) | 0 Participants |
| EGF816 100 mg (Phase I Part) | Number of Participants With Dose Limiting Toxicities (DLTs) (Phase I Part) | 0 Participants |
| EGF816 150 mg (Phase I Part) | Number of Participants With Dose Limiting Toxicities (DLTs) (Phase I Part) | 2 Participants |
| EGF816 200 mg (Phase I Part) | Number of Participants With Dose Limiting Toxicities (DLTs) (Phase I Part) | 0 Participants |
| EGF816 225 mg (Phase I Part) | Number of Participants With Dose Limiting Toxicities (DLTs) (Phase I Part) | 1 Participants |
| EGF816 300 mg (Phase I Part) | Number of Participants With Dose Limiting Toxicities (DLTs) (Phase I Part) | 0 Participants |
| EGF816 350 mg (Phase I Part) | Number of Participants With Dose Limiting Toxicities (DLTs) (Phase I Part) | 3 Participants |
Primary
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).
Time frame: From baseline up to 64 weeks
Population: Full Analysis Set (FAS) including participants who received at least one dose of EGF816
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| EGF816 75 mg (Phase I Part) | Overall Response Rate (ORR) by Blinded Independent Review Committee (BIRC) (Phase II Part) | 64.4 Percentage of participants |
Secondary
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)
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).
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).
Population: Pharmacokinetics Analysis Set (PAS) The PAS consists of all subjects who received at least one dose of EGF816 and have at least one evaluable PK sample.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| EGF816 75 mg (Phase I Part) | 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) | LMI258: C2D1 | 402 ng*hr/mL | Geometric Coefficient of Variation 65.7 |
| EGF816 75 mg (Phase I Part) | 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) | LMI258: C1D15 | 466 ng*hr/mL | Geometric Coefficient of Variation 82.1 |
| EGF816 75 mg (Phase I Part) | 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) | EFG816: C1D15 | 6370 ng*hr/mL | Geometric Coefficient of Variation 61.1 |
| EGF816 75 mg (Phase I Part) | 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) | EFG816: Cycle (C) 1 Day (D) 1 | 4340 ng*hr/mL | Geometric Coefficient of Variation 68.2 |
| EGF816 75 mg (Phase I Part) | 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) | EFG816: C2D1 | 5670 ng*hr/mL | Geometric Coefficient of Variation 44.7 |
| EGF816 75 mg (Phase I Part) | 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) | LMI258: C1D1 | 182 ng*hr/mL | Geometric Coefficient of Variation 56.8 |
| EGF816 100 mg (Phase I Part) | 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) | EFG816: C1D15 | 6770 ng*hr/mL | Geometric Coefficient of Variation 66 |
| EGF816 100 mg (Phase I Part) | 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) | LMI258: C1D1 | 162 ng*hr/mL | Geometric Coefficient of Variation 78 |
| EGF816 100 mg (Phase I Part) | 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) | EFG816: Cycle (C) 1 Day (D) 1 | 4000 ng*hr/mL | Geometric Coefficient of Variation 83.1 |
| EGF816 100 mg (Phase I Part) | 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) | LMI258: C2D1 | 499 ng*hr/mL | Geometric Coefficient of Variation 97.7 |
| EGF816 100 mg (Phase I Part) | 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) | LMI258: C1D15 | 523 ng*hr/mL | Geometric Coefficient of Variation 111.1 |
| EGF816 100 mg (Phase I Part) | 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) | EFG816: C2D1 | 6150 ng*hr/mL | Geometric Coefficient of Variation 58.6 |
| EGF816 150 mg (Phase I Part) | 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) | EFG816: C2D1 | 11800 ng*hr/mL | Geometric Coefficient of Variation 50.3 |
| EGF816 150 mg (Phase I Part) | 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) | LMI258: C1D15 | 1170 ng*hr/mL | Geometric Coefficient of Variation 69.5 |
| EGF816 150 mg (Phase I Part) | 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) | LMI258: C1D1 | 330 ng*hr/mL | Geometric Coefficient of Variation 62.1 |
| EGF816 150 mg (Phase I Part) | 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) | LMI258: C2D1 | 1380 ng*hr/mL | Geometric Coefficient of Variation 58.6 |
| EGF816 150 mg (Phase I Part) | 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) | EFG816: C1D15 | 11300 ng*hr/mL | Geometric Coefficient of Variation 53.2 |
| EGF816 150 mg (Phase I Part) | 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) | EFG816: Cycle (C) 1 Day (D) 1 | 6880 ng*hr/mL | Geometric Coefficient of Variation 53.3 |
| EGF816 200 mg (Phase I Part) | 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) | EFG816: C2D1 | 15800 ng*hr/mL | Geometric Coefficient of Variation 10.6 |
| EGF816 200 mg (Phase I Part) | 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) | EFG816: Cycle (C) 1 Day (D) 1 | 8310 ng*hr/mL | Geometric Coefficient of Variation 51.2 |
| EGF816 200 mg (Phase I Part) | 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) | EFG816: C1D15 | 13500 ng*hr/mL | Geometric Coefficient of Variation 44.1 |
| EGF816 200 mg (Phase I Part) | 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) | LMI258: C1D1 | 424 ng*hr/mL | Geometric Coefficient of Variation 56 |
| EGF816 200 mg (Phase I Part) | 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) | LMI258: C1D15 | 1810 ng*hr/mL | Geometric Coefficient of Variation 58.6 |
| EGF816 200 mg (Phase I Part) | 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) | LMI258: C2D1 | 2340 ng*hr/mL | Geometric Coefficient of Variation 45.2 |
| EGF816 225 mg (Phase I Part) | 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) | EFG816: C2D1 | 18600 ng*hr/mL | Geometric Coefficient of Variation 66.5 |
| EGF816 225 mg (Phase I Part) | 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) | LMI258: C1D1 | 559 ng*hr/mL | Geometric Coefficient of Variation 62.4 |
| EGF816 225 mg (Phase I Part) | 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) | EFG816: C1D15 | 20300 ng*hr/mL | Geometric Coefficient of Variation 54.6 |
| EGF816 225 mg (Phase I Part) | 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) | LMI258: C1D15 | 2460 ng*hr/mL | Geometric Coefficient of Variation 65.2 |
| EGF816 225 mg (Phase I Part) | 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) | EFG816: Cycle (C) 1 Day (D) 1 | 12100 ng*hr/mL | Geometric Coefficient of Variation 64.7 |
| EGF816 225 mg (Phase I Part) | 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) | LMI258: C2D1 | 1760 ng*hr/mL | Geometric Coefficient of Variation 90.3 |
| EGF816 300 mg (Phase I Part) | 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) | LMI258: C1D15 | 5940 ng*hr/mL | — |
| EGF816 300 mg (Phase I Part) | 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) | LMI258: C1D1 | 859 ng*hr/mL | Geometric Coefficient of Variation 50 |
| EGF816 300 mg (Phase I Part) | 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) | EFG816: C1D15 | 51200 ng*hr/mL | — |
| EGF816 300 mg (Phase I Part) | 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) | EFG816: Cycle (C) 1 Day (D) 1 | 15000 ng*hr/mL | Geometric Coefficient of Variation 61 |
| EGF816 300 mg (Phase I Part) | 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) | LMI258: C2D1 | 2360 ng*hr/mL | Geometric Coefficient of Variation 65.9 |
| EGF816 300 mg (Phase I Part) | 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) | EFG816: C2D1 | 26100 ng*hr/mL | Geometric Coefficient of Variation 53 |
| EGF816 350 mg (Phase I Part) | 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) | LMI258: C1D1 | 810 ng*hr/mL | Geometric Coefficient of Variation 47 |
| EGF816 350 mg (Phase I Part) | 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) | LMI258: C2D1 | 2820 ng*hr/mL | Geometric Coefficient of Variation 34.8 |
| EGF816 350 mg (Phase I Part) | 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) | EFG816: C2D1 | 22300 ng*hr/mL | Geometric Coefficient of Variation 19 |
| EGF816 350 mg (Phase I Part) | 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) | LMI258: C1D15 | 3420 ng*hr/mL | Geometric Coefficient of Variation 45.6 |
| EGF816 350 mg (Phase I Part) | 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) | EFG816: Cycle (C) 1 Day (D) 1 | 16900 ng*hr/mL | Geometric Coefficient of Variation 51 |
| EGF816 350 mg (Phase I Part) | 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) | EFG816: C1D15 | 25700 ng*hr/mL | Geometric Coefficient of Variation 26.1 |
| EGF816 150 mg (Phase II Part) | 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) | EFG816: C2D1 | 9830 ng*hr/mL | Geometric Coefficient of Variation 51.3 |
| EGF816 150 mg (Phase II Part) | 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) | LMI258: C2D1 | 1060 ng*hr/mL | Geometric Coefficient of Variation 67.7 |
| EGF816 150 mg (Phase II Part) | 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) | EFG816: Cycle (C) 1 Day (D) 1 | 5720 ng*hr/mL | Geometric Coefficient of Variation 42.7 |
| EGF816 150 mg (Phase II Part) | 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) | LMI258: C1D1 | 291 ng*hr/mL | Geometric Coefficient of Variation 45.3 |
Secondary
Disease Control Rate (DCR) by BIRC (Phase II Part)
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
Time frame: At least 24 weeks up to approx. 9 years
Population: Full Analysis Set (FAS) including participants who received at least one dose of EGF816
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| EGF816 75 mg (Phase I Part) | Disease Control Rate (DCR) by BIRC (Phase II Part) | 93.3 Percentage of participants |
Secondary
Disease Control Rate (DCR) by Investigator Assessment (Phase I & II Parts)
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 frame: At least 24 weeks up to approx. 4 years
Population: Full Analysis Set (FAS) including participants who received at least one dose of EGF816 and who had a response.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| EGF816 75 mg (Phase I Part) | Disease Control Rate (DCR) by Investigator Assessment (Phase I & II Parts) | 83.3 Percentage of participants |
| EGF816 100 mg (Phase I Part) | Disease Control Rate (DCR) by Investigator Assessment (Phase I & II Parts) | 97.1 Percentage of participants |
| EGF816 150 mg (Phase I Part) | Disease Control Rate (DCR) by Investigator Assessment (Phase I & II Parts) | 83.3 Percentage of participants |
| EGF816 200 mg (Phase I Part) | Disease Control Rate (DCR) by Investigator Assessment (Phase I & II Parts) | 100.0 Percentage of participants |
| EGF816 225 mg (Phase I Part) | Disease Control Rate (DCR) by Investigator Assessment (Phase I & II Parts) | 95.8 Percentage of participants |
| EGF816 300 mg (Phase I Part) | Disease Control Rate (DCR) by Investigator Assessment (Phase I & II Parts) | 100.0 Percentage of participants |
| EGF816 350 mg (Phase I Part) | Disease Control Rate (DCR) by Investigator Assessment (Phase I & II Parts) | 72.7 Percentage of participants |
| EGF816 150 mg (Phase II Part) | Disease Control Rate (DCR) by Investigator Assessment (Phase I & II Parts) | 91.1 Percentage of participants |
Secondary
Duration of Response (DOR) by BIRC (Phase II Part)
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
Time frame: At least 24 weeks up to approx. 9 years
Population: Full Analysis Set (FAS) including participants who received at least one dose of EGF816 and who had a response.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| EGF816 75 mg (Phase I Part) | Duration of Response (DOR) by BIRC (Phase II Part) | 18.6 Months |
Secondary
Duration of Response (DOR) by Investigator Assessment (Phase I & II Parts)
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
Time frame: At least 24 weeks up to approx. 9 years
Population: Full Analysis Set (FAS) including participants who received at least one dose of EGF816
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| EGF816 75 mg (Phase I Part) | Duration of Response (DOR) by Investigator Assessment (Phase I & II Parts) | 46.2 Months |
| EGF816 100 mg (Phase I Part) | Duration of Response (DOR) by Investigator Assessment (Phase I & II Parts) | 11.3 Months |
| EGF816 150 mg (Phase I Part) | Duration of Response (DOR) by Investigator Assessment (Phase I & II Parts) | 7.9 Months |
| EGF816 200 mg (Phase I Part) | Duration of Response (DOR) by Investigator Assessment (Phase I & II Parts) | 14.9 Months |
| EGF816 225 mg (Phase I Part) | Duration of Response (DOR) by Investigator Assessment (Phase I & II Parts) | 16.5 Months |
| EGF816 300 mg (Phase I Part) | Duration of Response (DOR) by Investigator Assessment (Phase I & II Parts) | 10.2 Months |
| EGF816 350 mg (Phase I Part) | Duration of Response (DOR) by Investigator Assessment (Phase I & II Parts) | 17.5 Months |
| EGF816 150 mg (Phase II Part) | Duration of Response (DOR) by Investigator Assessment (Phase I & II Parts) | 20.3 Months |
Secondary
Number of Participants With Dose Interruptions and Dose Reductions (Phase I & II Parts)
Assessment of the tolerability of EGF816 will be performed continuously during the treatment phase
Time frame: At least 24 weeks up to approx. 9 years
Population: Safety Set: The Safety Set includes all subjects who received at least one dose of EGF816.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| EGF816 75 mg (Phase I Part) | Number of Participants With Dose Interruptions and Dose Reductions (Phase I & II Parts) | Participants with at least one dose reductions | 0 Participants |
| EGF816 75 mg (Phase I Part) | Number of Participants With Dose Interruptions and Dose Reductions (Phase I & II Parts) | Participants with any dose Interruption | 3 Participants |
| EGF816 100 mg (Phase I Part) | Number of Participants With Dose Interruptions and Dose Reductions (Phase I & II Parts) | Participants with any dose Interruption | 17 Participants |
| EGF816 100 mg (Phase I Part) | Number of Participants With Dose Interruptions and Dose Reductions (Phase I & II Parts) | Participants with at least one dose reductions | 1 Participants |
| EGF816 150 mg (Phase I Part) | Number of Participants With Dose Interruptions and Dose Reductions (Phase I & II Parts) | Participants with any dose Interruption | 35 Participants |
| EGF816 150 mg (Phase I Part) | Number of Participants With Dose Interruptions and Dose Reductions (Phase I & II Parts) | Participants with at least one dose reductions | 9 Participants |
| EGF816 200 mg (Phase I Part) | Number of Participants With Dose Interruptions and Dose Reductions (Phase I & II Parts) | Participants with at least one dose reductions | 1 Participants |
| EGF816 200 mg (Phase I Part) | Number of Participants With Dose Interruptions and Dose Reductions (Phase I & II Parts) | Participants with any dose Interruption | 5 Participants |
| EGF816 225 mg (Phase I Part) | Number of Participants With Dose Interruptions and Dose Reductions (Phase I & II Parts) | Participants with at least one dose reductions | 17 Participants |
| EGF816 225 mg (Phase I Part) | Number of Participants With Dose Interruptions and Dose Reductions (Phase I & II Parts) | Participants with any dose Interruption | 20 Participants |
| EGF816 300 mg (Phase I Part) | Number of Participants With Dose Interruptions and Dose Reductions (Phase I & II Parts) | Participants with any dose Interruption | 5 Participants |
| EGF816 300 mg (Phase I Part) | Number of Participants With Dose Interruptions and Dose Reductions (Phase I & II Parts) | Participants with at least one dose reductions | 4 Participants |
| EGF816 350 mg (Phase I Part) | Number of Participants With Dose Interruptions and Dose Reductions (Phase I & II Parts) | Participants with any dose Interruption | 6 Participants |
| EGF816 350 mg (Phase I Part) | Number of Participants With Dose Interruptions and Dose Reductions (Phase I & II Parts) | Participants with at least one dose reductions | 6 Participants |
| EGF816 150 mg (Phase II Part) | Number of Participants With Dose Interruptions and Dose Reductions (Phase I & II Parts) | Participants with at least one dose reductions | 9 Participants |
| EGF816 150 mg (Phase II Part) | Number of Participants With Dose Interruptions and Dose Reductions (Phase I & II Parts) | Participants with any dose Interruption | 19 Participants |
Secondary
Observed Maximum Plasma Concentration (Cmax) of EGF816 and Metabolite LMI258 (Phase I & Phase II Part)
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 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).
Population: Pharmacokinetics Analysis Set (PAS) The PAS consists of all subjects who received at least one dose of EGF816 and have at least one evaluable PK sample.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| EGF816 75 mg (Phase I Part) | Observed Maximum Plasma Concentration (Cmax) of EGF816 and Metabolite LMI258 (Phase I & Phase II Part) | LMI258: C1D1 | 14.1 ng/mL | Geometric Coefficient of Variation 174.8 |
| EGF816 75 mg (Phase I Part) | Observed Maximum Plasma Concentration (Cmax) of EGF816 and Metabolite LMI258 (Phase I & Phase II Part) | EFG816: Cycle (C) 1 Day (D) 1 | 333 ng/mL | Geometric Coefficient of Variation 64.9 |
| EGF816 75 mg (Phase I Part) | Observed Maximum Plasma Concentration (Cmax) of EGF816 and Metabolite LMI258 (Phase I & Phase II Part) | EFG816: C1D15 | 402 ng/mL | Geometric Coefficient of Variation 62.3 |
| EGF816 75 mg (Phase I Part) | Observed Maximum Plasma Concentration (Cmax) of EGF816 and Metabolite LMI258 (Phase I & Phase II Part) | LMI258: C2D1 | 23.9 ng/mL | Geometric Coefficient of Variation 59.5 |
| EGF816 75 mg (Phase I Part) | Observed Maximum Plasma Concentration (Cmax) of EGF816 and Metabolite LMI258 (Phase I & Phase II Part) | EFG816: C2D1 | 348 ng/mL | Geometric Coefficient of Variation 43.4 |
| EGF816 75 mg (Phase I Part) | Observed Maximum Plasma Concentration (Cmax) of EGF816 and Metabolite LMI258 (Phase I & Phase II Part) | LMI258: C1D15 | 31.2 ng/mL | Geometric Coefficient of Variation 94.7 |
| EGF816 100 mg (Phase I Part) | Observed Maximum Plasma Concentration (Cmax) of EGF816 and Metabolite LMI258 (Phase I & Phase II Part) | EFG816: C1D15 | 477 ng/mL | Geometric Coefficient of Variation 53 |
| EGF816 100 mg (Phase I Part) | Observed Maximum Plasma Concentration (Cmax) of EGF816 and Metabolite LMI258 (Phase I & Phase II Part) | EFG816: Cycle (C) 1 Day (D) 1 | 301 ng/mL | Geometric Coefficient of Variation 81.8 |
| EGF816 100 mg (Phase I Part) | Observed Maximum Plasma Concentration (Cmax) of EGF816 and Metabolite LMI258 (Phase I & Phase II Part) | LMI258: C1D1 | 11.4 ng/mL | Geometric Coefficient of Variation 76.1 |
| EGF816 100 mg (Phase I Part) | Observed Maximum Plasma Concentration (Cmax) of EGF816 and Metabolite LMI258 (Phase I & Phase II Part) | LMI258: C2D1 | 32.4 ng/mL | Geometric Coefficient of Variation 76 |
| EGF816 100 mg (Phase I Part) | Observed Maximum Plasma Concentration (Cmax) of EGF816 and Metabolite LMI258 (Phase I & Phase II Part) | LMI258: C1D15 | 34.1 ng/mL | Geometric Coefficient of Variation 81.8 |
| EGF816 100 mg (Phase I Part) | Observed Maximum Plasma Concentration (Cmax) of EGF816 and Metabolite LMI258 (Phase I & Phase II Part) | EFG816: C2D1 | 426 ng/mL | Geometric Coefficient of Variation 50.1 |
| EGF816 150 mg (Phase I Part) | Observed Maximum Plasma Concentration (Cmax) of EGF816 and Metabolite LMI258 (Phase I & Phase II Part) | LMI258: C2D1 | 81.4 ng/mL | Geometric Coefficient of Variation 55.4 |
| EGF816 150 mg (Phase I Part) | Observed Maximum Plasma Concentration (Cmax) of EGF816 and Metabolite LMI258 (Phase I & Phase II Part) | LMI258: C1D1 | 25.2 ng/mL | Geometric Coefficient of Variation 61.7 |
| EGF816 150 mg (Phase I Part) | Observed Maximum Plasma Concentration (Cmax) of EGF816 and Metabolite LMI258 (Phase I & Phase II Part) | EFG816: Cycle (C) 1 Day (D) 1 | 541 ng/mL | Geometric Coefficient of Variation 53.2 |
| EGF816 150 mg (Phase I Part) | Observed Maximum Plasma Concentration (Cmax) of EGF816 and Metabolite LMI258 (Phase I & Phase II Part) | EFG816: C1D15 | 765 ng/mL | Geometric Coefficient of Variation 50.1 |
| EGF816 150 mg (Phase I Part) | Observed Maximum Plasma Concentration (Cmax) of EGF816 and Metabolite LMI258 (Phase I & Phase II Part) | EFG816: C2D1 | 767 ng/mL | Geometric Coefficient of Variation 46.7 |
| EGF816 150 mg (Phase I Part) | Observed Maximum Plasma Concentration (Cmax) of EGF816 and Metabolite LMI258 (Phase I & Phase II Part) | LMI258: C1D15 | 72.2 ng/mL | Geometric Coefficient of Variation 64 |
| EGF816 200 mg (Phase I Part) | Observed Maximum Plasma Concentration (Cmax) of EGF816 and Metabolite LMI258 (Phase I & Phase II Part) | EFG816: C2D1 | 938 ng/mL | Geometric Coefficient of Variation 53.9 |
| EGF816 200 mg (Phase I Part) | Observed Maximum Plasma Concentration (Cmax) of EGF816 and Metabolite LMI258 (Phase I & Phase II Part) | EFG816: C1D15 | 939 ng/mL | Geometric Coefficient of Variation 45.4 |
| EGF816 200 mg (Phase I Part) | Observed Maximum Plasma Concentration (Cmax) of EGF816 and Metabolite LMI258 (Phase I & Phase II Part) | LMI258: C1D15 | 113 ng/mL | Geometric Coefficient of Variation 54.1 |
| EGF816 200 mg (Phase I Part) | Observed Maximum Plasma Concentration (Cmax) of EGF816 and Metabolite LMI258 (Phase I & Phase II Part) | LMI258: C1D1 | 30.9 ng/mL | Geometric Coefficient of Variation 64.6 |
| EGF816 200 mg (Phase I Part) | Observed Maximum Plasma Concentration (Cmax) of EGF816 and Metabolite LMI258 (Phase I & Phase II Part) | EFG816: Cycle (C) 1 Day (D) 1 | 641 ng/mL | Geometric Coefficient of Variation 60.2 |
| EGF816 200 mg (Phase I Part) | Observed Maximum Plasma Concentration (Cmax) of EGF816 and Metabolite LMI258 (Phase I & Phase II Part) | LMI258: C2D1 | 114 ng/mL | Geometric Coefficient of Variation 75.1 |
| EGF816 225 mg (Phase I Part) | Observed Maximum Plasma Concentration (Cmax) of EGF816 and Metabolite LMI258 (Phase I & Phase II Part) | LMI258: C1D1 | 42.0 ng/mL | Geometric Coefficient of Variation 63.1 |
| EGF816 225 mg (Phase I Part) | Observed Maximum Plasma Concentration (Cmax) of EGF816 and Metabolite LMI258 (Phase I & Phase II Part) | EFG816: Cycle (C) 1 Day (D) 1 | 935 ng/mL | Geometric Coefficient of Variation 66.1 |
| EGF816 225 mg (Phase I Part) | Observed Maximum Plasma Concentration (Cmax) of EGF816 and Metabolite LMI258 (Phase I & Phase II Part) | EFG816: C1D15 | 1320 ng/mL | Geometric Coefficient of Variation 46 |
| EGF816 225 mg (Phase I Part) | Observed Maximum Plasma Concentration (Cmax) of EGF816 and Metabolite LMI258 (Phase I & Phase II Part) | EFG816: C2D1 | 1270 ng/mL | Geometric Coefficient of Variation 61 |
| EGF816 225 mg (Phase I Part) | Observed Maximum Plasma Concentration (Cmax) of EGF816 and Metabolite LMI258 (Phase I & Phase II Part) | LMI258: C1D15 | 131 ng/mL | Geometric Coefficient of Variation 56.8 |
| EGF816 225 mg (Phase I Part) | Observed Maximum Plasma Concentration (Cmax) of EGF816 and Metabolite LMI258 (Phase I & Phase II Part) | LMI258: C2D1 | 101 ng/mL | Geometric Coefficient of Variation 72.8 |
| EGF816 300 mg (Phase I Part) | Observed Maximum Plasma Concentration (Cmax) of EGF816 and Metabolite LMI258 (Phase I & Phase II Part) | LMI258: C2D1 | 142 ng/mL | Geometric Coefficient of Variation 55.1 |
| EGF816 300 mg (Phase I Part) | Observed Maximum Plasma Concentration (Cmax) of EGF816 and Metabolite LMI258 (Phase I & Phase II Part) | LMI258: C1D15 | 292 ng/mL | — |
| EGF816 300 mg (Phase I Part) | Observed Maximum Plasma Concentration (Cmax) of EGF816 and Metabolite LMI258 (Phase I & Phase II Part) | LMI258: C1D1 | 62.2 ng/mL | Geometric Coefficient of Variation 40.5 |
| EGF816 300 mg (Phase I Part) | Observed Maximum Plasma Concentration (Cmax) of EGF816 and Metabolite LMI258 (Phase I & Phase II Part) | EFG816: C1D15 | 2670 ng/mL | — |
| EGF816 300 mg (Phase I Part) | Observed Maximum Plasma Concentration (Cmax) of EGF816 and Metabolite LMI258 (Phase I & Phase II Part) | EFG816: C2D1 | 1700 ng/mL | Geometric Coefficient of Variation 41.3 |
| EGF816 300 mg (Phase I Part) | Observed Maximum Plasma Concentration (Cmax) of EGF816 and Metabolite LMI258 (Phase I & Phase II Part) | EFG816: Cycle (C) 1 Day (D) 1 | 1070 ng/mL | Geometric Coefficient of Variation 58.3 |
| EGF816 350 mg (Phase I Part) | Observed Maximum Plasma Concentration (Cmax) of EGF816 and Metabolite LMI258 (Phase I & Phase II Part) | LMI258: C1D15 | 164 ng/mL | Geometric Coefficient of Variation 22.7 |
| EGF816 350 mg (Phase I Part) | Observed Maximum Plasma Concentration (Cmax) of EGF816 and Metabolite LMI258 (Phase I & Phase II Part) | EFG816: C2D1 | 1270 ng/mL | Geometric Coefficient of Variation 30.4 |
| EGF816 350 mg (Phase I Part) | Observed Maximum Plasma Concentration (Cmax) of EGF816 and Metabolite LMI258 (Phase I & Phase II Part) | EFG816: C1D15 | 1530 ng/mL | Geometric Coefficient of Variation 23.5 |
| EGF816 350 mg (Phase I Part) | Observed Maximum Plasma Concentration (Cmax) of EGF816 and Metabolite LMI258 (Phase I & Phase II Part) | LMI258: C1D1 | 52.7 ng/mL | Geometric Coefficient of Variation 42.1 |
| EGF816 350 mg (Phase I Part) | Observed Maximum Plasma Concentration (Cmax) of EGF816 and Metabolite LMI258 (Phase I & Phase II Part) | EFG816: Cycle (C) 1 Day (D) 1 | 1190 ng/mL | Geometric Coefficient of Variation 50 |
| EGF816 350 mg (Phase I Part) | Observed Maximum Plasma Concentration (Cmax) of EGF816 and Metabolite LMI258 (Phase I & Phase II Part) | LMI258: C2D1 | 116 ng/mL | Geometric Coefficient of Variation 68.7 |
| EGF816 150 mg (Phase II Part) | Observed Maximum Plasma Concentration (Cmax) of EGF816 and Metabolite LMI258 (Phase I & Phase II Part) | EFG816: C2D1 | 648 ng/mL | Geometric Coefficient of Variation 50.9 |
| EGF816 150 mg (Phase II Part) | Observed Maximum Plasma Concentration (Cmax) of EGF816 and Metabolite LMI258 (Phase I & Phase II Part) | LMI258: C1D1 | 24.3 ng/mL | Geometric Coefficient of Variation 46.6 |
| EGF816 150 mg (Phase II Part) | Observed Maximum Plasma Concentration (Cmax) of EGF816 and Metabolite LMI258 (Phase I & Phase II Part) | EFG816: Cycle (C) 1 Day (D) 1 | 471 ng/mL | Geometric Coefficient of Variation 41.2 |
| EGF816 150 mg (Phase II Part) | Observed Maximum Plasma Concentration (Cmax) of EGF816 and Metabolite LMI258 (Phase I & Phase II Part) | LMI258: C2D1 | 62.5 ng/mL | Geometric Coefficient of Variation 60.7 |
Secondary
Overall Response Rate (ORR) by Investigator Assessment (Phase I & II Parts)
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
Time frame: At least 24 weeks up to approx. 4 years
Population: Full Analysis Set (FAS) including participants who received at least one dose of EGF816 and who had a response.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| EGF816 75 mg (Phase I Part) | Overall Response Rate (ORR) by Investigator Assessment (Phase I & II Parts) | 41.7 Percentage of participants |
| EGF816 100 mg (Phase I Part) | Overall Response Rate (ORR) by Investigator Assessment (Phase I & II Parts) | 50.0 Percentage of participants |
| EGF816 150 mg (Phase I Part) | Overall Response Rate (ORR) by Investigator Assessment (Phase I & II Parts) | 50.0 Percentage of participants |
| EGF816 200 mg (Phase I Part) | Overall Response Rate (ORR) by Investigator Assessment (Phase I & II Parts) | 62.5 Percentage of participants |
| EGF816 225 mg (Phase I Part) | Overall Response Rate (ORR) by Investigator Assessment (Phase I & II Parts) | 62.5 Percentage of participants |
| EGF816 300 mg (Phase I Part) | Overall Response Rate (ORR) by Investigator Assessment (Phase I & II Parts) | 60.0 Percentage of participants |
| EGF816 350 mg (Phase I Part) | Overall Response Rate (ORR) by Investigator Assessment (Phase I & II Parts) | 36.4 Percentage of participants |
| EGF816 150 mg (Phase II Part) | Overall Response Rate (ORR) by Investigator Assessment (Phase I & II Parts) | 55.6 Percentage of participants |
Secondary
Overall Survival (OS) (Phase II Part)
OS is defined as the time from first dose of the study treatment to the date of death due to any cause.
Time frame: At least 24 weeks up to approx. 9 years
Population: Full Analysis Set (FAS) including participants who received at least one dose of EGF816
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| EGF816 75 mg (Phase I Part) | Overall Survival (OS) (Phase II Part) | 48.3 Months |
Secondary
Percentage Change From Baseline in H-score for Immunohistochemistry (IHC) Biomarkers From Tumor Tissue Samples (Phase I Part)
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.
Time frame: Baseline and Cycle 1 Day 15
Population: Pharmacokinetics Analysis Set (PAS) The PAS consists of all subjects who received at least one dose of EGF816 and have at least one evaluable PK sample.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| EGF816 75 mg (Phase I Part) | Percentage Change From Baseline in H-score for Immunohistochemistry (IHC) Biomarkers From Tumor Tissue Samples (Phase I Part) | PD parameter: p-ERK: % Change from baseline in H-Score | -60.0 percentage change | — |
| EGF816 75 mg (Phase I Part) | Percentage Change From Baseline in H-score for Immunohistochemistry (IHC) Biomarkers From Tumor Tissue Samples (Phase I Part) | PD parameter: p-EGFR: % Change from baseline in H-Score | -165.0 percentage change | — |
| EGF816 75 mg (Phase I Part) | Percentage Change From Baseline in H-score for Immunohistochemistry (IHC) Biomarkers From Tumor Tissue Samples (Phase I Part) | Pharmacodynamics (PD) parameter: P_AKT: % Change from baseline in H-Score | -10.0 percentage change | — |
| EGF816 100 mg (Phase I Part) | Percentage Change From Baseline in H-score for Immunohistochemistry (IHC) Biomarkers From Tumor Tissue Samples (Phase I Part) | PD parameter: p-EGFR: % Change from baseline in H-Score | -21.8 percentage change | Standard Deviation 43.9 |
| EGF816 100 mg (Phase I Part) | Percentage Change From Baseline in H-score for Immunohistochemistry (IHC) Biomarkers From Tumor Tissue Samples (Phase I Part) | Pharmacodynamics (PD) parameter: P_AKT: % Change from baseline in H-Score | -39.0 percentage change | Standard Deviation 78.2 |
| EGF816 100 mg (Phase I Part) | Percentage Change From Baseline in H-score for Immunohistochemistry (IHC) Biomarkers From Tumor Tissue Samples (Phase I Part) | PD parameter: p-ERK: % Change from baseline in H-Score | -113.4 percentage change | Standard Deviation 84.2 |
| EGF816 150 mg (Phase I Part) | Percentage Change From Baseline in H-score for Immunohistochemistry (IHC) Biomarkers From Tumor Tissue Samples (Phase I Part) | PD parameter: p-ERK: % Change from baseline in H-Score | -2.4 percentage change | Standard Deviation 128.3 |
| EGF816 150 mg (Phase I Part) | Percentage Change From Baseline in H-score for Immunohistochemistry (IHC) Biomarkers From Tumor Tissue Samples (Phase I Part) | Pharmacodynamics (PD) parameter: P_AKT: % Change from baseline in H-Score | -31.8 percentage change | Standard Deviation 47.7 |
| EGF816 150 mg (Phase I Part) | Percentage Change From Baseline in H-score for Immunohistochemistry (IHC) Biomarkers From Tumor Tissue Samples (Phase I Part) | PD parameter: p-EGFR: % Change from baseline in H-Score | -19.5 percentage change | Standard Deviation 34.7 |
| EGF816 200 mg (Phase I Part) | Percentage Change From Baseline in H-score for Immunohistochemistry (IHC) Biomarkers From Tumor Tissue Samples (Phase I Part) | PD parameter: p-EGFR: % Change from baseline in H-Score | -38.8 percentage change | Standard Deviation 50.1 |
| EGF816 200 mg (Phase I Part) | Percentage Change From Baseline in H-score for Immunohistochemistry (IHC) Biomarkers From Tumor Tissue Samples (Phase I Part) | Pharmacodynamics (PD) parameter: P_AKT: % Change from baseline in H-Score | 3.5 percentage change | Standard Deviation 14.5 |
| EGF816 200 mg (Phase I Part) | Percentage Change From Baseline in H-score for Immunohistochemistry (IHC) Biomarkers From Tumor Tissue Samples (Phase I Part) | PD parameter: p-ERK: % Change from baseline in H-Score | 33.5 percentage change | Standard Deviation 86.7 |
| EGF816 225 mg (Phase I Part) | Percentage Change From Baseline in H-score for Immunohistochemistry (IHC) Biomarkers From Tumor Tissue Samples (Phase I Part) | PD parameter: p-EGFR: % Change from baseline in H-Score | 2.2 percentage change | Standard Deviation 23.7 |
| EGF816 225 mg (Phase I Part) | Percentage Change From Baseline in H-score for Immunohistochemistry (IHC) Biomarkers From Tumor Tissue Samples (Phase I Part) | Pharmacodynamics (PD) parameter: P_AKT: % Change from baseline in H-Score | 16.1 percentage change | Standard Deviation 65.3 |
| EGF816 225 mg (Phase I Part) | Percentage Change From Baseline in H-score for Immunohistochemistry (IHC) Biomarkers From Tumor Tissue Samples (Phase I Part) | PD parameter: p-ERK: % Change from baseline in H-Score | 8.8 percentage change | Standard Deviation 68 |
| EGF816 300 mg (Phase I Part) | Percentage Change From Baseline in H-score for Immunohistochemistry (IHC) Biomarkers From Tumor Tissue Samples (Phase I Part) | Pharmacodynamics (PD) parameter: P_AKT: % Change from baseline in H-Score | -2.5 percentage change | Standard Deviation 3.5 |
| EGF816 300 mg (Phase I Part) | Percentage Change From Baseline in H-score for Immunohistochemistry (IHC) Biomarkers From Tumor Tissue Samples (Phase I Part) | PD parameter: p-ERK: % Change from baseline in H-Score | -65.0 percentage change | Standard Deviation 35.4 |
| EGF816 300 mg (Phase I Part) | Percentage Change From Baseline in H-score for Immunohistochemistry (IHC) Biomarkers From Tumor Tissue Samples (Phase I Part) | PD parameter: p-EGFR: % Change from baseline in H-Score | -32.5 percentage change | Standard Deviation 38.9 |
| EGF816 350 mg (Phase I Part) | Percentage Change From Baseline in H-score for Immunohistochemistry (IHC) Biomarkers From Tumor Tissue Samples (Phase I Part) | PD parameter: p-ERK: % Change from baseline in H-Score | -1.3 percentage change | Standard Deviation 46.6 |
| EGF816 350 mg (Phase I Part) | Percentage Change From Baseline in H-score for Immunohistochemistry (IHC) Biomarkers From Tumor Tissue Samples (Phase I Part) | PD parameter: p-EGFR: % Change from baseline in H-Score | -12.5 percentage change | Standard Deviation 18.9 |
| EGF816 350 mg (Phase I Part) | Percentage Change From Baseline in H-score for Immunohistochemistry (IHC) Biomarkers From Tumor Tissue Samples (Phase I Part) | Pharmacodynamics (PD) parameter: P_AKT: % Change from baseline in H-Score | -51.3 percentage change | Standard Deviation 71.9 |
Secondary
Progression-Free Survival (PFS) by BIRC (Phase II Part)
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 frame: At least 24 weeks up to approx. 9 years
Population: Full Analysis Set (FAS) including participants who received at least one dose of EGF816
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| EGF816 75 mg (Phase I Part) | Progression-Free Survival (PFS) by BIRC (Phase II Part) | 18.9 months |
Secondary
Progression-free Survival (PFS) by Investigator Assessment (Phase I & Phase II Parts)
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
Time frame: At least 24 weeks up to approx. 9 years
Population: Full Analysis Set (FAS) including participants who received at least one dose of EGF816
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| EGF816 75 mg (Phase I Part) | Progression-free Survival (PFS) by Investigator Assessment (Phase I & Phase II Parts) | 6.3 Months |
| EGF816 100 mg (Phase I Part) | Progression-free Survival (PFS) by Investigator Assessment (Phase I & Phase II Parts) | 12.1 Months |
| EGF816 150 mg (Phase I Part) | Progression-free Survival (PFS) by Investigator Assessment (Phase I & Phase II Parts) | 7.4 Months |
| EGF816 200 mg (Phase I Part) | Progression-free Survival (PFS) by Investigator Assessment (Phase I & Phase II Parts) | 13.7 Months |
| EGF816 225 mg (Phase I Part) | Progression-free Survival (PFS) by Investigator Assessment (Phase I & Phase II Parts) | 11.1 Months |
| EGF816 300 mg (Phase I Part) | Progression-free Survival (PFS) by Investigator Assessment (Phase I & Phase II Parts) | 11.8 Months |
| EGF816 350 mg (Phase I Part) | Progression-free Survival (PFS) by Investigator Assessment (Phase I & Phase II Parts) | 11.0 Months |
| EGF816 150 mg (Phase II Part) | Progression-free Survival (PFS) by Investigator Assessment (Phase I & Phase II Parts) | 18.2 Months |
Secondary
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).
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).
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).
Population: Pharmacokinetics Analysis Set (PAS) The PAS consists of all subjects who received at least one dose of EGF816 and have at least one evaluable PK sample.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| EGF816 75 mg (Phase I Part) | 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). | LMI258: C2D1 | 3.38 hour (hr) | Geometric Coefficient of Variation 64.7 |
| EGF816 75 mg (Phase I Part) | 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). | LMI258: C1D15 | 2.89 hour (hr) | Geometric Coefficient of Variation 55.1 |
| EGF816 75 mg (Phase I Part) | 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). | EFG816: C1D15 | 2.91 hour (hr) | Geometric Coefficient of Variation 57.7 |
| EGF816 75 mg (Phase I Part) | 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). | EFG816: Cycle (C) 1 Day (D) 1 | 2.83 hour (hr) | Geometric Coefficient of Variation 63 |
| EGF816 75 mg (Phase I Part) | 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). | EFG816: C2D1 | 3.13 hour (hr) | Geometric Coefficient of Variation 44.7 |
| EGF816 75 mg (Phase I Part) | 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). | LMI258: C1D1 | 2.54 hour (hr) | Geometric Coefficient of Variation 65.7 |
| EGF816 100 mg (Phase I Part) | 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). | EFG816: C1D15 | 2.75 hour (hr) | Geometric Coefficient of Variation 75.8 |
| EGF816 100 mg (Phase I Part) | 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). | LMI258: C1D1 | 3.14 hour (hr) | Geometric Coefficient of Variation 43.6 |
| EGF816 100 mg (Phase I Part) | 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). | EFG816: Cycle (C) 1 Day (D) 1 | 3.24 hour (hr) | Geometric Coefficient of Variation 42.7 |
| EGF816 100 mg (Phase I Part) | 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). | LMI258: C2D1 | 3.04 hour (hr) | Geometric Coefficient of Variation 57.6 |
| EGF816 100 mg (Phase I Part) | 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). | LMI258: C1D15 | 2.76 hour (hr) | Geometric Coefficient of Variation 63.8 |
| EGF816 100 mg (Phase I Part) | 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). | EFG816: C2D1 | 2.81 hour (hr) | Geometric Coefficient of Variation 49 |
| EGF816 150 mg (Phase I Part) | 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). | EFG816: C2D1 | 3.14 hour (hr) | Geometric Coefficient of Variation 54 |
| EGF816 150 mg (Phase I Part) | 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). | LMI258: C1D15 | 3.32 hour (hr) | Geometric Coefficient of Variation 54.7 |
| EGF816 150 mg (Phase I Part) | 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). | LMI258: C1D1 | 2.78 hour (hr) | Geometric Coefficient of Variation 65.2 |
| EGF816 150 mg (Phase I Part) | 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). | LMI258: C2D1 | 3.43 hour (hr) | Geometric Coefficient of Variation 55 |
| EGF816 150 mg (Phase I Part) | 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). | EFG816: C1D15 | 3.11 hour (hr) | Geometric Coefficient of Variation 46.4 |
| EGF816 150 mg (Phase I Part) | 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). | EFG816: Cycle (C) 1 Day (D) 1 | 2.74 hour (hr) | Geometric Coefficient of Variation 54.7 |
| EGF816 200 mg (Phase I Part) | 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). | EFG816: C2D1 | 3.53 hour (hr) | Geometric Coefficient of Variation 35.3 |
| EGF816 200 mg (Phase I Part) | 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). | EFG816: Cycle (C) 1 Day (D) 1 | 3.66 hour (hr) | Geometric Coefficient of Variation 74.1 |
| EGF816 200 mg (Phase I Part) | 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). | EFG816: C1D15 | 3.52 hour (hr) | Geometric Coefficient of Variation 44.3 |
| EGF816 200 mg (Phase I Part) | 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). | LMI258: C1D1 | 3.19 hour (hr) | Geometric Coefficient of Variation 73.6 |
| EGF816 200 mg (Phase I Part) | 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). | LMI258: C1D15 | 4.05 hour (hr) | Geometric Coefficient of Variation 32.6 |
| EGF816 200 mg (Phase I Part) | 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). | LMI258: C2D1 | 5.00 hour (hr) | Geometric Coefficient of Variation 56.1 |
| EGF816 225 mg (Phase I Part) | 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). | EFG816: C2D1 | 3.17 hour (hr) | Geometric Coefficient of Variation 38.2 |
| EGF816 225 mg (Phase I Part) | 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). | LMI258: C1D1 | 2.99 hour (hr) | Geometric Coefficient of Variation 71.4 |
| EGF816 225 mg (Phase I Part) | 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). | EFG816: C1D15 | 3.46 hour (hr) | Geometric Coefficient of Variation 36.1 |
| EGF816 225 mg (Phase I Part) | 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). | LMI258: C1D15 | 4.03 hour (hr) | Geometric Coefficient of Variation 38.7 |
| EGF816 225 mg (Phase I Part) | 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). | EFG816: Cycle (C) 1 Day (D) 1 | 2.64 hour (hr) | Geometric Coefficient of Variation 64.9 |
| EGF816 225 mg (Phase I Part) | 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). | LMI258: C2D1 | 3.26 hour (hr) | Geometric Coefficient of Variation 46.6 |
| EGF816 300 mg (Phase I Part) | 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). | LMI258: C1D15 | 7.12 hour (hr) | — |
| EGF816 300 mg (Phase I Part) | 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). | LMI258: C1D1 | 3.37 hour (hr) | Geometric Coefficient of Variation 41.5 |
| EGF816 300 mg (Phase I Part) | 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). | EFG816: C1D15 | 6.08 hour (hr) | — |
| EGF816 300 mg (Phase I Part) | 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). | EFG816: Cycle (C) 1 Day (D) 1 | 3.37 hour (hr) | Geometric Coefficient of Variation 41 |
| EGF816 300 mg (Phase I Part) | 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). | LMI258: C2D1 | 3.77 hour (hr) | Geometric Coefficient of Variation 42.4 |
| EGF816 300 mg (Phase I Part) | 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). | EFG816: C2D1 | 2.99 hour (hr) | Geometric Coefficient of Variation 0.6 |
| EGF816 350 mg (Phase I Part) | 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). | LMI258: C1D1 | 3.53 hour (hr) | Geometric Coefficient of Variation 31.8 |
| EGF816 350 mg (Phase I Part) | 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). | LMI258: C2D1 | 4.13 hour (hr) | Geometric Coefficient of Variation 47.8 |
| EGF816 350 mg (Phase I Part) | 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). | EFG816: C2D1 | 3.97 hour (hr) | Geometric Coefficient of Variation 44.1 |
| EGF816 350 mg (Phase I Part) | 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). | LMI258: C1D15 | 4.54 hour (hr) | Geometric Coefficient of Variation 39.3 |
| EGF816 350 mg (Phase I Part) | 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). | EFG816: Cycle (C) 1 Day (D) 1 | 3.45 hour (hr) | Geometric Coefficient of Variation 22.4 |
| EGF816 350 mg (Phase I Part) | 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). | EFG816: C1D15 | 4.45 hour (hr) | Geometric Coefficient of Variation 35.4 |
| EGF816 150 mg (Phase II Part) | 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). | EFG816: C2D1 | 3.48 hour (hr) | Geometric Coefficient of Variation 52.7 |
| EGF816 150 mg (Phase II Part) | 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). | LMI258: C2D1 | 3.92 hour (hr) | Geometric Coefficient of Variation 45.5 |
| EGF816 150 mg (Phase II Part) | 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). | EFG816: Cycle (C) 1 Day (D) 1 | 2.81 hour (hr) | Geometric Coefficient of Variation 43.4 |
| EGF816 150 mg (Phase II Part) | 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). | LMI258: C1D1 | 2.70 hour (hr) | Geometric Coefficient of Variation 43.3 |
Secondary
Time to Response (TTR) by BIRC (Phase II Part)
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
Time frame: At least 24 weeks up to approx. 9 years
Population: Full Analysis Set (FAS) including participants who received at least one dose of EGF816
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| EGF816 75 mg (Phase I Part) | Time to Response (TTR) by BIRC (Phase II Part) | 48.3 Months |
Secondary
Time to Response (TTR) by Investigator Assessment (Phase I & II Parts)
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
Time frame: At least 24 weeks up to approx. 9 years
Population: Full Analysis Set (FAS) including participants who received at least one dose of EGF816 and who had a response.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| EGF816 75 mg (Phase I Part) | Time to Response (TTR) by Investigator Assessment (Phase I & II Parts) | NA Months |
| EGF816 100 mg (Phase I Part) | Time to Response (TTR) by Investigator Assessment (Phase I & II Parts) | 5.5 Months |
| EGF816 150 mg (Phase I Part) | Time to Response (TTR) by Investigator Assessment (Phase I & II Parts) | 11.6 Months |
| EGF816 200 mg (Phase I Part) | Time to Response (TTR) by Investigator Assessment (Phase I & II Parts) | 4.5 Months |
| EGF816 225 mg (Phase I Part) | Time to Response (TTR) by Investigator Assessment (Phase I & II Parts) | 1.9 Months |
| EGF816 300 mg (Phase I Part) | Time to Response (TTR) by Investigator Assessment (Phase I & II Parts) | 1.7 Months |
| EGF816 350 mg (Phase I Part) | Time to Response (TTR) by Investigator Assessment (Phase I & II Parts) | NA Months |
| EGF816 150 mg (Phase II Part) | Time to Response (TTR) by Investigator Assessment (Phase I & II Parts) | 1.9 Months |