| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10049280 |
| E.1.2 | Term | Solid tumour |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Phase I part: To estimate the MTD or RDE of EGF816
Phase II part: To investigate the anti-tumor activity of EGF816 |
|
| E.2.2 | Secondary objectives of the trial |
Phase I part:
1. To characterize the safety and tolerability of EGF816
2. To evaluate overall response rate (ORR), duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), and time to response (TTR) determined by Investigator assessments
3. To characterize the pharmacokinets (PK) properties of EGF816 and metabolite LMI258
4. To assess the tumor EGFR signaling inhibition by EGF816 (prior to protocol amendment 05)
Phase 2 part:
1. To further characterize the safety and tolerability of EGF816
2. To evaluate ORR by Investigator assessment
3. To evaluate duration of response (DOR), disease control rate (DCR), progression-free survival (PFS) and time to response (TTR) by BIRC and Investigator assessment
4. To evaluate overall survival (OS)
5. To characterize the pharmacokinetcs (PK) properties of EGF816 and metabolite LMI258 for all groups |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
For all patients (unless otherwise specified):
1. Written informed consent obtained prior to any screening procedures
2. Patient (male or female) ≥ 18 years of age
3. Patients must have histologically or cytologically confirmed locally advanced (stage IIIB not amendable to definitive multi-modality therapy including surgery) or metastatic (stage IV) EGFR mutant NSCLC
4. Patients with controlled brain metastases may participate in the trial.
They must complete any planned radiation therapy and/or surgery > 2 weeks prior to the first dose of study treatment and remain asymptomatic. Patients on steroids must have been on a stable low dose for 2 weeks prior to initiating study treatment.
5. ECOG performance status: Phase I part: 0, 1, or 2; Phase II part: 0 or 1
6. Presence of at least one measurable lesion according to RECIST 1.1 per Investigator assessment. A previously irradiated site lesion may be counted as a target lesion only if there is clear sign of progression since the irradiation (see Section 14.1 Appendix 1)
7. Patients must be screened for HBV. Patients who are either HBsAq positivie or HBVDNA positive must be willing 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.
8. Patients must be screened for HCV. 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 to enroll into the study.
9. Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests and other study procedures
10. Requirement of EGFR mutation status and prior lines of treatment for Phase I patients- (Please see section 5.2 of the protocol for more details)
11. Requirements of EGFR mutation status and prior lines of treatment for Phase II patients:
Locally advanced or metastatic NSCLC with EGFR activating mutation
(e.g. L858R and/or ex19del); Who have not received any systemic antineoplastic therapy, including EGFR TKI treatment, for advanced NSCLC; Note: patients who have received no more than 1 cycle of chemotherapy in the advanced setting are allowed.
Other protocol-defined inclusion criteria may apply |
|
| E.4 | Principal exclusion criteria |
For all patients (unless otherwise specified):
1. Patients with a history or presence of interstitial lung disease or interstitial pneumonitis, including clinically significant radiation pneumonitis (i.e. affecting activities of daily living or requiring therapeutic intervention)
2. Patients with tumors harboring an EGFR exon 20 insertion or deletion (except for Group 4 patients in the Phase II par)
3. Presence or History of another malignancy
Exception: Patients who have been disease-free for 3 years, or patients with a history of adequately treated in-situ carcinoma of the uterine cervix, basal or squamous cell carcinoma, non-melanomatous cancer of skin, history of stage IA melanoma that has been cured, are eligible.
4. Undergone a bone marrow or solid organ transplant
5. Known history of human immunodeficiency virus (HIV) seropositivity (HIV testing is not mandatory)
6. 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
7. Any medical condition that would, in the investigator's judgment, prevent the patient's participation in the clinical study due to safety concerns or compliance with clinical study procedures
8. Patients with out of range laboratory values defined as:
• Absolute Neutrophil Count (ANC) < 1.5 x 10^9/L (1.5 x 103/μL)
• Hemoglobin (Hgb) < 9 g/dL
• Platelets < 75 x 10^9/L
• Total bilirubin >1.5 x ULN. For patients with Gilbert's syndrome total bilirubin >3.0 x upper limit of normal (ULN)
• Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) >3 x ULN for patients without hepatic metastasis. AST and/or ALT >5 x ULN for patients with hepatic metastasis
• Alkaline phosphatase (ALP) > 5 xULN
• Fasting plasma glucose > 175 mg/dL (> 9.8 mmol/L)
• Measured or calculated creatinine clearance < 45 mL/min (0.75 mL/sec)
9. Patients with electrolytes outside the laboratory normal limits that
cannot be corrected with supplements during screening:
• Potassium
• Magnesium
• Phosphorus
• Total calcium (corrected for serum albumin)
10. Patients 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.
Other protocol-defined exclusion criteria may apply |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase I part: Incidence of dose limiting toxicity (DLT)
Phase II part: Overall response rate (ORR) by Blinded Independent Review Committee (BIRC) assessment in accordance to Response
Evaluation Criteria in Solid Tumors (RECIST 1.1) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Phase I part: first 28 days of dosing
Phase II part: After at least 6 cycles (until Cycle 7 Day 1) of treatment or if discontinued treatment prior to that time |
|
| E.5.2 | Secondary end point(s) |
1. Safety: Incidence and severity of AEs and SAEs, including changes in laboratory values, vital signs and ECGs. Tolerability: number of dose interruptions and reductions
2. overall response rate (ORR), duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), and time to response (TTR) determined by Investigator assessments
3. Plasma concentration vs. time profiles, plasma PK parameters
4. Pre- and on- treatment immunohistochemistry of EGFR pathway molecules (e.g., p-EGFR, p-AKT, p-ERK) in newly obtained tumor samples
Phase II part:
1. Safety: Incidence and severity of AEs and SAEs, including changes in laboratory values, vital signs and ECGs. Tolerability: Dose interruptions and reductions
2. ORR by Investigator assessment in accordance to RECIST 1.1
3. DOR, DCR, PFS and TTR will be evaluated by BIRC and Investigator assessment in accordance to RECIST 1.1: DOR, DCR, PFS and TTR
4. Overall survival (OS)
5. Plasma concentration vs. time profiles, and plasma PK parameters as appropriate |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Phase I:
1.Throughout study including safety follow-up up to 30 days after discontinuing treatment
2.Baseline, every 8 weeks until disease progression or discontinuing study treatment due to unacceptable toxicity or withdrawal of consent
3.Cycle 1 day 1,2,8,15; Cycle 2 day 1,2; Cycle 3 day 1; Cycle 4 day 1
4.Baseline and cycle 1 day 15
Phase II:
1.Throughout study including a safety follow-up (up to 30 days) after discontinuation of the study treatment
2.After at least 6 cycles of treatment or if discontinued treatment prior to that time
3.After at least 6 cycles of treatment or if discontinued treatment prior to that time
4.After at least 6 cycles of treatment or if discontinued treatment prior to that time
5.Cycle 1 day 1,2,8, 15; cycle 2 day 1, 2; cycle 3 day 1; cycle 4 day 1 |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | Yes |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 40 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Canada |
| Hong Kong |
| India |
| Israel |
| Japan |
| Korea, Republic of |
| Mexico |
| New Zealand |
| Russian Federation |
| Singapore |
| Taiwan |
| Turkey |
| United States |
| Austria |
| Belgium |
| Denmark |
| France |
| Germany |
| Hungary |
| Italy |
| Norway |
| Sweden |
| United Kingdom |
| Netherlands |
| Spain |
| Switzerland |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
End of study defined as the earliest occurrence of the following:
• At least 75% of all patients have died or are lost to follow up of OS
• Another clinical study becomes available that can continue to provide EGF816 in this patient population of this study and all patients ongoing are eligible to be transferred to that clinical study. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
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