| 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 | 18.0 |
| 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 BIRC and 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
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 |
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
Page 26/42
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. Willingness and ability to comply with scheduled visits, treatment
plans, laboratory tests and other study procedures
8. Requirement of EGFR mutation status and prior lines of treatment for
Phase I patients:
• All patients participating in the Phase I part must have recurring or
progressive disease following standard therapy.
• Locally advanced or metastatic NSCLC harboring a documented EGFR
T790M mutation. An archival or newly obtained tumor sample must be
available for molecular pre-screening if prior documentation of EGFR
T790M mutation status is not available; No more than a total of 3 prior
lines of antineoplastic therapies, including EGFR TKI, in the advanced
setting; No prior treatment with any investigational EGFR-TKI targeting
EGFR T790M mutation (i.e. 3rd-generation EGFR TKI)
9. Requirements of EGFR mutation status and prior lines of treatment for
Phase II patients:
• Group 1: 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.
• Group 2: Locally advanced or metastatic NSCLC with EGFR activating
mutation (e.g. L858R and/or ex19del) and an acquired EGFR T790M
mutation; Who have progressed on 1 and only 1 prior treatment with a
1st-generation EGFR TKI (e.g., erlotinib, gefitinib or icotinib) or 2ndgeneration
EGFR TKI (e.g., afatinib or dacomitinib); No more than 3 prior
lines of systemic antineoplastic therapies (including EGFR TKI) in the
advanced setting; 1st/2nd-generation EGFR TKI treatment must be the
last prior treatment before study entry
• Group 3: Locally advanced or metastatic NSCLC with a "de novo" EGFR
T790M mutation; For purposes of this protocol, "de novo" T790M will be
defined as the presence of EGFR T790M mutation in NSCLC patients who
have NOT been previously treated with any therapy known to inhibit
EGFR; No more than 3 prior lines of systemic antineoplastic therapies in
the advanced setting; No prior treatment with any therapy known to
inhibit EGFR, including EGFR TKI
• Group 4: Locally advanced or metastatic NSCLC whose tumor harbors
EGFR exon 20 insertion or deletion; No more than 3 prior lines of
systemic antineoplastic therapies, including EGFR TKI, in the advanced
setting
• Group 5: Locally advanced or metastatic NSCLC with EGFR activating
mutation (e.g. L858R and/or ex19del) AND without an acquired EGFR
T790M mutation; Who have progressed on 1 and only 1 prior treatment
with a 1st-generation EGFR TKI (e.g., erlotinib, gefitinib or icotinib), or
2nd-generation EGFR TKI (e.g., afatinib or dacomitinib); No more than 3
prior lines of systemic antineoplastic therapies (including EGFR TKI) in
the advanced setting; EGFR TKI treatment must be the last prior
treatment before study entry.
• Group 6: Locally advanced or metastatic NSCLC with EGFR activating
mutations (e.g. L858R or ex19del) and an acquired T790M mutation;
Who have had treatment with a 1st/2nd-generation EGFR TKI; Who have
progressed on or are intolerant to a 3rd-generation EGFR TKI (i.e.
AZD9291, CO-1686, or ASP8273); No more than 3 prior lines of systemic
antineoplastic therapies (including EGFR TKIs) in the advanced setting;
3rd-generation EGFR TKI treatment must be the last prior treatment
before study entry.
Other protocol-defined inclusion criteria may apply
|
|
| E.4 | Principal exclusion criteria |
English 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. Patients with unstable brain metastases.
4. 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
5. Patients with out of range laboratory values defined as:
• Absolute Neutrophil Count (ANC) < 1.5 x 10^9/L
• 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
6. 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)
7. 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) |
Phase I part:
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 BIRC and by Investigator assessments
3. Plasma concentration vs. time profiles, plasma PK parameters
4. Pre- and post- 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
| Information not present in EudraCT |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Information not present in EudraCT |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 40 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 6 |
| 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 |
| Austria |
| Belgium |
| Canada |
| China |
| Denmark |
| France |
| Germany |
| Hong Kong |
| Hungary |
| India |
| Israel |
| Italy |
| Japan |
| Korea, Republic of |
| Lebanon |
| Mexico |
| Netherlands |
| New Zealand |
| Norway |
| Poland |
| Russian Federation |
| Singapore |
| Spain |
| Sweden |
| Switzerland |
| Taiwan |
| Turkey |
| United Kingdom |
| United States |
|
| 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
|
| The end of study will be upon completion of the disease progression period or 30 day safety follow up period (whichever is later) for all patients treated in all arms or when the study is terminated early. |
|
| 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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