| 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 maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) 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 PK properties of EGF816 and metabolite LMI258
4. To assess the tumor EGFR signaling inhibition by EGF816 (prior to protocol amendment 5)
Phase 2 part:
1. To further characterize the safety and tolerability of EGF816
2. To evaluate overall response rate (ORR) by investigator assessments.
3. To evaluate duration of response (DOR), disease control rate (DCR), progression-free survival (PFS) and time to response (TTR) determined by BIRC and investigator assessments.
4. To evaluate overall survival (OS)
5. To characterize the pharmacokinetics (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
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
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 unstable brain metastases.
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: Objective response rate (ORR) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Phase I part: first 28 days of dosing
Phase II part: baseline, every 8 weeks until disease progression,consent withdraw or death up to 3 years |
|
| 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 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
3.After at least 6 cycles of treatment or if discontinued treatment prior
to that
4.After at least 6 cycles of treatment or if discontinued treatment prior
to that
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 | 5 |
| 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 | 3 |
| 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 |
| Singapore |
| Taiwan |
| United States |
| Russian Federation |
| Turkey |
| Austria |
| Belgium |
| Denmark |
| France |
| Germany |
| Hungary |
| Italy |
| Netherlands |
| Norway |
| Spain |
| Sweden |
| United Kingdom |
|
| 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 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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