Clinical Trials Register

Summary
EudraCT Number:	2019-003106-28
Sponsor's Protocol Code Number:	73841937NSC2001
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	GB - no longer in EU/EEA
Date on which this record was first entered in the EudraCT database:	2019-10-10
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

UK - MHRA

A.2

EudraCT number

2019-003106-28

A.3

Full title of the trial

A Phase I/II, Open-Label, Multicenter Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Anti-Tumor Activity of YH25448 in Patients with EGFR Mutation Positive Advanced Non-Small Cell Lung Cancer (NSCLC)

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

A Clinical Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Anti-Tumor Activity of YH25448 in Patients with EGFR Mutation Positive Advanced Non-Small Cell Lung Cancer (NSCLC)

A.4.1

Sponsor's protocol code number

73841937NSC2001

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT03046992

A.5.4

Other Identifiers

Name:

YH25448-201

Number:

Yuhan Corporation

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Janssen Research & Development, LLC
B.1.3.4	Country	Belgium
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Janssen Research & Development, LLC
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Janssen-Cilag International N.V.
B.5.2	Functional name of contact point	Clinical Registry Group
B.5.3	Address:
B.5.3.1	Street Address	Archimedesweg 29
B.5.3.2	Town/ city	Leiden
B.5.3.3	Post code	2333
B.5.3.4	Country	Netherlands
B.5.4	Telephone number	+31 715242166
B.5.5	Fax number	+31 715242110
B.5.6	E-mail	ClinicalTrialsEU@its.jnj.com
B.Sponsor: 2
B.1.1	Name of Sponsor	Yuhan Corporation
B.1.3.4	Country	Korea, Republic of
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Yuhan Corporation
B.4.2	Country	Korea, Republic of
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Janssen-Cilag International N.V.
B.5.2	Functional name of contact point	Clinical Registry Group
B.5.3	Address:
B.5.3.1	Street Address	Archimedesweg 29
B.5.3.2	Town/ city	Leiden
B.5.3.3	Post code	2333
B.5.3.4	Country	Netherlands
B.5.4	Telephone number	+31715242166
B.5.5	Fax number	+31715242166
B.5.6	E-mail	ClinicalTrialsEU@its.jnj.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	lazertinib
D.3.2	Product code	YH25448A/JNJ-73841937-ABV
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Lazertinib
D.3.9.1	CAS number	1903008-80-9
D.3.9.2	Current sponsor code	YH25448/JNJ-73841937
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	10 to 80
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Advanced or Metastatic Non-Small Cell Lung Cancer (NSCLC)

E.1.1.1

Medical condition in easily understood language

A specific type of lung cancer called "Non-Small Cell Lung Cancer"

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	21.1
E.1.2	Level	PT
E.1.2	Classification code	10061873
E.1.2	Term	Non-small cell lung cancer
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The primary objective of Part D of the trial is to evaluate the safety, tolerability and pharmacokinetic (PK) of YH25448 when given orally to patients with EGFRm+ locally advanced or metastatic NSCLC.

E.2.2

Secondary objectives of the trial

The secondary objectives of Part D of the trial are:
1. To characterize the PK profiles of potential YH25448 metabolites in plasma, including M7, following a single oral dose and at steady state.
2. To obtain additional assessments of the anti-tumor activity of YH25448 by evaluation of overall response rate (ORR), duration of response (DoR), disease control rate (DCR), tumor shrinkage and progression free survival (PFS) using RECIST 1.1 as assessed by investigator review of radiological information and overall survival (OS).

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

For inclusion in the study, patients must fulfill all of the following criteria.
1. Signed Written Informed Consent
● Provision of signed and dated, written informed consent prior to any study specific procedures, sampling and analyses. For inclusion in optional genetic and/or biomarker research, patients must provide informed consent for the research.
2. Age and Sex
● At least 20 years of age and older or adult men and women for each country.
● Females should agree to use adequate contraceptive measure, should not be breast feeding and must have a negative pregnancy test prior to start of dosing if of child-bearing potential or must have evidence of non-child-bearing potential by fulfilling one of following criteria at screening:
- Post-menopausal defined as aged more than 50 years and ameorrhoeic for at least 12 months following cessation of all exogenous hormonal treatments.
- Documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation.
- Women under 50 years old would be considered postmenopausal if they have been ameorrhoeic for at least 12 months following cessation of exogenous hormonal treatment, and have serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels in postmenopausal range for the institution.
● Male patients who have not undergone a vasectomy must agree to use barrier contraception i.e. condoms, and refrain from donating sperm until 3 months after last drug is taken.
● During the study, and for 3 months after receiving the last dose of study drug, female patients must agree not to donate eggs (ova, oocytes) and male patients must agree not to donate sperm for the purposes of assisted reproduction.
3. Target disease
● Parts A, B and C only: Histologically or cytologically(i.e., pleural effusion, ascites cases) confirmed diagnosis of NSCLC with single activating EGFR mutations (L858R or Exon19Del or G719X or L861Q). EGFR mutation status should have been determined using well-validated and robust methodology which has been approved by the regulatory authority. In the country where diagnosis of EGFR mutation does not need to use regularity approved kit, well-validated methodology will be used.
- In Part D: Patients outside Korea with histologically or cytologically (ie, using pleural effusion, ascites) confirmed NSCLC with previously diagnosed EGFRm+, and who have had progressive disease on prior EGFR-TKI therapy.
● Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1 with no deterioration over the previous 2 weeks and a minimum life expectancy of 3 months.
● Patients who have at least one measurable extracranial lesion, not previously irradiated and not chosen for biopsy during the study screening period or one measurable lesion that has passed 14 days or more after biopsy, that can be accurately measured at baseline as ≥ 10mm in the longest diameter (except lymph nodes which must have short axis ≥ 15mm) with computerized tomography (CT) or magnetic resonance imaging (MRI), are suitable for accurate repeated measurement.

E.4

Principal exclusion criteria

Patients must not enter the study if any of the following exclusion criteria are fulfilled.
1. Intervention with any the following:
● An unapproved investigational product from another clinical study within 30 days of the first dose of study treatment
● Treatment with an EGFR TKIs within 8 days or approximately 5x half-life, whichever is the longer, of the first dose of study treatment or other investigational products within approved indication of marketed product
● Any cytotoxic chemotherapy or other anticancer drugs for the treatment of advanced NSCLC from a previous treatment regimen within 14 days of the first dose of study treatment
● Major surgery (excluding for vascular access) within 4 weeks of the first dose of study treatment, or have an anticipated need for major surgery during the study
● Radiotherapy with a wide field of radiation within 4 weeks or radiotherapy with a limited field of radiation for palliation within 1 week of the first dose of study treatment with the exception of patients receiving radiation to more than 30% of the bone marrow marrow which must be completed within 4 weeks of the first dose of study treatment
● Patients currently receiving (or unable to stop use at least 1 week prior to receiving the first dose of YH25448) medications or herbal supplements known to be inhibitors or inducers of CYP3A4
● Any unresolved toxicities from prior therapy, greater than Common Terminology Criteria for Adverse Events (CTCAE) grade 1 at the time of starting 1st study treatment with the exception of alopecia
2. Medical History and Concurrent Disease
● Symtomatic spinal cord compression (if steroid treatment is not required within at least 2 weeks prior to the start of the study treatment then the patient may be enrolled)
● Brain metastases with symptomatic and/or requiring emergency treatment
● Intracranial hemorrhage with symptomatic and/or requiring treatment
● CNS complications that require urgent neurosurgical intervention
● Leptomeningeal metastasis prior to study treatment
● Past medical history of interstitial lung disease (ILD), drug-induced IDL, radiation pneumonitis which required steroid treatment, or any evidence of clinically active ILD
● Carcinoma besides NSCLC requiring treatment or any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension and active bleeding diatheses, which in the investigator’s opinion makes it undesirable for the patient to participate in trial or which would jeopardise compliance with the protocol. Screening for chronic condition is not required
● Any cardiovascular disease as followed,
a) History of symptomatic CHF or serious cardiac arrhythmia requiring treatment
b) History of myocardial infarction or unstable angina within 6 months of the first dose of study treatment
c) LVEF <50%
● Active hepatitis with HbsAg+ or anti-HCV Ab+, confirmed positive HIV test results
● Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection that would preclude adequate absorption of study medication
● History of hypersensitivity to active or inactive excipients of YH25448 or drugs with a similar chemical structure or class to YH25448
● Clinically significant chronic infection or significant medical or psychiatric illness
● Judgment by investigators that the patient should not participate in the study if the patient is unlikely to comply with study procedure, restrictions and requirements
● In addition, the following are considered criterion for exclusion from the exploratory genetic research: Previous allergenic bone marrow transplant, Non-leukocyte depleted whole blood transfusion within 120 days of the date of the genetic sample collection
3. Cardiac and Clinical Laboratory Criteria
● Any of following cardiac criteria:
a) Mean resting corrected QT interval (QTc) > 470 msec obtained from 3 electrocardiograms (ECGs), using the screening ECG machine derived QTc value
b) Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG eg, complete left bundle branch block, third degree heart block, second degree heart block, PR interval >250msec
c) Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or administration of concomitant medication known to prolong the QT interval
● Inadequate bone marrow reserve or organ function as demonstrated by any of the following laboratory values;
a) Absolute neutrophil count (ANC) < 1.5 x 10^9/L
b) Platelet count < 100 x 10^9/L
c) Hemoglobin <90 g/L
d) In case of Troponin I test result finally confirmed by central lab exceeded ULN (TnI+). In Part D, central laboratroy confirmation of TnI+ is not required.

E.5 End points

E.5.1

Primary end point(s)

Safety, tolerability, and PK of YH25448

E.5.1.1

Timepoint(s) of evaluation of this end point

At each dose level(s) of dose escalation phase in NSCLC patients who progressed following prior EGFR TKIs treatment and harbouring confirmed T790M mutation

E.5.2

Secondary end point(s)

1. Pharmacokinetic (PK) profiles of potential YH25448 metabolites in plasma, including M7, following a single oral dose and at steady state
2. Overall response rate (ORR)
3. Duration of response (DoR)
4. Disease control rate (DCR)
5. Tumor shrinkage
6. Progression free survival (PFS)
7. Overall survival (OS)

E.5.2.1

Timepoint(s) of evaluation of this end point

1. Cycle 0 (Day 1[D1], D2, D3), Cycle 1 (D1, D8, D15), Cycle 2
2 to 7. Screening, Cycle 1 (D1, D8, D15), Cycle 2 (D1) until follow up visit

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

E.6.10

Pharmacogenetic

Yes

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Tolerability

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

Yes

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

Yes

E.7.1.3.1

Other trial type description

Safety, tolerability, efficacy and pharmacokinetic (PK) in patients outside of Korea

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

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

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

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

Information not present in EudraCT

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

Spain

United Kingdom

United States

E.8.7

Trial has a data monitoring committee

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

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

Standard of care

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2019-10-16

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-11-26

P. End of Trial
P.	End of Trial Status	GB - no longer in EU/EEA

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