Clinical Trials Register

Summary
EudraCT Number:	2015-001435-21
Sponsor's Protocol Code Number:	HM-EMSI-202
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2015-12-21
Trial 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

Germany - BfArM

A.2

EudraCT number

2015-001435-21

A.3

Full title of the trial

A single-arm, open-label, Phase 2 study evaluating the efficacy, safety and pharmacokinetics of HM61713 (BI 1482694) in patients with T790M-positive non-small cell lung cancer (NSCLC) after treatment with an epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI)

A.3.1

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

A study to assess effects (how safe and effective) of HM61713 (BI 1482694) (new medicine) on specific type of non-small cell lung cancer, which characterized by being positive to certain type of mutation (T790M) , after treatment with a class of drugs known as (EGFR-TKI). The study will also test the drug concentrations’ changes in the patient blood at certain time points.

A.4.1

Sponsor's protocol code number

HM-EMSI-202

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT02485652

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	Hanmi Pharmaceutical Co., Ltd.
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	Hanmi Pharmaceutical Co., Ltd.
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	Hanmi Pharm. Co., Ltd.
B.5.2	Functional name of contact point	Clinical director’s office
B.5.3	Address:
B.5.3.1	Street Address	14, Wiryeseong-daero, Songpa-gu
B.5.3.2	Town/ city	Seoul
B.5.3.3	Post code	05545
B.5.3.4	Country	Korea, Republic of
B.5.4	Telephone number	82 2 410 8724
B.5.5	Fax number	82 2 410 9278
B.5.6	E-mail	prayernote@hanmi.co.kr

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	HM61713
D.3.2	Product code	HM61713
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	not assigned yet
D.3.9.1	CAS number	1353550-13-6
D.3.9.2	Current sponsor code	HM61713
D.3.9.3	Other descriptive name	HM61713
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	200
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.IMP: 2
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	HM61713
D.3.2	Product code	HM61713
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	not assigned yet
D.3.9.1	CAS number	1353550-13-6
D.3.9.2	Current sponsor code	HM61713
D.3.9.3	Other descriptive name	HM61713
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	400
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

Non-small cell lung cancer (NSCLC)

E.1.1.1

Medical condition in easily understood language

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	19.0
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

To assess the anti-tumor efficacy of oral single agent HM61713 administered to subjects with T790M-positive NSCLC after treatment with an EGFR-TKI as measured by objective response rate (ORR).

E.2.2

Secondary objectives of the trial

To assess secondary measures of clinical efficacy including disease control rate (DCR), duration of overall response (DR), progression-free survival (PFS), overall survival (OS), time to progression (TTP) and tumor shrinkage.
To determine the pharmacokinetic (PK) profile of HM61713 in this population using population-based PK (PopPK) methods and to explore potential exposure-response (E-R) relationships.
To assess patient reported outcomes (PROs) of health-related quality of life (HRQoL), disease/treatment-related symptoms of lung cancer, and general health status.
To evaluate the effect of HM61713 on the QTc interval.
To assess the safety and tolerability of HM61713.

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

PHARMACOGENETIC TESTING
The purpose of this additional research study is to identify specific genetic bio markers which may help in predicting the response to the treatment with HM61713, the study medication. On a larger scale, this research may also lead to the development of more effective (personalized) treatment for cancer subjects.

E.3

Principal inclusion criteria

1. Provide written informed consent before any study-specific procedures (including special Screening tests) are performed.
2. At least 20 years of age at the time of signing informed consent.
3. Cytologically or histologically confirmed adenocarcinoma of locally advanced or metastatic NSCLC which is not amenable to curative surgery or radiotherapy.
4. Radiologically confirmed disease progression after at least one line of treatment with an EGFR-TKI with or without at least one line of chemotherapy.
5. At least one documented EGFR mutation which is known to be related with susceptibility to EGFR-TKIs (including G719X, exon 19 deletion, L858R, and L861Q).
6. World Health Organization (WHO) performance score of 0 to 1 with life expectancy of at least 3 months.
7. Centrally confirmed T790M mutation positive tumor status from a tumor sample taken after confirmation of disease progression on the most recent anticancer treatment regimen.
8. At least one lesion (excluding the brain), not previously irradiated that can be accurately measured per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
9. Adequate hematological and biological function as follows:
a. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L; hemoglobin ≥ 9.0 g/dL; platelets ≥ 100 x 109/L without the use of hematopoietic growth factors.
b. Total bilirubin ≤ 1.5 times the upper limit of normal (ULN), or ≤ 4 x ULN for patients who are known to have Gilbert’s syndrome.
c. Creatinine ≤ 1.5 x ULN.
d. Aspartate transaminase (AST) and ALT ≤ 3 x ULN if no demonstrable liver metastases, or otherwise ≤ 5 x ULN.
e. Potassium and magnesium ≤ 1.0 x ULN (supplementation is permissible).
10. Females of child-bearing potential (not surgically sterilized and between menarche and one-year post-menopause) must agree to use adequate contraception (one of the following listed below) during the study (both men and women as appropriate) and for 3 months after the last dose of study drug. Subjects who are not surgically sterilized must have a negative urine or serum pregnancy test completed during the Screening period. The following measures need to be followed for females of child-bearing potential:
a. Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal).
b. Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable).
c. Intrauterine device (IUD).
d. Intrauterine hormone-releasing system (IUS).
e. Bilateral tubal occlusion.
f. Vasectomised partner.
g. Sexual abstinence.
11. Male patients should be documented to be sterile or agree to use barrier contraception i.e. condoms.
12. Recovery to ≤ Grade 1 or baseline of any toxicities due to prior treatments, except for stable sensory neuropathy
≤ Grade 2 and alopecia.

E.4

Principal exclusion criteria

1. Known history of hypersensitivity to active or inactive excipients of HM61713 or drugs with a similar chemical structure of HM61713.
2. Treatment with any of the following:
a. Anticancer therapies including chemotherapy, hormonal treatment, or immunotherapy within 14 days of the first administration of study drug.
b. Treatment with an EGFR-TKI (including erlotinib, gefitinib, and afatinib) within 8 days or 5-fold half-life, whichever is the longer, of the first administration of study drug.
c. Previous treatment with the combination of afatinib+cetuximab HM61713, or other drugs that target T790M-positive mutant EGFR with sparing of wild-type EGFR (e.g. AZD9291, CO-1686).
d. Treatment with any investigational agent(s) within 28 days prior to the first administration of study drug.
e. Radiotherapy with wide-field or more than 30% of the bone marrow within the past 2 weeks prior to the first administration of study drug; localized palliative radiation (e.g. localized skeletal metastasis) is permitted.
f. Any non-study related significant surgical procedures within the past 28 days prior to the first administration of study drug, except those related to this study.
3. Spinal cord compression, leptomeningeal carcinomatosis or active symptomatic brain metastases except for the followings:
a. Asymptomatic brain metastases incidentally found during screening process which do not require corticosteroids and/or local treatment in the opinion of the investigator.
b. Asymptomatic brain metastases for which local treatment has been given; at least 1 week off corticosteroids and/or anticonvulsants treatment before study randomization.
4. History of any other malignancy (other than curatively treated cervical cancer in situ, non-melanoma skin cancer, superficial bladder tumors Ta [non-invasive tumor] and TIS [carcinoma in situ]) unless it has been definitively treated with no ongoing therapy or evidence of relapse or recurrence within the past 3 years.
5. Clinically significant uncontrolled condition(s), including but not limited to:
a. Refractory nausea and vomiting, inability to swallow the formulated product, or any gastrointestinal disorder, which may interfere with the administration or metabolism of the study drug.
b. Active infection that requires parenteral antibiotics.
c. Known human immunodeficiency virus (HIV), active hepatitis B or active hepatitis C.
d. Psychiatric illness/social situations that would limit compliance with study requirements.
e. Known or suspected substance abuse or alcohol abuse.
f. Any medical condition which, in the opinion of the investigator, places the patient at an unacceptably high risk for toxicities.
6. Active or chronic pancreatitis assessed by the investigator
7. Any of the following cardiac abnormalities or history:
a. Abnormal 12-lead ECG considered to be clinically significant by the investigator.
b. Mean QT interval corrected using Fridericia’s (QTcF) method > 450 msec.
c. Personal or family history of long QT syndrome, second or third degree heart block.
d. Implanted pacemaker or cardioverter defibrillator.
e. Resting bradycardia < 55 beats/min.
f. Uncontrolled hypertension.
g. New York Heart Association (NYHA) class III or IV cardiac insufficiency, experienced unstable angina pectoris or cardiac infarction within 6 months, uncontrolled cardiac arrhythmia.
h. Left ventricular ejection fraction (LVEF) < 40%.
8. Presence or history of interstitial lung disease (ILD), drug-induced ILD, or presence of radiation pneumonitis.
9. Pregnant or breast feeding.
10. In the opinion of the investigator, the patient is an unsuitable candidate to receive HM61713.

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint of the study is objective response rate (ORR), defined as a best overall confirmed response of either complete response (CR) or partial response (PR) according to the RECIST version 1.1. and assessed by an independent central review.

E.5.1.1

Timepoint(s) of evaluation of this end point

Tumor response will be assessed at Screening and every 6 weeks relative to the first administration of study drug until PD using RECIST version 1.1. or for subjects who progressed but continue to take study drug until discontinuation. Each subject will be assigned one of the following categories: 1) CR, 2) PR, 3) stable disease (SD), 4) PD, or 5) not evaluable (NE).

E.5.2

Secondary end point(s)

Disease control rate (DCR), defined as the proportion of subjects with a documented CR, PR, and stable disease (SD) during the treatment cycles according to the RECIST version 1.1.
Duration of overall tumor response (DR), defined as the interval between the date of the first observation of tumor response (CR or PR) and the date of disease progression or death.
Progression-free survival (PFS), defined as the time from first administration of study drug to determination of tumor progression by RECIST version 1.1 or death due to any cause, whichever occurs first.
Overall survival (OS), defined as the time from first administration of study drug until death from any cause.
Time to progression (TTP), defined as the time from first administration of study drug to determination of tumor progression by RECIST version 1.1.
Tumor shrinkage calculated as absolute change and percentage change from baseline in sum of tumor size at each assessment using RECIST version 1.1.

E.5.2.1

Timepoint(s) of evaluation of this end point

Described in section E.5.2

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

Yes

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

E.6.10

Pharmacogenetic

Yes

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

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.8.3

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

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

Germany

Italy

Korea, Republic of

Malaysia

Philippines

Spain

Taiwan

United States

E.8.7

Trial has a data monitoring committee

Yes

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 the study is defined as the 28-day follow up visit of the last subject to discontinue study treatment.

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:

100

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

150

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)

Not different from the expected normal treatment

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

2016-02-18

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-03-03

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2020-03-18

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