Clinical Trials Register

Summary
EudraCT Number:	2017-001833-15
Sponsor's Protocol Code Number:	ASLAN001-012
National Competent Authority:	Estonia - SAM
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2017-07-06
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

Estonia - SAM

A.2

EudraCT number

2017-001833-15

A.3

Full title of the trial

A Two-Part Phase 2/3 Multicenter, Double-Blind, Randomized, Placebo-Controlled Study Of Varlitinib Plus mFOLFOX6 Versus Placebo Plus mFOLFOX6 in Subjects with HER1/ HER2 Co-Expressing Advanced or Metastatic Gastric Cancer Without Prior Exposure to Systemic Therapy

Kaheosaline II/III faasi mitmekeskuseline topeltpime randomiseeritud platseebokontrollitud uuring varlitiniibi ja mFOLFOX6 ravimikombinatsiooni võrdlemiseks platseebo ja mFOLFOX6 ravimikombinatsiooniga HER1/HER2 koekspressiooniga kaugelearenenud või metastaatilise maovähiga uuringus osalejate ravis, keda pole varem süsteemselt ravitud

A.3.1

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

Varlitinib in Combination With mFOLFOX6 for Advanced or Metastatic Gastric Cancer Without Prior Exposure to Systemic Therapy

A.4.1

Sponsor's protocol code number

ASLAN001-012

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	ASLAN Pharmaceuticals
B.1.3.4	Country	Singapore
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	ASLAN Pharmaceuticals
B.4.2	Country	Singapore
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	ASLAN Pharmaceuticals
B.5.2	Functional name of contact point	Juliana Wang
B.5.3	Address:
B.5.3.1	Street Address	83 Clemenceau Avenue, #12-03 UE Square
B.5.3.2	Town/ city	Singapore
B.5.3.3	Post code	239920
B.5.3.4	Country	Singapore
B.5.4	Telephone number	+65 6222 4235
B.5.5	Fax number	+65 6225 2419
B.5.6	E-mail	juliana.wang@aslanpharma.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	Varlitinib
D.3.2	Product code	ASLAN001
D.3.4	Pharmaceutical form	Film-coated 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	Varlitinib
D.3.9.1	CAS number	845272-21-1
D.3.9.2	Current sponsor code	ASLAN001
D.3.9.3	Other descriptive name	VARLITINIB
D.3.9.4	EV Substance Code	SUB188182
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	100
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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Film-coated tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

HER1/ HER2 Co-Expressing Advanced or Metastatic Gastric Cancer

E.1.1.1

Medical condition in easily understood language

Advanced or Metastatic Gastric Cancer

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Phase 2 Part:
To compare the efficacy between Varlitinib in combination with mFOLFOX6 to placebo in combination with mFOLFOX6, as measured by the percentage change from baseline in TS at 12 weeks.

Phase 3 Part:
To compare the efficacy between Varlitinib in combination with mFOLFOX6 to placebo in combination with mFOLFOX6 as measured by OS.

E.2.2

Secondary objectives of the trial

Phase 2 Part:
• To further evaluate the efficacy of Varlitinib in combination with mFOLFOX6 compared to placebo in combination with mFOLFOX6, as measured by ORR, PFS, OS, time to response (TTR), duration of response (DoR) and disease control rate (DCR);
• To assess the safety and tolerability of Varlitinib in combination with mFOLFOX6;
• To evaluate the PK of Varlitinib and any relevant circulating Varlitinib metabolite when Varlitinib is given in combination with mFOLFOX6.

Phase 3 Part:
• To further evaluate the efficacy of Varlitinib in combination with mFOLFOX6 compared to placebo in combination with mFOLFOX6, as measured by ORR, PFS, TTR, DoR and DCR;
• To assess the safety and tolerability of Varlitinib in combination with mFOLFOX6;
• To evaluate subject for health-related quality of life (QoL) in the two treatment arms.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Phase 2 Part:
Subjects will be entered into this study only if they meet all of the following criteria:
1. Subjects of respective country’s legal age or older at the time of written informed consent.
2. Subjects with histologically confirmed inoperable locally advanced, recurrent, or metastatic adenocarcinoma of the stomach or gastro-esophageal junction (GEJ) cancers may include Siewert Class I, II, or III types.
3. Mandatory provision of an unstained, archived tumor tissue sample in a quantity sufficient to allow for lab analysis of HER1 and HER2 expression status. If archived tumor tissue is not available, subject must agree to undergo fresh core biopsy to obtain adequate tumor tissue.
4. Subjects with tumors with immunohistochemistry (IHC) evidence of expression of HER1 (at level of + or ++ or +++) and HER-2 (at level of +, or ++) using standard criteria. Subjects with HER-2 over expression at level of +++ determined by IHC and subject confirmed HER2 2+ by IHC with HER2 gene amplification confirmed by fluorescence in situ hybridization (FISH) but has contradiction to trastuzumab*.
*Trastuzumab contradiction can be determined by:
• Allergic to trastuzumab after 1 to 2 cycles of trastuzumab (without Progressive disease [disease progression])
• Left ventricular ejection fraction (LVEF) decline ≥equal to 10% from baseline and below 50% after 1 to 2 cycles of trastuzumab (without disease progression)
5. Have radiographically measurable disease as defined by RECIST v1.1
6. Subjects with Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1
7. Estimated life expectancy of more than 4 months
8. Able to swallow and retain oral medication
9. Subject with adequate organ and hematological function:
a) Hematological function, as follows:
i. Absolute neutrophil count (ANC) ≥1.5 x 109/L
ii. Platelet count ≥100 x 109/L
iii. Hemoglobin ≥9 g/dL (packed red cell blood transfusions are not allowed within one week prior to baseline hematology profile).
b) Renal functions, as follows:
i. Serum creatinine ≤1.5x upper limit of normal (ULN) or estimated glomerular filtration rate (eGFR) >60 mL/min/1.73m2
c) Hepatic function, as follows:
i. Total bilirubin ≤1.5 x ULN
ii. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 x ULN (or ≤5 x ULN in subjects with liver metastasis)
iii. Albumin ≥25 g/L
10. Negative serum human chorionic gonadotropin (HCG)/ or urine pregnancy test within 7 days prior to randomization for premenopausal women of reproductive capacity and for women 12 months after menopause
11. Willingness to use highly effective birth control method (failure rate <1%) while on study.

Phase 3 Part:
1. Subjects of respective country’s legal age or older at the time of written informed consent.
2. Subjects with histologically confirmed inoperable locally advanced, recurrent, or metastatic adenocarcinoma of the stomach or GEJ cancers may include Siewert Class I, II, or III types.
3. Mandatory provision of an unstained, archived tumor tissue sample in a quantity sufficient to allow for lab analysis of HER1 and HER2 expression status. If archived tumor tissue is not available, subject must agree to undergo fresh core biopsy to obtain adequate tumor tissue.
4. Subjects with tumors with IHC evidence of expression of HER1 (at level of + or ++ or +++) and HER-2 (at level of +, or ++). Subjects with HER-2 over expression at level of +++ determined by IHC and subject confirmed HER2 2+ by IHC with HER2 gene amplification confirmed by FISH but has contradiction to trastuzumab*.
*Trastuzumab contradiction can be determined by:
• Allergic to trastuzumab after 1 to 2 cycles of trastuzumab (without disease progression)
• LVEF decline ≥equal to 10% from baseline and below 50% after 1 to 2 cycles of trastuzumab (without disease progression)
5. Subjects with ECOG performance status of 0 to 1
6. Able to swallow and retain oral medication
7. Subject with adequate organ and hematological function:
a) Hematological function, as follows:
i. ANC ≥1.5 x 109/L
ii. Platelet count ≥ 100 x 109/L
iii. HgB ≥9 g/dL (packed red cell blood transfusions are not allowed within one week prior to baseline hematology profile).
b) Renal functions, as follows:
i. Serum creatinine ≤1.5x ULN or eGFR >60 mL/min/1.73m2
c) Hepatic function, as follows:
i. Total bilirubin ≤1.5 x ULN
ii. AST and ALT ≤2.5 x ULN (or ≤5 x ULN in subjects with liver metastasis)
iii. Albumin ≥25 g/L
8. Negative serum HCG/ or urine pregnancy test within 7 days prior to randomization for premenopausal women of reproductive capacity and for women 12 months after menopause
9. Willingness to use highly effective birth control method (failure rate <1%) while on study.

E.4

Principal exclusion criteria

Phase 2 and Phase 3 Part:
1. Subject with HER-2 over expression at level of +++ determined by IHC or subject confirmed HER2 2+ by IHC with HER2 gene amplification confirmed positive by FISH.
2. Prior systemic anti-cancer treatment for inoperable locally advanced, recurrent, or metastatic adenocarcinoma of the stomach or GEJ. However, previous (neo-) adjuvant chemotherapy is allowed if subject has progression of disease more than 6 months after (neo-) adjuvant treatment.
3. Subjects have undergone major surgery within 28 days prior to randomization.
4. Subject with brain lesion, known brain metastases (unless previously treated and well controlled for a period of at least 4 weeks).
5. Subject with malabsorption syndrome, diseases significantly affecting gastrointestinal function, extensive resection of the stomach or small bowel, or
difficulty in swallowing and retaining oral medications.
6. Subjects with an uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, NYHA III or IV congestive heart failure, unstable angina pectoris, clinically significant cardiac arrhythmia, diabetes, hypertension, or psychiatric illness/social situations that would limit compliance with study requirements.
7. Subjects with any history of other malignancy unless in remission for more than 1 year. (Nonmelanoma skin carcinoma and carcinoma-in-site of uterine cervix treated with curative intent is not exclusionary).
8. Female subjects who are pregnant or breast feeding.
9. Subjects who were previously treated with Varlitinib.
10. Subjects who took other investigational drugs and/or used investigational medical devices before initiating Varlitinib therapy.
11. Are currently on or have received radiation or local treatment within the past 28 days
12. Subject with unresolved or unstable serious toxicity (≥ Common Terminology Criteria for Adverse Events [CTCAE] 4.03 Grade 2) from prior administration of another investigational drug and/or prior cancer treatment (excluding hair loss)
13. Subjects with a known history of human immunodeficiency virus, decompensated cirrhosis, hepatitis B infection with hepatitis B virus deoxyribose nucleic acid exceeding 2000 IU/mL or hepatitis C (treatment naïve or after treatment without sustained virologic response).
14. Known history of drug addiction within the past 1 year.
15. Subjects who need continuous treatment with proton pump inhibitors during the study period.
16. Any history or presence of clinically significant cardiovascular, respiratory, hepatic, renal, hematologic, gastrointestinal, endocrine, immunologic, dermatologic, neurologic or psychiatric disease or any other condition which in the opinion of the Investigator could jeopardize the safety of the subject or the validity of the study results.

E.5 End points

E.5.1

Primary end point(s)

Phase 2 Part:
Percentage change from baseline in TS at Week 12: defined as the percentage change from baseline in the sum of longest diameters of target lesions as assessed by ICR and defined by the RECIST v1.1 criteria.

Phase 3 Part:
Overall Survival (OS): Defined as the time from randomization until death by any cause. Any subject not known to have died at the time of the analysis will be censored based on the last recorded date on which the subject was known to be alive.

E.5.1.1

Timepoint(s) of evaluation of this end point

Per Protocol

E.5.2

Secondary end point(s)

Phase 2 Part:
• Objective Response Rate (ORR): Defined as the proportion of subjects with a best objective response (BOR) of complete response (CR) or partial response (PR), as defined by the RECIST v1.1 criteria.
• Progression-free survival (PFS): Defined as the time from randomization until the date of objective disease progression or death (by any cause in the absence of disease progression), whichever comes first. Progression is defined in accordance with the RECIST v1.1 criteria.
• Time to response (TTR): Defined as the time between date of randomization and first documented response (CR or PR), in the subset of subjects classified as responders in the assessment of ORR.
• Duration of Response (DoR): Defined as the time, in days, from the first recorded achievement of a response (PR or above) until time of objective disease progression in the subset of subjects classified as responders in the assessment of ORR.
• Disease Control Rate (DCR): Defined as the proportion of subjects with a (BOR of CR or PR, or SD maintained for a minimum of twelve weeks (-5 days) from randomization, as defined by the RECIST v1.1 criteria.
• Overall Survival (OS): Defined as the time from randomization until death by any cause. Any subject not known to have died at the time of the analysis will be censored based on the last recorded date on which the subject was known to be alive.
• Pharmacokinetic parameters for Varlitinib including, but not limited to area under the plasma concentration time curve (AUC) from 0 to 6 hours (AUC0-6), maximum observed plasma concentration (Cmax), time to Cmax (tmax), accumulation ratio for AUC (Rac AUC0-6), and accumulation ratio for Cmax (Rac Cmax).

Phase 3 Part:
• Objective response rate, PFS, TTR, DoR, and DCR: As defined for Phase 2 Part
• Safety and tolerability as determined by:
o Adverse events (categorized in accordance with CTCAE 4.03)
o Laboratory tests (clinical chemistry, hematology, coagulation and urinalysis)
o Vital signs (systolic blood pressure (SBP), diastolic blood pressure (DBP), pulse rate, respiratory rate, and body temperature)
o ECG
o Physical examination
o Exposure and dose intensity
Health-related quality of life will be evaluated over time based on the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 and EORTC-QLQ-ST022 questionnaire

E.5.2.1

Timepoint(s) of evaluation of this end point

Per Protocol

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

Yes

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Quality of Life Assessment

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)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

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

Yes

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

Yes

E.8.4

The trial involves multiple sites in the 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

China

Estonia

Hong Kong

Korea, Republic of

Lithuania

Malaysia

Singapore

Taiwan

Thailand

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

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:

315

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

350

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)

At the end of both phases of the study, when the treatment allocation is unblinded, all subjects receiving an active treatment and who, in the opinion of the Investigator, may benefit from continued Varlitinib treatment, will be offered participation in an open-label extension study where only Varlitinib would be provided by the sponsor or be managed under a compassionate use program governed by the Regulatory Authorities in the respective countries.

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

2017-08-08

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-06-29

P. End of Trial
P.	End of Trial Status	Prematurely Ended

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