Clinical Trials Register

Summary
EudraCT Number:	2019-002345-37
Sponsor's Protocol Code Number:	MK-7902-012
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2020-02-04
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

2019-002345-37

A.3

Full title of the trial

A Phase 3 Multicenter, Randomized, Double-blinded, Active-controlled, Clinical Study to Evaluate the Safety and Efficacy of Lenvatinib (E7080/MK-7902) with Pembrolizumab (MK-3475) in Combination with Transarterial Chemoembolization (TACE) Versus TACE in Participants with Incurable/Non-metastatic Hepatocellular Carcinoma (LEAP-012)

A.3.1

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

Phase 3 Study of Pembrolizumab and Lenvatinib in Combination with TACE for Incurable/Non-metastatic Hepatocellular Carcinoma

A.4.1

Sponsor's protocol code number

MK-7902-012

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT04246177

A.5.4

Other Identifiers

Name:

IND

Number:

140284

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	Merck Sharp & Dohme LLC
B.1.3.4	Country	United States
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	Merck Sharp & Dohme LLC
B.4.2	Country	United States
B.4.1	Name of organisation providing support	Eisai Limited
B.4.2	Country	United Kingdom
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Merck Sharp & Dohme LLC
B.5.2	Functional name of contact point	GCTO
B.5.3	Address:
B.5.3.1	Street Address	126 East Lincoln Avenue P.O. Box 2000
B.5.3.2	Town/ city	Rahway, New Jersey
B.5.3.3	Post code	07065
B.5.3.4	Country	United States
B.5.4	Telephone number	+1732594 1053
B.5.6	E-mail	leo.dubrovsky@merck.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	Yes
D.2.1.1.1	Trade name	KEYTRUDA (pembrolizumab, MK-3475)
D.2.1.1.2	Name of the Marketing Authorisation holder	Merck Sharp & Dohme B.V.
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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.3.4	Pharmaceutical form	Concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Pembrolizumab
D.3.9.1	CAS number	1374853-91-4
D.3.9.2	Current sponsor code	MK-3475
D.3.9.4	EV Substance Code	SUB167136
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	25
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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)	Yes
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Yes
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	Lenvatinib
D.3.2	Product code	E7080/MK-7902
D.3.4	Pharmaceutical form	Capsule, hard
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	LENVATINIB MESILATE
D.3.9.1	CAS number	857890-39-2
D.3.9.2	Current sponsor code	MK-7902
D.3.9.3	Other descriptive name	LENVATINIB MESILATE
D.3.9.4	EV Substance Code	SUB72971
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	4
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	Solution for infusion
D.8.4	Route of administration of the placebo	Intravenous use
D.8 Placebo: 2
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Capsule
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

Incurable/Non-metastatic Hepatocellular Carcinoma

E.1.1.1

Medical condition in easily understood language

Incurable/Non-metastatic Hepatocellular Carcinoma

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	20.0
E.1.2	Level	PT
E.1.2	Classification code	10073071
E.1.2	Term	Hepatocellular carcinoma
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

1. To compare pembrolizumab plus lenvatinib in combination with transarterial chemoembolization (TACE) versus placebo plus TACE with regard to progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) assessed by blinded, independent central review (BICR).

2. To compare pembrolizumab plus lenvatinib in combination with TACE versus placebo plus TACE with regard to overall survival (OS).

E.2.2

Secondary objectives of the trial

1. To evaluate pembrolizumab plus lenvatinib in combination with TACE versus placebo plus TACE with regard to PFS, objective response rate (ORR), disease control rate (DCR), duration of response (DOR) and time to progression (TTP) per modified Response Evaluation Criteria in Solid Tumors (mRECIST) assessed by BICR.

2. To evaluate the safety and tolerability of pembrolizumab plus lenvatinib in combination with TACE versus placebo plus TACE.

3. To evaluate pembrolizumab plus lenvatinib in combination with TACE versus placebo plus TACE with regard to efficacy outcomes per RECIST 1.1 assessed by BICR.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1.Has a diagnosis of HCC confirmed by radiology, histology, or cytology.
Has a radiologic diagnosis of HCC as per the AASLD guidelines, which requires:
-liver cirrhosis and a liver mass confirmed by BICR that shows arterial phase hyperenhancement on triphasic CT or MRI, AND EITHER:
Is ≥20 mm with either non-peripheral portal washout or an enhancing capsule OR
Is 10-19 mm with non-peripheral portal venous washout AND an enhancing capsule.
2.Has HCC localized to the liver without portal vein thrombosis, and not amenable to curative treatment such as resection, ablation, or liver transplant. No extrahepatic HCC is permitted, confirmed by BICR.
3.Has at least one measurable HCC lesion based on RECIST 1.1, confirmed by BICR.
4.Has all lesions treatable with TACE in 1 or 2 sessions.
5.Is amenable, without any contraindications, to the TACE procedure and chemotherapy agent pre specified at the study site.
6.Has a CP class A liver score within 7 days prior to first dose of study intervention.
7.Has a predicted life expectancy of >3 months.
8.Has an ECOG PS of 0 to 1 within 7 days prior to first dose of study intervention.
9.Is male or female ≥ 18 years of age at the time of signing the informed consent.
10.Male participants are eligible to participate if they agree to the following during the intervention period and for at least the time needed to eliminate each study intervention after the last dose of study intervention. The length of time required to continue contraception for each study intervention is as follows:
- Lenvatinib 7 days
- TACE 95 days
• Refrain from donating sperm
PLUS either:
-Be abstinent from heterosexual intercourse as their preferred and usual lifestyle and agree to remain abstinent OR
-Must agree to use contraception unless confirmed to be azoospermic.
-Contraceptive use by men should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
11.A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:
-Is not a WOCBP OR
-Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of <1% per year), with low user dependency, or be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis), during the intervention period and for at least the time needed to eliminate each study intervention after the last dose of study intervention and agrees not to donate eggs (ova, oocytes) to others or freeze/store for her own use for the purpose of reproduction during this period. The length of time required to continue contraception for each study intervention is as follows:
- Pembrolizumab 120 days
- Lenvatinib 30 days
- Tace 180 days
The investigator should evaluate the potential for contraceptive method failure in relationship to the first dose of study intervention.
-A WOCBP must have a negative highly sensitive pregnancy test within 24 hours for urine or 72 hours for serum before the first dose of study intervention.
-If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy
result is positive.
·The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy.
·Contraceptive use by women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
12.The participant (or legally acceptable representative if applicable) provides written informed consent/assent for the study.
13.Participants with past or ongoing HCV infection will be eligible for the study. Treated participants must have completed their treatment at least 1 month prior to starting study intervention.
14.Participants with controlled HBV will be eligible as long as they meet the following criteria:
-Antiviral therapy for HBV must be given for at least 4 weeks and HBV viral load must be <500 IU/mL prior to first dose of study interventions. Participants on active HBV therapy with viral loads <500 IU/mL should stay on the same therapy throughout study intervention.
-Participants who are positive for HBc, negative for HBsAg, and negative or positive for HBs, and who have an undetectable HBV viral load, do not require HBV antiviral prophylaxis.
-Participants not on HBV therapy with undetectable HBV viral load, but positive for HBsAg, may begin anti-viral prophylaxis at any time prior to first dose of study interventions.
15.Has adequately controlled blood pressure (BP) with or without antihypertensive medications, defined as BP ≤150/90 mm Hg at screening and no change in antihypertensive medications within 1 week before Cycle 1 Day 1

E.4

Principal exclusion criteria

1.Has HCC lesion(s) measuring ≥10 cm in any dimension, has more than 10 lesions on radiographic evaluation or has HCC lesions occupying ≥50% of the liver volume, confirmed by BICR.
2.Has had esophageal or gastric variceal bleeding within the last 6 months.
3.Has bleeding or thrombotic disorders or is using anticoagulants requiring therapeutic INR monitoring, eg, warfarin or similar agents. Treatment with antiplatelet agents and low molecular weight heparin is permitted.
4.Has clinically apparent ascites on physical examination that is not controlled with medication. Ascites detectable on imaging studies only is allowed.
5.Has any macrovascular tumor thrombosis in the portal veins, confirmed by BICR. Microvascular tumor thrombosis detected on biopsy, but not radiographic scan, is permitted.
6.Has had clinically diagnosed hepatic encephalopathy in the last 6 months unresponsive to therapy. Participants on rifaximin or lactulose during screening to control their hepatic encephalopathy are excluded.
7.Has received any systemic chemotherapy, including anti-VEGF therapy, or any systemic investigational anticancer agents for HCC.
8. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX-40, CD137).

E.5 End points

E.5.1

Primary end point(s)

1. Progression-free Survival (PFS) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)
2. Overall Survival (OS)

E.5.1.1

Timepoint(s) of evaluation of this end point

1. Up to ~43 months
2. Up to ~95 months

E.5.2

Secondary end point(s)

1. PFS per Modified Response Evaluation Criteria in Solid Tumors (mRECIST)
2. Objective Response Rate (ORR) per mRECIST
3. Disease Control Rate (DCR) per mRECIST
4. Duration of Response (DOR) per mRECIST
5. Time to Progression (TTP) per mRECIST
6. Percentage of Participants Who Experience At Least One Adverse Event (AE)
7. Percentage of Participants Who Experience At Least One Serious Adverse Event (SAE)
8. Percentage of Participants Who Experience At Least One Hepatic Event of Clinical Interest (ECI)
9. Percentage of Participants Who Discontinue Study Drug Due to an AE
10. ORR per RECIST 1.1
11. DCR per RECIST 1.1
12. DOR per RECIST 1.1
13. TTP per RECIST 1.1

E.5.2.1

Timepoint(s) of evaluation of this end point

1. Up to ~43 months
2. Up to ~95 months
3. Up to ~95 months
4. Up to ~95 months
5. Up to ~95 months
6. Up to ~95 months
7. Up to ~95 months
8. Up to ~95 months
9. Up to ~95 months
10. Up to ~95 months
11. Up to ~95 months
12. Up to ~95 months
13. Up to ~95 months

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

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Health Utility Scores; anti-MK3475 antibody levels

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)

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

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

Brazil

Chile

China

Colombia

Hong Kong

Israel

Japan

Korea, Republic of

New Zealand

Puerto Rico

Taiwan

Thailand

United States

France

Sweden

Netherlands

Spain

Germany

Italy

Denmark

Hungary

Ireland

Norway

Portugal

Turkey

Ukraine

United Kingdom

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

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:

270

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

180

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

450

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)

None

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

2020-07-20

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-07-07

P. End of Trial
P.	End of Trial Status	Ongoing

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