Clinical Trials Register

Summary
EudraCT Number:	2018-000995-14
Sponsor's Protocol Code Number:	MIV-818-101/201
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:	2018-06-08
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

UK - MHRA

A.2

EudraCT number

2018-000995-14

A.3

Full title of the trial

A Phase 1/2a Study in 3 Parts (Phase 1a and Phase 1b - Dose Escalations and Phase 2a Expansion Cohorts) to Evaluate the Safety, Tolerability, Pharmacokinetics, and Preliminary Antitumor Activity of MIV-818 in Patients with Liver Cancer Manifestations

A.3.1

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

This is an open-label, multi-center, dose escalation Phase 1/2a study to establish the recommended dose for Phase 2 (RP2D) from Phase 1a and Phase 1b, as well as evaluating the preliminary efficacy of the RP2D in expansion cohorts (Phase 2a) in patients with liver related cancers.

A.4.1

Sponsor's protocol code number

MIV-818-101/201

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	Medivir AB
B.1.3.4	Country	Sweden
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	Medivir AB
B.4.2	Country	Sweden
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Worldwide Clinical Trials
B.5.2	Functional name of contact point	Project Manager
B.5.3	Address:
B.5.3.1	Street Address	1st Floor, Waterfront House, Beeston Business
B.5.3.2	Town/ city	Nottingham
B.5.3.3	Post code	NG9 1LA
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	+44 115 956 7711

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	MIV-818
D.3.2	Product code	MIV-818
D.3.4	Pharmaceutical form	Capsule
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	Troxacitabine based prodrug
D.3.9.2	Current sponsor code	MIV-818 (HCl)
D.3.9.3	Other descriptive name	MIV-818 (HCl), MV087313, Troxacitabine based prodrug
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	1
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Troxacitabine based prodrug
D.3.9.2	Current sponsor code	MIV-818 (HCl)
D.3.9.3	Other descriptive name	MIV-818 (HCl), MV087313, Troxacitabine based prodrug
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	10
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Troxacitabine based prodrug
D.3.9.2	Current sponsor code	MIV-818 (HCl),
D.3.9.3	Other descriptive name	MIV-818 (HCl), MV087313, Troxacitabine based prodrug
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	60
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Troxacitabine based prodrug
D.3.9.2	Current sponsor code	MIV-818 (HCl)
D.3.9.3	Other descriptive name	MIV-818 (HCl), MV087313, Troxacitabine based prodrug
D.3.9.4	EV Substance Code	SUB22612
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	30
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

hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (iCCA), or, metastatic liver disease

E.1.1.1

Medical condition in easily understood language

Liver related Cancer Manifestations

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.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10073077
E.1.2	Term	Intrahepatic cholangiocarcinoma
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10027479
E.1.2	Term	Metastatic liver 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

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

If not specified otherwise, all study objectives apply to all phases of the study.
The primary objectives of this study are:
• To determine the Recommended Phase 2 Dose (RP2D) by evaluating the safety and tolerability of escalating doses of MIV-818 in patients with HCC, iCCA, or metastatic liver disease (Phase 1a and Phase 1b)
• To evaluate the Objective Response Rate (ORR) measured by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 in Phase 2a expansion cohorts of patients with HCC and iCCA treated with the established RP2D of MIV-818

E.2.2

Secondary objectives of the trial

If not specified otherwise, all study objectives apply to all phases of the study.
The secondary objectives of this study are:
• To evaluate the ORR measured by Modified Response Evaluation Criteria in Solid Tumors (mRECIST) in patients treated with MIV-818
• To evaluate the ORR measured by RECIST v1.1 in liver lesions only in patients treated with MIV-818
• To evaluate the ORR based on RECIST v1.1 in patients treated with escalating doses of MIV-818 (Phase 1a and Phase 1b)
• To assess the effects of MIV-818 on plasma levels of AFP
• Phase 2a cohorts (HCC or iCCA):
- To evaluate the safety and tolerability of MIV-818 RP2D
- To assess duration of Progression Free Survival (PFS)
- To assess Clinical Benefit Rate (CBR) defined as complete response plus partial response plus SD (CR+PR+SD)
- To assess Duration of Response (DOR)
- To assess OS (Overall Survival)
- To assess Time to Response (TTR)

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Unless otherwise stated, inclusion criteria apply to all phases and cohorts in the study.
1. Male or female ≥ 18 years of age on the day of signing informed consent.
2. Able to understand and voluntarily sign a written informed consent and is willing, and able, to comply with the protocol requirements.
3. Must have measurable disease based on RECIST v1.1 as determined by the site study team. Must have at least 1 target lesion in the liver. Tumor lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
4.Must have a Child-Pugh A status for Phase 1a and a Child-Pugh A or B status Phase 1b and 2a. SRC discretion to restrict to Child- Pugh A status for Phase 1b and 2a.
5. Must have an ECOG performance status of 0 or 1 at Screening.
6. Must have life expectancy of > 12 weeks in the investigator’s opinion.
7. Must have ALT and AST ≤ 5.0 × upper limit of normal (ULN) at Screening.
8. Must have total bilirubin (TBil) ≤ 3.0 mg/dL at Screening.
9. Must have adequate renal function with estimated creatinine clearance ≥ 60 mL/min (based on Cockcroft and Gault formula or similar) at Screening
10. Must have platelets ≥ 75,000/mL at Screening.
11. Must have International Normalized Ratio (INR) ≤ 1.7 at Screening.
12. Female who is postmenopausal,
OR
Female who is of childbearing potential (postmenarchal) who agrees to use a highly efficient method of contraception (ie, a method with less than 1% failure rate [eg, sterilization, hormone implants, hormone injections, intrauterine devices, or vasectomized partner or combined birth control pills]) from Screening until 90 days after the final dose of MIV-818.
OR
Male who agrees to use condoms from Screening until 90 days after the final dose of MIV-818.
OR
Male with a female partner of childbearing potential (WOCBP) who is using a highly efficient method of contraception as described above.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the patient.
13. WOCBP must have a negative serum pregnancy test at Screening and negative (serum or urine) pregnancy test within 72 h before the first study drug dose. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. The serum pregnancy test must be negative for the patient to be eligible.

Phase 1a- and Phase 1b-specific Inclusion Criteria
14. Must have progressed on or are intolerant of standard therapy with:
a. Histologically or cytologically confirmed HCC, including fibrolamellar HCC; patients with HCC that received their diagnosis according to the agreed international radiological guideline are also admissible upon agreement between the investigator and the medical monitor, or
b. Histologically or cytologically confirmed iCCA, or
c. Liver metastases from colon, rectal or gastric solid tumors, with limited extrahepatic tumor burden. (any extrahepatic metastases should be limited to 1 other site and a maximum of 1 target lesion outside the liver).

Phase 2a-specific Inclusion Criteria
15. Must have:
- Histologically or cytologically confirmed HCC (patients with HCC that received their diagnosis according to the agreed international radiological guideline are also admissible upon agreement between the investigator and the medical monitor) with limited extrahepatic tumor burden who have progressed or are intolerant of standard therapy, or
- Histologically or cytologically confirmed iCCA with limited extrahepatic tumor burden who have progressed or are intolerant of standard therapy.

E.4

Principal exclusion criteria

Patients are excluded from this study if any 1 or more of the following criteria is met:
1. Tumor volume exceeding 50% of liver.
2. History of previous malignancy within the last 2 years except basal cell carcinoma or carcinoma in situ in solid organ.
3. Known CNS or brain metastases, unless previously treated and stable for 3 months.
4. Ongoing significant disease other than target disease as judged by the investigator to compromise the patients’ ability to complete this study.
5. History of solid organ transplant or bone marrow transplant.
6. Receiving immunosuppressive therapy including oral corticosteroids exceeding 15 mg daily of prednisone, 2 mg daily of dexamethasone or equivalent.
7.Active hepatitis B (eg, hepatitis B surface antigen [HBsAg] reactive) and patients with active hepatitis C (eg, hepatitis C RNA is [qualitative] detected).
8. Positive human immunodeficiency virus (HIV) infection.
9. Poorly controlled ascites and/or requirement for therapeutic paracentesis more frequently than once every 3 months.
10. Symptomatic encephalopathy within 3 months prior to Screening and/or requirement for medication for encephalopathy.
11. Esophageal variceal bleeding within 2 weeks prior to Screening.
12. Receiving anticancer therapy within 4 weeks prior to first dose of MIV-818.
13. Receiving any other investigational agent within 4 weeks prior to Screening
14. Enrolled in another clinical study with an investigational drug.
15. Presence of residual toxicities of CTCAE Grade > 1 after prior anticancer therapy within 2 weeks of first treatment with MIV-818, except for alopecia.
16. History of allergic reactions attributed to compounds of similar chemical or biological composition to MIV-818.
17. HCC of diffuse infiltrative type.
18. Receiving drugs that are extensively metabolized by cytochrome P450 (CYP) 3A4. Drugs that are extensively metabolized by CYP3A4 must be discontinued 5 half-lives before first dose of MIV-818.

Phase 2a-specific Exclusion Criteria
Patients are excluded from Phase 2a of this study if the following criterion is met:
1. Patients with a diagnosis of fibrolamellar HCC.

E.5 End points

E.5.1

Primary end point(s)

Phase 1a and Phase 1b
Safety and tolerability in escalating doses of MIV-818 will be assessed by monitoring:
• Incidence and severity of AEs
• Incidence and magnitude of clinically significant changes in clinical laboratory parameters, or overall pattern of shifts by treatment group in individual laboratory values suggestive of possible trends, but not necessarily establishing clinical abnormality
• Incidence and severity of clinically significant adverse findings in vital signs, electrocardiogram (ECG), Holter ECG (1a only), and other physical examination parameters

Phase 2a
• ORR will be assessed by monitoring tumor response and progression using RECIST v1.1

E.5.1.1

Timepoint(s) of evaluation of this end point

- recommended phase 2 dose, which will be determined at completion of phase 1b of the study;
- evaluation of ORR in phase 2a expansion cohorts, which will be determined on completion of phase 2a of the study (each of the two cohorts may complete at different times due to differential rates of accrual)

E.5.2

Secondary end point(s)

Phase 1a and Phase 1b
• ORR (objective response rate) will be assessed by monitoring tumor response and progression using RECIST v1.1
• ORR will be assessed by monitoring tumor response and progression using mRECIST
• ORR will be assessed by monitoring tumor response and progression using RECIST v1.1 in liver lesions only
• Plasma levels of AFP (α-fetoprotein)

Phase 2a
• ORR will be assessed by monitoring tumor response and progression using mRECIST
• ORR will be assessed by monitoring tumor response and progression using RECIST v1.1 in liver lesions only
• Plasma levels of AFP
• PFS (progression free survival)
• CBR clinical benefit rate (CR+PR+SD)
• DOR (duration of response)
• OS (overall survival)
• TTR (time to response)

Safety and tolerability will be assessed by monitoring:
• Incidence and severity of AEs.
• Incidence and magnitude of clinically significant changes in clinical laboratory parameters or overall pattern of shifts by treatment group in individual laboratory values suggestive of possible trends, but not necessarily establishing clinical abnormality.
• Incidence and severity of clinically significant adverse findings in vital signs, ECG, and other physical examination parameters.

E.5.2.1

Timepoint(s) of evaluation of this end point

Throughout the study as per schedule of assessments in the protocol ie by evaluable RECIST assessment

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

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Open label Dose escalation Phase 1/2a study to establish the RP2D (Phase 1a and Phase 1b), as well as evaluating the preliminary efficacy of the RP2D in expansion cohorts (Phase 2a). Phase 1a and Phase 1b will include patients with either HCC, iCCA, or metastatic liver disease. Phase 2a will comprise 2 cohorts: HCC and iCCA.

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

E.7.1.3

Other

Yes

E.7.1.3.1

Other trial type description

Phase 1/2a study

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

Information not present in EudraCT

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)

Information not present in EudraCT

E.8.2.2

Placebo

Information not present in EudraCT

E.8.2.3

Other

Information not present in EudraCT

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

Belgium

Korea, Republic of

United Kingdom

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

LPLV

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

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

102

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 discretion of the investigator, patients may continue to receive MIV-818 treatment if the investigator believes the patient has clinical benefit from continuing the treatment despite disease progression.

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

2018-07-26

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-08-10

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

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