Clinical Trials Register

Summary
EudraCT Number:	2019-002026-75
Sponsor's Protocol Code Number:	UV1-202
National Competent Authority:	Belgium - FPS Health-DGM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2020-05-19
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

Belgium - FPS Health-DGM

A.2

EudraCT number

2019-002026-75

A.3

Full title of the trial

A Randomized Phase II, Open-label, Active-controlled, Multicenter Study Investigating the Efficacy and Safety of UV1 Vaccination in Combination with Nivolumab and Ipilimumab as First-line Treatment of Patients with Unresectable or Metastatic Melanoma

A.3.1

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

Clinical research study to investigate effectiveness and safety of UV1 Vaccination in Combination with Nivolumab and Ipilimumab as First-line Treatment of Patients with Unresectable or Metastatic Melanoma

A.4.1

Sponsor's protocol code number

UV1-202

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	Ultimovacs ASA
B.1.3.4	Country	Norway
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	Ultimovacs ASA
B.4.2	Country	Norway
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Ultimovacs ASA
B.5.2	Functional name of contact point	Ultimovacs information
B.5.3	Address:
B.5.3.1	Street Address	Ullernchausséen 64
B.5.3.2	Town/ city	Oslo
B.5.3.3	Post code	N-0379
B.5.3.4	Country	Norway
B.5.4	Telephone number	+4741380 080
B.5.5	Fax number	---
B.5.6	E-mail	mail@ultimovacs.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	UV1
D.3.4	Pharmaceutical form	Powder for solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intradermal use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Not available
D.3.9.1	CAS number	1331848-79-3
D.3.9.3	Other descriptive name	P719-20
D.3.9.4	EV Substance Code	SUB171636
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	0.450
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Not available
D.3.9.1	CAS number	1221082-45-6
D.3.9.3	Other descriptive name	P725
D.3.9.4	EV Substance Code	SUB171638
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	0.225
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Not available
D.3.9.1	CAS number	524061-04-9
D.3.9.3	Other descriptive name	P728
D.3.9.4	EV Substance Code	SUB171637
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	0.225
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	LEUKINE
D.3.4	Pharmaceutical form	Powder for solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intradermal use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	SARGRAMOSTIM
D.3.9.1	CAS number	123774-72-1
D.3.9.4	EV Substance Code	SUB10450MIG
D.3.10	Strength
D.3.10.1	Concentration unit	µg microgram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	75
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)	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	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.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

Unresectable or Metastatic Melanoma

E.1.1.1

Medical condition in easily understood language

A melanoma not capable of being surgically removed or that has been spread to other parts of the body

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	10027480
E.1.2	Term	Metastatic malignant melanoma
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	21.1
E.1.2	Level	PT
E.1.2	Classification code	10025671
E.1.2	Term	Malignant melanoma stage IV
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	21.1
E.1.2	Level	PT
E.1.2	Classification code	10025670
E.1.2	Term	Malignant melanoma stage III
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 compare progression free survival (PFS) of UV1 vaccination in combination with nivolumab and ipilimumab to that of nivolumab and ipilimumab

E.2.2

Secondary objectives of the trial

• To compare overall survival (OS) of UV1 vaccination in combination with nivolumab and ipilimumab to that of nivolumab and ipilimumab
• To compare the objective response rate (ORR) of UV1 vaccination in combination with nivolumab and ipilimumab to that of nivolumab and ipilimumab
• To compare duration of response (DOR) of UV1 vaccination in combination with nivolumab and ipilimumab to that of nivolumab and ipilimumab
• To compare the safety of UV1 vaccination in combination with nivolumab and ipilimumab to that of nivolumab and ipilimumab

Exploratory
• To elucidate the immunological mechanisms underlying the interplay between immune activation provoked by UV1 vaccination and inhibition of tumor resistance mechanisms and peripheral immune tolerance induced by checkpoint blockade, and how biological factors affect the efficacy of the combination therapy

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Male or female patients at least 18 years of age at the time of signing the ICF.
2. Histologically confirmed diagnosis of unresectable stage IIIB D, or unresectable stage IV malignant melanoma. Patient must have at least 1 measurable lesion at Screening according to the RECIST 1.1 criteria.
Note that lesions not measurable on computed tomography or magnetic resonance imaging (MRI) will be considered as non measurable lesions.
3. Eligible for combination treatment with nivolumab and ipilimumab.
4. An ECOG performance status of 0 or 1.
5. Adequate organ function as indicated by the following laboratory values:
- Hematological
a. Absolute neutrophil count ≥1,500/µL
b. Platelet count ≥100 x 103/µL
c. Hemoglobin ≥9 g/dL or ≥5.6 mmol/L
- Renal
d. Creatinine ≤1.5 x upper limit of normal (ULN)
Hepatic
e. Total bilirubin ≤1.5 x ULN or direct bilirubin ≤ ULN for patients with total bilirubin levels >1.5 ULN
f. Aspartate aminotransferase/glutamic oxaloacetic transaminase and alanine aminotransferase/glutamic pyruvic transaminase ≤2.5 x ULN for patients without liver metastasis or ≤5 x ULN for patients with liver metastasis.
6. Male patients who are sexually active with a female of childbearing potential must agree to use an adequate method of contraception prior to the first dose through 5 months after the last dose of UV1 vaccination, nivolumab, or ipilimumab, whichever is administered last. The recommended method is using a male condom.
7. Women of childbearing potential (WOCBP) must have a negative urine or serum/plasma pregnancy test. If the urine test is positive or cannot be confirmed as negative, a serum/plasma pregnancy test will be performed. The serum/plasma pregnancy test must be negative for the patient to be eligible.
8. WOCBP must use adequate contraception. Adequate contraception must be maintained throughout the study, starting with the first dose through 5 months after the last dose of UV1 vaccination, nivolumab, or ipilimumab, whichever is administered last. The acceptable contraceptive methods for WOCBP included in the study are:
Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal or transdermal), progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable or implantable), Intrauterine device (IUD), Intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, vasectomized partner (provided that the partner is the sole sexual partner of the WOCBP trial participant and that the vasectomized partner has received medical assessment of the surgical success) or sexual abstinence (if this is the preferred and usual lifestyle of the subject)
9. Written informed consent prior to any study-specific procedures.

E.4

Principal exclusion criteria

1. Previous non melanoma malignancies unless curatively treated and complete remission was achieved at least 2 years prior to randomization. Patients with prior curatively treated basal or squamous cell carcinoma of the skin, carcinoma in situ of the cervix, or carcinoma in situ of the breast, or other in situ cancers are allowed irrespective of time passed since curative treatment. Patients with prior completely resected malignant melanoma are also allowed.
2. Known brain metastases or leptomeningeal metastases. If a patient experiences neurological symptoms indicative of brain metastases, a brain MRI should be performed.
3. Diagnosis of uveal or ocular melanoma.
4. Known history or any evidence of active, non-infectious pneumonitis.
5. History of New York Heart Association class 3-4 congestive heart failure or history of myocardial infarction within 6 months of starting induction therapy.
6. Active infection requiring systemic treatment.
7. Diagnosis of immunodeficiency.
8. Known history of severe hypersensitivity reactions to nivolumab, ipilimumab, sargramostim, or their excipients.
9. Known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies). No HIV testing is required unless mandated by local health authority.
10. History of or active hepatitis B (hepatitis B surface antigen reactive) or active hepatitis C (hepatitis C virus antibody). Testing must be performed to determine eligibility.
11. Women who are breastfeeding.
12. Prior systemic treatment for unresectable stage IIIB D or unresectable stage IV malignant melanoma. Prior systemic BRAF/MEK or immunotherapy as neoadjuvant or adjuvant or other setting treatment of stage I IIIA, resectable IIIB D, or resectable IV if patient progressed earlier than 6 months after last dose of such treatment.
13. Systemic corticosteroid treatment (doses exceeding 10 mg daily of prednisone or equivalent) or any other form of immunosuppressive treatment within 7 days prior to the first dose of induction therapy. Topical, ocular, intra-articular, intranasal, and inhalational corticosteroids (with minimal systemic absorption) are allowed. Physiologic replacement doses of systemic corticosteroids, a brief course of corticosteroids for prophylaxis (eg, contrast dye allergy) or for treatment of non-autoimmune conditions is permitted even with >10 mg/day prednisone equivalents.
14. Receipt of a live vaccine within 30 days prior to start of induction therapy.
15. Receipt of any other investigational treatment within 4 weeks of the first dose of induction therapy.
16. Any medical, psychological, or social condition that would make it difficult for the patient to participate in the study and comply with the study procedures, restrictions, and requirements.

E.5 End points

E.5.1

Primary end point(s)

• PFS per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
Time from randomization to progressive disease (PD) or death from any cause

E.5.1.1

Timepoint(s) of evaluation of this end point

Screening at Day -14 to 1
Week 12
Week 19
every 8 weeks for 32 weeks
every 12 weeks until PD per iRECIST or until 70 PFS events are reached (whichever comes first)

E.5.2

Secondary end point(s)

Secondary
• OS
Time from randomization to death from any cause
• ORR per RECIST 1.1
Proportion of patients with a best response of complete response (CR) or partial response (PR)
• DOR per RECIST 1.1
Time from first CR or PR to PD or death from any cause
• Adverse events (AEs), deaths, vital signs, laboratory assessments, and Eastern Cooperative Oncology Group (ECOG) performance status

Exploratory
• Change in immune and tumor related gene, cell, and protein profiles in blood over time in both treatment arms (analysis of plasma proteins, cell-free plasma DNA and cellular genomic DNA)
• Other endpoints related to analysis conducted on biological material collected from the Extended Exploratory Cohort

E.5.2.1

Timepoint(s) of evaluation of this end point

Screening at Day -14 to 1
Week 12
Week 19
every 8 weeks for 32 weeks
every 12 weeks until PD per iRECIST or until 70 PFS events are reached (whichever comes first)
every 12 weeks from iCPD per iRECIST until 70 PFS events reached
From the time of 70 PFS events the survival follow-up visits will continue every 6 months for 2 years.

Exploratory
- Experimental arm:
• Day 1
• Day 31
• Day 52
• Safety Follow-up
• 18 weeks post last dose of induction therapy (2nd response follow-up visit)

- Control arm
• Day 1
• Day 43
• Day 64
• Safety Follow-up
• 18 weeks post last dose of induction therapy (2nd response 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

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

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

Yes

E.8.1.1

Randomised

Yes

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)

Yes

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

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

Norway

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

The primary and secondary endpoint analysis will be conducted at 70 PFS endpoints. From the time of 70 PFS events reached, all patients will have survival follow-up visits every 6 months for 2 years. The end of study (EOS) is defined as the date of the last survival follow-up visit of the last patient undergoing the study

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

154

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

2020-07-24

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-07-23

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2024-04-10

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