Clinical Trials Register

Summary
EudraCT Number:	2019-001972-12
Sponsor's Protocol Code Number:	AA1817
National Competent Authority:	Denmark - DHMA
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2019-06-24
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

Denmark - DHMA

A.2

EudraCT number

2019-001972-12

A.3

Full title of the trial

A phase 1b/2 open-label, dose-escalating study of safety and efficacy of disulfiram, copper and vinorelbine in advanced solid tumors and advanced breast cancer

Et fase 1b/2 åbent, dosis eskalering behandlingsforsøg for sikkerhed og effekt af disulfiram, kobber og vinorelbin til avancerede solide tumorer samt til avanceret brystkræft

A.3.1

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

A phase 1b/2 study on the safety and efficacy of disulfiram, copper and vinorelbine in advanced solid tumors and advanced breast cancer

A.3.2

Name or abbreviated title of the trial where available

Disulfiram trial

A.4.1

Sponsor's protocol code number

AA1817

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	Department of Oncology, Herlev & Gentofte Hospital
B.1.3.4	Country	Denmark
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Danish Cancer Society
B.4.2	Country	Denmark
B.4.1	Name of organisation providing support	Neye Fond
B.4.2	Country	Denmark
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Department of Oncology, Herlev & Gentofte Hospital
B.5.2	Functional name of contact point	PI Rikke Løvendahl Eefsen
B.5.3	Address:
B.5.3.1	Street Address	Borgmester Ib Juuls Vej 7
B.5.3.2	Town/ city	Herlev
B.5.3.3	Post code	2730
B.5.3.4	Country	Denmark
B.5.4	Telephone number	+453868 9381
B.5.5	Fax number	+453868 3570
B.5.6	E-mail	rikke.helene.loevendahl.eefsen@regionh.dk

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.2.1.2	Country which granted the Marketing Authorisation	Denmark
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	disulfiram
D.3.4	Pharmaceutical form	Effervescent 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	DISULFIRAM
D.3.9.1	CAS number	97-77-8
D.3.9.4	EV Substance Code	SUB06326MIG
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.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	Yes
D.2.1.2	Country which granted the Marketing Authorisation	Denmark
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	vinorelbine
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	VINORELBINE
D.3.9.1	CAS number	71486-22-1
D.3.9.4	EV Substance Code	SUB00069MIG
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	10
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: 3
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.2.1.2	Country which granted the Marketing Authorisation	Denmark
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	disulfiram
D.3.4	Pharmaceutical form	Effervescent 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	DISULFIRAM
D.3.9.1	CAS number	97-77-8
D.3.9.4	EV Substance Code	SUB06326MIG
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.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

in phase 1b part: advanced and/or treatment refractory solid malignancies
in phase 2 part : advanced or metastatic HER2-negative breast cancer

E.1.1.1

Medical condition in easily understood language

in phase 1b part: advanced solid tumors
in phase 2 part: advanced breast 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	20.1
E.1.2	Level	PT
E.1.2	Classification code	10055113
E.1.2	Term	Breast cancer metastatic
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	10070308
E.1.2	Term	Refractory cancer
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	21.0
E.1.2	Level	LLT
E.1.2	Classification code	10048683
E.1.2	Term	Advanced 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

Phase 1b: To assess the safety and tolerability of increasing doses of disulfiram in combination with copper and vinorelbine and to determine the dose-limiting toxicities (DLTs) and/or the Recommended Phase 2 Dose (RP2D) to patients with advanced and/or refractory solid malignancies.
Phase 2: To determine the efficacy of treatment with disulfiram, copper and vinorelbine in patients with advanced or metastatic HER2-negative breast cancer by assessing the clinical benefit rate (CBR=CR+PR+SD≥18 weeks) per RECIST 1.1.

E.2.2

Secondary objectives of the trial

Phase 1b:
•To assess the efficacy of the treatment with disulfiram, copper and vinorelbine by overall response rate (ORR) (RECIST 1.1) at 6 months and at 1 year
•Progression free survival (PFS)
•Duration of response (DoR)
•Overall survival (OS)

Phase 2:
To assess the efficacy of the treatment with disulfiram, copper and vinorelbine by
•Overall response rate (ORR) at 6 months and 1 year
•Progression free survival (PFS)
•Duration of response (DoR)
•Overall survival (OS)
To assess the safety and tolerability of treatment with disulfiram, copper and vinorelbine in patients with advanced or metastatic HER2-negative breast cancer.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1.For phase 1b part:
a)Patients with histologically confirmed advanced and/or refractory solid malignancies, who have progressive disease and/or intolerable adverse effects with established therapy.
For phase 2 part:
b)Women with histologically confirmed breast cancer. At the time of enrollment patients have advanced breast cancer.
c)Tumor cells from the primary tumor or from a biopsy of a metastatic site should be tested HER2 negative from the primary tumor or by biopsy of metastatic sites (measured with IHC 0-1+ or IHC 2+ with negative FISH, CISH).
d)A maximum of two prior chemotherapies for advanced breast cancer will be allowed.
e)Prior treatment with a taxane in the adjuvant or metastatic setting.
2.Age over 18 years.
3.ECOG performance status <2.
4.Measurable disease according to RECIST 1.1 (for patients in phase 1b part not measurable disease is allowed
5.Adequate bone marrow function defined by neutrophil counts ≥ 1.5 x 109 /l and platelets ≥ 100 x 109 /l.
6.Adequate hepatic function defined by bilirubin ≤ 1.5 upper normal limit (UNL) and/or ALT≤2.5 x UNL or ALT≤5xUNL if the patient has liver metastases.
7.Adequate renal function defined by se-creatinine ≤ 1.5 x UNL or creatinine clearance ≥ 50 ml/min.
8.Patients who, after oral and written information, agree to be included in the study by written consent.
9.Willingness to refrain from the consumption of alcohol during the trial and 14 days after last treatment with disulfiram

E.4

Principal exclusion criteria

1.Parallel treatment with other anti-cancer treatments or prior vinorelbine treatment for their metastatic disease.
2.Previous treatment with cytostatics within 3 weeks prior to initiation of the study.
3.Life expectancy < 12 weeks
4.Patients with peripheral sensory neuropathy > NCI-CTC grade 2.
5.Difficulty in swallowing tablets.
6.Current alcohol abuse or consumption
7.Pregnant or breast-feeding women. There must be a negative pregnancy test, hcg blood sample, during the screening period for women with childbearing potential.
8.Women of childbearing potential, who are not using adequate contraception
•The following list of birth control methods are considered adequate:
i.Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (hormonal contraception applicable in phase 1b only, as it should not be used by breast cancer patients):
1.Oral
2.Intravaginal
3.Transdermal
ii.Progestogen-only hormonal contraception associated with inhibition of ovulation (hormonal contraception applicable in phase 1b only, as it should not be used by breast cancer patients):
1.Oral
2.Injectable
3.Implantable
iii.Intrauterine device (IUD)
iv.Intrauterine hormone-releasing system (IUS)
v.Bilateral tubal occlusion
vi.Vasectomised partner
vii.Sexual abstinence (if refraining from heterosexual intercourse during the entire period of risk associated with the study treatments. The reliability of sexual abstinence needs to be evaluated in relation to the preferred and usual lifestyle of the subject).
•Adequate contraception must be used during treatment and at least 3 months after the last dose of study treatment.
9.Fertile men not using an effective method of birth control if their partners are women of childbearing potential throughout the study period and up to 3 months after the last dose of study treatment (phase 1b only).
10.Clinical symptoms of CNS metastases requiring steroids.
11.Uncontrolled hypertension, if systolic blood pressure is above 160 or diastolic blood pressure is above 100.
12.Severe personality disorder, suicidal risk, psychosis
13.Other severe medical conditions, including serious heart disease, unstable diabetes, uncontrolled hypercalcaemia, clinically active infections or previous organ transplants.
14.Participation in another clinical trial with experimental medication within 30 days prior to registration.
15.Vaccination with Yellow fewer-vaccine or any live virus vaccine. Inactivated annual influenza vaccination is allowed.
16.Patients that are allergic to vinorelbine, other vinca alkaloids or have known hypersensitivity to any excipient contained in the drug formulation.
17.Patients with known hypersensitivity to disulfiram, copper or any excipient contained in the drug formulation.

E.5 End points

E.5.1

Primary end point(s)

Phase 1b:
Safety and tolerability assessments include adverse event (AE), vital signs, physical examination, electrocardiogram (ECG) and clinical laboratory tests.

Phase 2:
clinical benefit rate (CBR=CR+PR+SD≥18 weeks) per RECIST 1.1.

E.5.1.1

Timepoint(s) of evaluation of this end point

phase 1b: during complete treatment period with DLT period of 3 weeks
phase 2: every 9 weeks during complete treatment period for the patient,

E.5.2

Secondary end point(s)

Both phases
•Overall response rate (ORR) at 6 months and 1 year
•Progression free survival (PFS)
•Duration of response (DoR)
•Overall survival (OS)
phase 2 additionally: safety

E.5.2.1

Timepoint(s) of evaluation of this end point

at end of trial

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

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

Biomarker analysis

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

Yes

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

Yes

E.7.1.3.1

Other trial type description

dose finding for combinational therapy

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.8.2.4

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

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

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.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, patients may be treated as per local/institutional standards

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

2019-07-24

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-09-13

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

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