Clinical Trials Register

Summary
EudraCT Number:	2016-001386-81
Sponsor's Protocol Code Number:	2016-1-DSF-MBC
National Competent Authority:	Czechia - SUKL
Clinical Trial Type:	EEA CTA
Trial Status:	Trial now transitioned
Date on which this record was first entered in the EudraCT database:	2016-04-07
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

Czechia - SUKL

A.2

EudraCT number

2016-001386-81

A.3

Full title of the trial

PHASE II OPEN LABELED TRIAL OF DISULFIRAM WITH COPPER IN METASTATIC BREAST CANCERS.

OTEVŘENÉ KLINICKÉ HODNOCENÍ FÁZE II S DISULFIRAMEM A MĚDÍ U METASTATICKÉHO KARCINOMU PRSU.

A.3.1

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

PHASE II OPEN LABELED TRIAL OF DISULFIRAM WITH COPPER IN METASTATIC BREAST CANCERS.

OTEVŘENÉ KLINICKÉ HODNOCENÍ FÁZE II S DISULFIRAMEM A MĚDÍ U METASTATICKÉHO KARCINOMU PRSU.

A.3.2

Name or abbreviated title of the trial where available

A.4.1

Sponsor's protocol code number

2016-1-DSF-MBC

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	Univerzita Palackého v Olomouci
B.1.3.4	Country	Czech Republic
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	Univerzita Palackého v Olomouci
B.4.2	Country	Czech Republic
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Masarykova univerzita
B.5.2	Functional name of contact point	doc. MUDr. Regina Demlová, Ph.D.
B.5.3	Address:
B.5.3.1	Street Address	Žerotínovo náměstí 617/9
B.5.3.2	Town/ city	Brno
B.5.3.3	Post code	60177
B.5.3.4	Country	Czech Republic
B.5.4	Telephone number	00420549496526
B.5.6	E-mail	demlova@med.muni.cz

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	Czech Republic
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	375 to 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.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

Metastatic breast cancer

Metastatický karcinom prsu

E.1.1.1

Medical condition in easily understood language

Metastatic breast cancer

Metastatický karcinom prsu

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

Primary efficacy objectives: to evaluate the efficacy of the treatment by
assessment of 1)clinical response rate (RR), 2)clinical benefit rate
(CBR).

Primárním cílem účinnosti je zhodnotit: 1) Míry klinické odpovědi -
clinical response rate (RR), 2)Míry klinického přínosu - clinical benefit
rate (CBR)

E.2.2

Secondary objectives of the trial

Secondary efficacy objectives:
To evaluate the efficacy of the treatment by assessment of:
1) to evaluate time to progression (TTP)
2) to evaluate overal survival (OS)

Safety objective: to describe safety profile of disulfiram administered in
combination with copper supplements

Pharmacokinetic objectives: to determine pharmacokinetic parameters
for disulfiram with its active metabolites administered in combination
with supplements with copper in patient with MBC.

Exploratory objectives: Parallel analysis to assess (identify) potential
candidate surrogate biomarkers of disulfiram efficacy, as well as
identification of potential predictive biomarkers of disulfiram sensitivity
or resistence will be performed. Surrogate biomarker analysis will focus
on in vivo UPS inhibition, cell cycle and DNA damage.

Sekundární cíle účinnosti:
Zhodnotit účinnost léčby na základě hodnocení:
• Doby do progrese - time to progression (TTP)
• Celkového přežití - overal survival (OS)

Bezpečnostní cíle: popsat bezpečnostní profil disulfiramu podávaného v
kombinaci s doplňky stravy s mědí.

Farmakokinetické cíle: stanovit
farmakokinetické parametry disulfiramu a jeho aktivních metabolitů při
podávání v kombinaci s doplňky stravy s mědí u pacientů s MBC.

Průzkumné cíle: Paralelní analýza s cílem zhodnotit (identifikovat)
potenciální kandidáty pro biomarkery účinnosti disulfiramu, navíc bude
provedena identifikace (pomocí proteomických, biochemických a
molekulárně genetických studií) potenciálních prediktivních biomarkerů
citlivosti nebo rezistence k disulfiramu. Analýza náhradních biomarkerů
se zaměří na in vivo UPS inhibici, buněčný cyklus a poškození DNA.

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

Full title: Pharmacokinetics analysis - The effect of disulfiram and cupper treatment in patients with a metastatic breast cancer: prospective, open, singlearm study phase II.
Date: 20.1.2019
Version: 3.0

Related objectives: analysis of the biochemical blood parameters related to detection and concentration of disulfiram in blood.

Farmakokinetická analýza - účinek léčba disulfiramem a mědí u pacientů s metastatickým karcinomem prsu: prospektivní, otevřená, jednoramenná studie fáze II.
Datum: 20.1.2019
verze: 3.0

Analýza biochemických krevních parametrů, které se týkají stanovení hladiny disulfiramu a jeho koncentrace v krvi.

E.3

Principal inclusion criteria

1. Male or female patients with stage IV breast or IIIb-IV NSCLC with
metastases demonstrated by appropriate imaging
techniques (CT, PET or PET/CT, MRI, ultrasound, etc.)
2. Histologically or cytologically confirmed tumor
3. Age of 18 years or more
4. ECOG performance status of 0 - 2
5. Patients have failed, in tolerated or refused standard therapeutic modalities or for whom other systemic therapies are not an option
6. Not received systemic anticancer therapy or radiation or had major surgery in last 2 weeks
7. Not currently participating in another study
8. Anticipated survival of at least 2 months
9. Baseline AST and ALT not greater than 2.5 X upper institutional limit for patient without liver metastasis/not greater than 5.0 x upper institutional limit for patient with liver metastasis
10. Serum copper less than 40 micromol/l
11. Serum ceruloplasmin > 17 mg/dL but not greater than 2.5 x upper institutional limit
12. Able and willing to sign informed consent and to comply with study procedures
13. Able to ingest oral medications
14. No known allergy to disulfiram or copper
15. Willing to refrain from ingestion of alcoholic beverages while on the study

1. Pacienti s karcinomem prsu ve stádiu IV s metastázami prokázanými
vhodnými zobrazovacími technikami (CT, PET nebo PET / CT, MRI, ultrazvuk, atd.)
2. Nádor potvrzen histologicky nebo cytologicky
3. Věk 18 let a více
4. ECOG performance status 0 - 2
5. Pacienti, u kterých standardní léčebné modality selhaly nebo je nesnášeli nebo odmítli nebo pro které není jiná systematická léčba volbou
6. Pacienti, kteří neabsolvovali systémovou protinádorovou léčbu nebo
ozařování nebo neprodělali velký chirurgický zákrok v posledních 2 týdnech
7. Pacienti, kteří se aktuálně neúčastní jiné klinické studie
8. Předpokládaná doba přežití nejméně 2 měsíce
9. Základní AST a ALT není vyšší než 2,5 násobek horní hranice normy pro pacienta bez jaterní metastáze/ vyšší než 5,0 násobek horní hranice normy pro pacienta s jaterní metastází
10. Hodnota mědi v séru méně než 40 micromol/l
11. Hodnota ceruloplasminu v séru > 17 mg/dl ale ne více než 2,5 x násobek horní hranice normy
12. Pacient je schopen a ochoten podepsat informovaný souhlas a dbát
studijních postupů v souladu s protokolem studie
13. Pacient je schopen přijímat léky per os
14. Žádná známá alergie na disulfiram nebo na měd
15. Pacient je ochoten se zdržet konzumace alkoholických nápojů během účasti ve studii

E.4

Principal exclusion criteria

1. Participation in another clinical trial of a therapeutic drug during the past 14 days
2. Addiction to alcohol or drugs
3. Baseline AST or ALT greater than 2.5 X upper institutional limit for patient without liver metastasis/not greater than 5.0 x upper institutional limit for patient with liver metastasis
4. Unable to ingest oral medications
5. Unable to undergo CT/SPECT scanning because of inability to lie recumbent in the scanner
6. Actively receiving cytotoxic cancer chemotherapy agents
7. Anticipated survival of less than 2 months
8. Women of child-bearing potential who are not using a commonly accepted effective means of contraception; women of child-bearing potential had a positive pregnancy test before enrollment; the pregnancy test was used more than 7 days before screening visit
9. History of active liver disease, including chronic active hepatitis, viral hepatitis (hepatitis B, C and CMV), cholestatic jaundice of any etiology, toxic hepatitis, or cholestatic hepatitis or jaundice with bilirubin greater than 2.0 X upper institutional limit
10. History of Wilson's disease or family member with Wilson's disease
11. History of iron overload syndron, hemochromatosis or family member with hemochromatosis
12. Need for metronidazole, warfarin and/or theophylline medication, the metabolism of which is likely influenced by disulfiram
13. Pregnant women and nursing
14. Patients who are taking medications metabolized by cytochrome P450 2E1, including chlorzoxazone or halothane and its derivatives

1. Účast v další klinické studii se studijní medikací během posledních 14 dnů
2. Závislost na alkoholu nebo drogách
3. Baseline AST nebo ALT vyšší než 2,5 násobek horní hranice normy pro pacienta bez jaterní metastáze/ vyšší než 5,0 násobek horní hranice normy pro pacienta s jaterní metastází
4. Pacient, který není schopen přijímat léky per os
5. Pacient není schopen podstoupit vyšetření skenem CT / SPECT kvůli
neschopnosti si lehnout do skeneru
6. Pacienti, kteří aktivně užívají protinádorovou chemoterapii
7. Předpokládaná doba přežití kratší než 2 měsíce
8. Ženy ve fertilním věku, které nepoužívají běžné účinné metody
antikoncepce; ženy ve fertilním věku musí mít před zařazením negativní
těhotenský test, který nesmí být starší více než 7 dní (včetně) před screeningovou návštěvou
9. Pacient s prodělaným onemocněním jater, zahrnující chronickou
aktivní hepatitidu, virové hepatitidy (hepatitidy B, C a CMV),
cholestatickou žloutenkou jakékoli etiologie, toxickou hepatitidu nebo
cholestatickou hepatitidu nebo žloutenku s bilirubinem vyšším než 2,0
násobek horní meze normy
10. Wilsonova choroba nebo člen rodiny s Wilsonovou chorobou v anamnéze
11. Hromadění železa v anamnéze, hemochromatóza nebo člen rodiny s hemochromatózou v anamnéze
12. Užívání metronidazolu, warfarinu a / nebo léků s teofylinem, jejichž
metabolismus, je pravděpodobně ovlivněn disulfiramem
13. Těhotné ženy a kojící matky
14. Pacienti, kteří užívají léky metabolizované cytochromem P450 2E1,
včetně chlorzoxazonu nebo halotanu a jejích derivátů

E.5 End points

E.5.1

Primary end point(s)

Efficacy Outcome Measures
Primary:
• effect of treatment with disulfiram and copper on clinical response
rate (RR, percentage of patients whose cancer shrinks; termed a partial
response, PR; or disappears after treatment; termed a complete
response, CR; RR=PR+CR)
• effect of treatment with disulfiram and copper on clinical benefit rate
(CBR=CR+PR+SD).

RR and CBR will be evaluated using RECIST version 1.1 criteria.

Parametry účinnosti:
Primární:
• vliv léčby disulfiramem s mědí na clinical response rate (RR = PR +
CR, PR – partial response = procento pacientů, jejichž karcinom se
zmenší, CR- complete response, procento pacientů, jejichž karcinom
zmizí po léčbě)
• vliv léčby disulfiramem s mědí na clinical benefit rate (CBR = CR + PR
+ SD)

RR a CBR budou hodnoceny pomocí RECIST verze 1.1 kritéria.

E.5.1.1

Timepoint(s) of evaluation of this end point

RR and CBR will be evaluated using RECIST version 1.1 criteria.

RR a CBR budou hodnoceny pomocí RECIST verze 1.1 kritéria.

E.5.2

Secondary end point(s)

Efficacy Outcome Measures:
Secondary:
• Time to progression (TTP)
• Overall survival (OS)

Patients will be evaluated with CT/SPECT scan every 12 weeks (3 months). The extent of tumor control less than 10% after 3 months (at the second CT scan) is regarded not clinically relevant.

Parametry účinnosti sekundární:
• Doba do progrese (TTP)
• Celkové přežití (OS)

Pacienti budou hodnoceni pomocí CT / SPECT scanu každých 12 týdnů (3 měsíce). Rozsah kontroly nádoru menší než 10% po 3 měsících (na druhém CT) není považován za klinicky relevantní.

E.5.2.1

Timepoint(s) of evaluation of this end point

Patients will be evaluated with CT/SPECT scan every 12 weeks (3 months). The extent of tumor control less than 10% after 3 months (at the second CT scan) is regarded not clinically relevant.

Pacienti budou hodnoceni pomocí CT / SPECT scanu každých 12 týdnů (3 měsíce). Rozsah kontroly nádoru menší než 10% po 3 měsících (na druhém CT) není považován za klinicky relevantní.

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

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

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

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

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

150

F.4.2

For a multinational trial

F.4.2.2

In the whole clinical trial

150

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

Žádná

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

2019-01-11

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-05-14

P. End of Trial
P.	End of Trial Status	Trial now transitioned

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