Clinical Trials Register

Summary
EudraCT Number:	2011-002080-21
Sponsor's Protocol Code Number:	DETECT-01
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2012-02-27
Trial results	View 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

Italy - Italian Medicines Agency

A.2

EudraCT number

2011-002080-21

A.3

Full title of the trial

Open-label phase 2 study of dacarbazine in patients with metastatic colorectal carcinoma based on expression of O6-methylguanine-DNA-methyltransferase (MGMT)

Studio aperto di fase II sull'attivita' antitumorale della dacarbazina in base all'espressione dell'enzima O6-metilguanina-DNA-metiltransferasi (MGMT) in pazienti affetti da carcinoma del colon-retto metastatico

A.3.1

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

DETECT-01 DETICENE EVALUATION FOR COLORECTAL CANCER THERAPY

VALUTAZIONE DELLE TERAPIA DEL CARCINOMA COLON-RETT0 CON DETICENE

A.3.2

Name or abbreviated title of the trial where available

DETECT-01

A.4.1

Sponsor's protocol code number

DETECT-01

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	AZIENDA OSPEDALIERA OSPEDALE NIGUARDA CA' GRANDA (A.O. DI RILIEVO NAZIONALE)
B.1.3.4	Country	Italy
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	oncologia onlus (ocgo)
B.4.2	Country	Italy
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	ONCOLOGIA
B.5.2	Functional name of contact point	ONCOLOGIA
B.5.3	Address:
B.5.3.1	Street Address	P.ZZA MAGGIORE N. 3
B.5.3.2	Town/ city	MILANO
B.5.3.3	Post code	20162
B.5.3.4	Country	Italy
B.5.4	Telephone number	0264442291
B.5.5	Fax number	0264442957
B.5.6	E-mail	salvatore.siena@ospedaleniguarda.it

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	DETICENE
D.2.1.1.2	Name of the Marketing Authorisation holder	SANOFI AVENTIS
D.2.1.2	Country which granted the Marketing Authorisation	France
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	Powder and solvent 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	NA
D.3.9.1	CAS number	NA
D.3.9.2	Current sponsor code	NA
D.3.9.3	Other descriptive name	NA
D.3.9.4	EV Substance Code	NA
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	100
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 colorectal carcinoma (mCRC) refractory to fluoropyrimidine-,
irinotecan-, oxaliplatin- (if KRAS mutated) and panitumumab- or cetuximab- (if KRAS wild
type) containing regimens

Tumori del colon metastatici (mCRC) con mutazioni di KRAS o BRAF e
resistenti a regimi di trattamento contenenti fluoropirimidine, irinotecan, oxaliplatino oppure
mCRC privi di mutazioni KRAS o BRAF (KRAS wild-type), resistenti a regimi di
trattamento contenenti fluoropirimidine, irinotecan, oxaliplatino, cetuximab o panitumumab

E.1.1.1

Medical condition in easily understood language

Patients with metastatic colorectal cancer gene mutations resistant to previous treatment lines

Pazienti affetti da carcinoma colon retto metastatico con mutazioni geniche resistenti a precedenti linee di trattamento

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	14.1
E.1.2	Level	LLT
E.1.2	Classification code	10052362
E.1.2	Term	Metastatic colorectal 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

This trial aims to assess activity dacarbazine in terms of objective response rate (ORR) in
patients with mCRC refractory to standard therapies.

Determinare l'attività del farmaco dacarbazina in termini di percentuale di risposta in
pazienti affetti da mCRC resistente ai trattamenti standard

E.2.2

Secondary objectives of the trial

Evaluation of clinical benefit (disease control rate)
2. Evaluation of progression-free survival (PFS)
3. Identification of biomarkers of response to dacarbazine based on molecular
characteristics of individual tumor samples:
· loss of expression of O6-methylguanine-DNA-methyltransferase (MGMT) as
evaluated by immunohistochemistry (IHC) and promoter hypermethylation;
· KRAS status (wild type vs mutated)
· population of mCRC with BRAF mutation will be also evaluated separately

Valutare la presenza di biomarcatori di risposta alla dacarbazina tramite l'analisi di alcune
caratteristiche su campioni delle neoplasie:
· perdita di espressione dell'enzima O6-metilguanina-DNA-metiltransferasi (MGMT)
valutata tramite immunoistochimica (IHC) ed ipermetilazione del promotore;
· KRAS status (WT vs mutato)
· altre mutazioni rilevanti

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Male or female ≥ 18 years of age;
2. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 1;
3. Life expectancy of at least 3 months;
4. Understand and voluntarily sign an informed consent form;
5. Histologically or cytologically confirmed metastatic colorectal adenocarcinoma;
6. Measurable disease (RECIST criteria v1.1) using conventional techniques (CT
scan or MRI);
7. Previous treatment including: fluoropyrimidine, oxaliplatin, irinotecan for patients
with mutant KRAS (as assessed in primary tumor or metastases evaluating
codon 12 and 13 mutations) or fluoropyrimidine, oxaliplatin, irinotecan,
cetuximab and/or panitumumab for patients with wild-type KRAS.
8. Imaging confirmed (CT/MRI) disease progression within 3 months of previous
standard treatment. Patients who have been withdrawn from standard treatment
due to unacceptable toxicity will also be allowed into the study. Patients treated
with oxaliplatin in an adjuvant setting should have progressed during or within 6
months of completion of adjuvant therapy;
9. Women of childbearing potential and men must agree to use adequate
contraception since signing of the informed consent form until at least 3 months
after the last study drug administration;
5
10. Adequate bone marrow, liver and renal function as assessed by the following
laboratory requirements conducted within 7 days of starting study treatment:
· Total bilirubin < 1.5 x the upper limit of normal (ULN);
· Alanine transaminase (ALT) and aspartate aminotransferase (AST) < 2.5 x
ULN (<5 x ULN for patients with liver involvement of their cancer);
· Serum creatinine < 1.5 x the ULN;
· INR/PTT < 1.5 x ULN (patients who are being therapeutically anti-coagulated
with an agent such as warfarin or heparin will be allowed to participate
provided that no prior evidence of underlying abnormality in this parameter
exists. Close monitoring of at least weekly evaluations will be performed until
INR/PTT is stable based on a measurement that is pre-dose as defined by
the local standard of care.);
· Platelet count >100000 /mm3, Hemoglobin (Hb) >9 g/dL, Absolute Neutrophil
Count (ANC) >1500/mm3;
· Alkaline phosphatase limit < 2.5 x ULN (<5 x ULN for patients with liver
involvement by mCRC);
11. Able to adhere to the study visit schedule and other protocol requirements.

1. Maschio o femmina ≥ 18 anni di età;
2. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1;
3. Aspettativa di vita di almeno 3 mesi;
4. Capacità di intendere e firmare il consenso informato;
5. Disponibilità di campione paraffinato del tumore primitivo resecato o di biopsia
tumorale
6. Presenza di adenocarcinoma del colon metastatico (mCRC) confermato
istologicamente;
7. Malattia misurabile (RECIST criteria v1.1) tramite tecniche convenzionali (TC o
RMN);
8. Trattamento standard precedente comprendente: 5-FU/capecitabina,
oxaliplatino, irinotecan nei pazienti con KRAS or BRAF mutato; 5-
FU/capecitabina, oxaliplatino, irinotecan, cetuximab e/o panitumumab per
pazienti con KRAS e BRAF non mutato.
9. Conferma con metodica CT o MRI della progressione di malattia dopo il
trattamento standard precedente. I pazienti che hanno abbandonato il
trattamento standard per tossicità inaccettabile possono essere includi nello
studio.
10. Donne fertili e gli uomini devono acconsentire all’utilizzo di una contraccezione
adeguata a partire dalla firma del conenso informato sino a 3 mesi dopo l’ultima
somministrazione di dacarbazine.
11. Funzione midollare epatica e renale adeguate, valutate tramite i seguenti esami
di laboratorio effettuati entro 7 giorni dall’inizio del trattamento:
· Bilirubina totale < 1.5 x i limiti superiori della norma (ULN);

· ALT ed AST < 2.5 x i limiti superiori della norma (<5 x ULN per pazienti con
metastasi epatiche);
· Creatinina < 1.5 x i limiti superiori della norma (ULN);
· INR/PTT < 1.5 x ULN (pazienti in trattamento con warfarin o eparina a
dosaggio terapeutico possono essere inclusi, purché venga effettuato un
monitoraggio di INR/PTT);
· Piastrine >100000 /mm3, Emogliobina (Hb) >9 g/dL, Conteggio neutrofilo
assoluto (ANC) >1500/mm3;
· Fosfatasi alcalina < 2.5 x ULN (<5 x ULN per i pazienti con metastasi
epatiche);
12. Possibilità di aderire al protocollo di studio ed agli esami programmati.

E.4

Principal exclusion criteria

Prior treatment with dacarbazine or temozolomide;
2. Previous or concurrent cancer that is distinct in primary site or histology from
colorectal cancer within 5 years prior to randomization EXCEPT for curatively
treated cervical cancer in situ, non-melanoma skin cancer and superficial bladder
tumors [Ta (Non-invasive tumor),Tis (Carcinoma in situ) and T1 (Tumor invades
lamina propria)];
3. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days
before start of study medication;
4. Pregnant or breast-feeding patients. Women of childbearing potential must have a
pregnancy test performed a maximum of 7 days before start of treatment, and a
negative result must be documented before start of treatment;
5. Congestive heart failure > New York Heart Association (NYHA) class 2;
6
6. Unstable angina (angina symptoms at rest), new-onset angina (begun within the
last 3 months). Myocardial infarction less than 6 months before start of study
medication.
7. Arterial or venous thrombotic or embolic events such as cerebrovascular accident
(including transient ischemic attacks), or pulmonary embolism within the 6 months
before start of study medication;
8. Ongoing infection > grade 2 NCI-CTC version 3.0;
9. Untreated, symptomatic brain metastases (brain radiologic imaging not required);
10. Non-healing wound, ulcer, or bone fracture;
11. Renal failure requiring hemo-or peritoneal dialysis;
12. Substance abuse, medical, psychological or social conditions that may interfere
with the patient’s participation in the study or evaluation of the study results;
13. Known hypersensitivity to any of the study drugs, study drug classes, or excipients
in the formulation.
Investigational Product Dosage and

Precedente trattamento con dacarbazine o temozolomide;
2. Precedente o concomitante tumore di distinta istologia entro 5 anni prima della
randomizzazione TRANNE per il caso di tumore della cervice in situ trattato con
intento curativo, tumori cutanei non melanomatosi e tumori superficiali della vescica
[Ta (tumore non invasivo), Tis (carcinoma in situ) e T1 (tumore che invade la lamina
propria)];
3. Intervento chirurgico maggiore, biopsia aperta, o significative lesioni traumatiche
entro 28 giorni prima dell'inizio del farmaco in studio;
4. Pazienti In stato di gravidanza o in allattamento al seno. Le donne in età fertile
devono avere un test di gravidanza eseguito un massimo di 7 giorni prima dell'inizio
del trattamento, e un risultato negativo deve essere documentato prima dell'inizio
del trattamento;
5. Insufficienza cardiaca congestizia> New York Heart Association (NYHA) classe 2;
6. Angina instabile (sintomi di angina a riposo), od esordio di angina nuovo (iniziato
negli ultimi 3 mesi). Infarto miocardico meno di 6 mesi prima dell'inizio del farmaco
in studio.
7. Eventi tromboembolici arteriosi o venosi quali accidenti cerebrovascolari (compresi
attacchi ischemici transitori) o embolia polmonare entro i 6 mesi prima dell'inizio del
farmaco in studio;
8. L'infezione in corso di grado 2 NCI-CTC versione 3.0;
Protocollo DETECT-01 – Versione 1 del 6.05.2011
5
9. Se non trattate, metastasi cerebrali sintomatiche
10. Ferite, ulcere, o fratture ossee non guarite
11. Insufficienza renale che richiede la dialisi peritoneale o emodialisi
12. Abuso di sostanze, condizioni mediche, psicologiche o sociali che possono
interferire con la partecipazione del paziente allo studio o con la valutazione dei
risultati dello studio;
13. Ipersensibilità nota ad uno qualsiasi dei farmaci dello studio, classi di farmaci di
studio, o eccipienti della formulazione.

E.5 End points

E.5.1

Primary end point(s)

ORR by RECIST criteria

Percentuale di risposta obiettiva (ORR)

E.5.1.1

Timepoint(s) of evaluation of this end point

eighteen weeks

18 settimane

E.5.2

Secondary end point(s)

Disease control rate (ORR + Stable Disease by RECIST criteria)
· PFS
· Association of response/resistance with loss of expression of O6-methylguanine-
DNA-methyltransferase (MGMT) and KRAS or BRAF mutations

Percentuale di controllo di malattia (ORR + SD)
· Sopravvivenza libera da progressione (PFS)
· Associazione della risposta/resistenza al trattamento con la perdita di espressione
di MGMT (ipermetilazione del suo promotore) e con mutazioni di KRAS e BRAF

E.5.2.1

Timepoint(s) of evaluation of this end point

eighteen weeks more six months

18 settimane + 6 mesi

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

Yes

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)

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.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

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

Number of subjects for this age range:

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)

STANDARD OF CARE

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

2011-05-17

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2011-07-21

P. End of Trial
P.	End of Trial Status	Completed

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IMP with orphan designation in the indication
Orphan Designation Number:
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