Clinical Trials Register

Summary
EudraCT Number:	2011-001410-33
Sponsor's Protocol Code Number:	UZB-VUB-11-01
National Competent Authority:	Belgium - FPS Health-DGM
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2011-05-09
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

2011-001410-33

A.3

Full title of the trial

Randomized phase II clinical trial on mRNA electroporated autologous dendritic cells for stage III/IV melanoma in patients who are free from measurable tumor lesions following the local treatment of macro metastases

A.3.1

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

A.3.2

Name or abbreviated title of the trial where available

DCMEL

A.4.1

Sponsor's protocol code number

UZB-VUB-11-01

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	UZ BRUSSEL
B.1.3.4	Country	Belgium
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	UZ BRUSSEL
B.4.2	Country	Belgium
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	UZ Brussel
B.5.2	Functional name of contact point	Prof Bart Neyns
B.5.3	Address:
B.5.3.1	Street Address	Laarbeeklaan 101
B.5.3.2	Town/ city	Jette
B.5.3.3	Post code	1090
B.5.3.4	Country	Belgium
B.5.4	Telephone number	0032024776415
B.5.5	Fax number	0032024775460
B.5.6	E-mail	bart.neyns@uzbrussel.be

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	TriMix-DC
D.3.2	Product code	TriMix-DC
D.3.4	Pharmaceutical form	Solution for injection/infusion in pre-filled syringe
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intradermal use Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	TriMix-DC
D.3.9.2	Current sponsor code	TriMix-DC
D.3.9.3	Other descriptive name	TriMix-DC
D.3.10	Strength
D.3.10.1	Concentration unit	Other
D.3.10.2	Concentration type	up to
D.3.10.3	Concentration number	24000000
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)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	Yes
D.3.11.3.1	Somatic cell therapy medicinal product	Yes
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

stage III/IV melanoma in patients who are free from measurable tumor lesions following the local treatment of macro metastases

E.1.1.1

Medical condition in easily understood language

stage III/IV melanoma in patients who are free from measurable tumor lesions following the local treatment of macro metastases

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	13.1
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	13.1
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 estimate the disease-free survival following therapeutic administration of autologous mRNA-electroporated monocyte derived DC in patients with stage III/IV melanoma who are free from measurable tumor lesions following the local treatment of macrometastases (e.g. by surgical resection, isolated limb perfusion, radiofrequency ablation, radiotherapy, …).

E.2.2

Secondary objectives of the trial

Applicable to both arms of the study:
1. To document the feasibility of manufacturing, and the product characteristics of the cellular IATMP (: autologous mRNA electroporated monocyte derived DC);
2. To document the safety, and feasibility of therapeutic administration of autologous mRNA electroporated monocyte derived DC;
3. To determine the recurrence-free survival (RFS), distant metastasis-free survival (DMFS), and overall survival (OS) using Kaplan-Meier survival estimates;
Applicable to Arm B of the clinical trial only:
4. To determine the best objective response according to the RECIST (v1.1), and the immune-related response criteria (irRC);
5. To determine the progression-free survival (PFS) according to the RECIST (V1.1), and immune-related response criteria (irRC) using Kaplan-Meier survival estimates.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Able and willing to give valid written informed consent before undergoing any study-related activities; patients must be willing to cooperate for the whole period of the study, and accept to be treated according to the study protocol regardless of the study arm the patient is allocated to following the randomization step;
2. Histological documentation of AJCC stage III (Tx, N1b,-2b,-2c or -3, M0), or stage IV melanoma;
3. Primary melanoma of the skin, unknown primary; patients with primary mucosal, or uveal melanoma (melanoma originating in the choroid, iris or ciliar body) are not eligible;
4. At baseline tumor assessment by whole-body FDG-PET/CT, patients should be free from measurable tumor lesions (measurability is defined according to RECIST (v1.1)), and free from symptomatic non-measurable tumor lesions (e.g. bone metastasis, or pleural effusion);
5. Prior local treatment of primary and metastatic tumor lesions is allowed (e.g. surgical resection, isolated limb perfusion, radiofrequency ablation, radiotherapy, cryotherapy, …). Treated tumor lesions should be free from progression at baseline assessment;
6. Normal organ function and normal hematological parameters (as reflected by blood values); baseline laboratory parameters should be within normal range, except for the following laboratory parameters, which must be within the ranges specified:
BLOOD PARAMETER RANGE
HEMOGLOBIN ≥ 10 G/DL
GRANULOCYTES ≥ 1,500/µL
LYMPHOCYTES ≥ 500/µL
PLATELETS ≥ 100,000/µL
SERUM CREATININ ≤ 2.0 MG/DL
SERUM BILIRUBIN ≤ 2.0 MG/DL
AST AND ALT ≤ 2 X THE NORMAL UPPER LIMITS
LDH ≤ 1,5X NORMAL UPPER LIMIT
CRP ≤ 1,5X NORMAL UPPER LIMIT
PROTHROMBIN TIME (PT) INTERNATIONAL NORMALIZED RATIO (INR) AND PARTIAL THROMBOPLASTIN TIME (PTT) WITHIN NORMAL LIMITS
7. Negative serology for HCV, and HIV; absence of active infection with HBV, and Syphilis; If positive results for HepB or Syphilis indicate immunity and are not indicative of active infection, the patient can enter the study.
8. Adequate venous access that allows to undergo leukapheresis;
9. No prior systemic therapy for melanoma;
10. Full recovery from all prior therapies. A minimal period of 4 weeks following major surgery, radiation therapy, or ILP, or any other major invasive procedure is required;
11. Baseline WHO performance status of 0, or 1 (see Appendix D);
12. Male and female patients ≥ 18 years of age;
13. No need for uninterrupted therapeutic anticoagulation (e.g. for recent thrombo-embolism, or cardiac valve prosthesis)
14. No prior history of a serious autoimmune disorder
15. No concomitant medication with immune suppressive drugs (e.g. oral corticosteroids).
16. Women of childbearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study and for up to 8 weeks after the study in such a manner that the risk of pregnancy is minimized. WOCBP include any female who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation or bilateral oophorectomy) or is not postmenopausal [defined as amenorrhea ≥ 12 consecutive months; or women on hormone replacement therapy (HRT) with documented serum follicle stimulating hormone (FSH) level > 35mIU/mL]. Even women who are using oral, implanted or injectable contraceptive hormones or mechanical products such as an intrauterine device or barrier methods (diaphragm, condoms, spermicides) to prevent pregnancy or practicing abstinence or where partner is sterile (e.g., vasectomy), should be considered to be of child bearing potential. WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) prior to the start of study.

E.4

Principal exclusion criteria

1. Evidence of immunodeficiency. Autoimmune disease requiring medical treatment (e.g. corticosteroids or other immunosuppressive drugs). Vitiligo (skin depigmentation) is not an exclusion criterion;
2. Any serious acute or chronic illnesses (e.g. heart disease NYHA Class III or IV, renal-, liver- or pulmonary insufficiency) or other conditions requiring concurrent medications not allowed during this study (e.g. active chronic infections requiring antibiotics).
3. History of malignancy. Subjects with curatively treated cervical carcinoma in situ, or squamous-, or basal cell carcinoma of the skin, or subjects who have been treated and recurrence-free of other malignancies for  5 years following the diagnosis are eligible for this study;
4. Inability to undergo FDG-PET/CT, or MRI examination;
5. Mental impairment that may compromise the ability to give informed consent and comply with the requirements of the study;
6. Participation in any other clinical trial involving another investigational agent within 4 weeks prior to enrollment;
7. Subject is pregnant (positive serum beta human chorionic gonadotropin [-HCG] test at screening) or is currently breast-feeding, anticipates becoming pregnant/ impregnating their partner during the study or within 6 months after study participation, or subject does not agree to follow acceptable methods of birth control, such as hormonal contraception, intra-uterine pessar, condoms or sterilization, to avoid conception during the study and for at least 6 months after receiving the last dose of study treatment;
8. Current alcohol dependence or drug abuse;
9. Known hypersensitivity to the study treatment;
10. Legal incapacity or limited legal capacity;
11. Presence of any psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol and follow-up schedule.
12. Signs and symptoms suggestive of transmissible spongiform encephalopathy, or family members who suffer(ed) from such.

E.5 End points

E.5.1

Primary end point(s)

percentage of patients who are alive and free from melanoma macrometastases at 1 year (: 52 weeks) following randomization.

E.5.1.1

Timepoint(s) of evaluation of this end point

Week 52 following the initiation of study treatment

E.5.2

Secondary end point(s)

Applicable to both arms of the study:
1. the IATMP will be characterized for: the number of DC, purity and viability, electroporation efficiency (measured by the % of cells expressing CD70), the immunophenotype (including CD40, CD80, CD83, CCR7, CD14 expression), and functional characterization by IL-12p70 secretion at 0-24h and 24-48h. DC samples will be analyzed for sterility by long-term microbiological culture. The results will be tabulated, analyzed and summarized using descriptive statistics.
2. Safety will be evaluated for all treated patients using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events v4.0 (CTCAE). Safety assessments will be based on medical review of adverse event (AE) reports and the results of vital sign measurements, physical examinations and clinical laboratory tests. The incidence of AEs will be tabulated and reviewed for potential significance and clinical importance. The reporting period for safety data will be from the date of the first leukapheresis until the end of study visit.
3. time of recurrence (locoregional and/or distant), time of death; median values with 95% confidence intervals will be determined using Kaplan-Meier survival estimates;

Applicable to Arm B of the clinical trial only:
Secondary endpoints: time of progression (according to irRC, and RECIST), or death.

E.5.2.1

Timepoint(s) of evaluation of this end point

Continuous during the conduct of the study

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

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

Yes

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

Yes

E.8.2.3.1

Comparator description

Follow-up without therpeutic intervention

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.8.5

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

The end of the trial will occur at the date of the last study visit (= up to the week 52 visit in the Arm-A and –B DC-treatment Phase) of the last subject undergoing the trial.

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