Clinical Trials Register

Summary
EudraCT Number:	2015-002549-72
Sponsor's Protocol Code Number:	PH-L19IL2TNF-02/15
National Competent Authority:	Germany - PEI
Clinical Trial Type:	EEA CTA
Trial Status:	Trial now transitioned
Date on which this record was first entered in the EudraCT database:	2015-07-03
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

Germany - PEI

A.2

EudraCT number

2015-002549-72

A.3

Full title of the trial

A Phase III, open-label, randomized, controlled multi-center study of the efficacy of L19IL2/L19TNF neoadjuvant intratumoral treatment followed by surgery versus surgery alone in clinical stage IIIB and IIIC melanoma patients.

A.3.1

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

Study of the efficacy of intratumoral injections of L19IL2/L19TNF followed by surgery to prevent or retard appearance of new metastases

A.3.2

Name or abbreviated title of the trial where available

Neoadjuvant L19IL2/L19TNF- Pivotal study

A.4.1

Sponsor's protocol code number

PH-L19IL2TNF-02/15

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	Philogen S.p.A.
B.1.3.4	Country	Italy
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	Philogen S.p.A.
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	Philogen S.p.A.
B.5.2	Functional name of contact point	Regulatory Department
B.5.3	Address:
B.5.3.1	Street Address	Località Bellaria 35
B.5.3.2	Town/ city	Sovicille (Siena)
B.5.3.3	Post code	53018
B.5.3.4	Country	Italy
B.5.4	Telephone number	0039057717816
B.5.5	Fax number	003905771781690
B.5.6	E-mail	regulatory@philogen.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	Darleukin
D.3.2	Product code	L19IL2
D.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intratumoral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Bifikafusp alfa
D.3.9.1	CAS number	1957239-90-5
D.3.9.3	Other descriptive name	Darleukin
D.3.9.4	EV Substance Code	SUB27376
D.3.10	Strength
D.3.10.1	Concentration unit	IU international unit(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	13000000
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.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	Fibromun
D.3.2	Product code	L19TNF
D.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intratumoral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Onfekafusp alfa
D.3.9.1	CAS number	1957239-88-1
D.3.9.3	Other descriptive name	Fibromun
D.3.9.4	EV Substance Code	SUB29010
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	400
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

Malignant melanoma of the skin in patients with locally advanced and fully resectable melanoma with/without prior therapy and presence of injectable cutaneous and/or subcutaneous or nodal lesions.

E.1.1.1

Medical condition in easily understood language

Malignant melanoma of the skin in patients with locally advanced and fully resectable melanoma with/without prior therapy and presence of injectable cutaneous and/or subcutaneous or nodal lesions.

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	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

Efficacy of L19IL2/L19TNF neoadjuvant treatment followed by surgery to improve in a statistically significant manner the recurrence-free survival (RFS) of patients with locally advanced and fully resectable melanoma with respect to surgery alone: post-surgery adjuvant treatment is allowed in both arms.

E.2.2

Secondary objectives of the trial

Secondary objective of the study is to demonstrate that a neoadjuvant L19IL2/L19TNF treatment followed by surgery improves in a statistically significant manner the overall survival (OS) of patients with fully resectable locally advanced melanoma with respect to surgery.
Other secondary objectives include a demonstration of improvement of Local recurrence-free survival (LRFS) and distant metastasis-free survival (DMFS) and, for patients included in Arm 1 only, pathological responses (i.e., pathological Complete Response, pathological near-Complete Response, pathological Partial Response, pathological Non Response) assessed on the surgical specimen after tumor removal, as well as demonstration of safety and tolerability of the L19IL2/L19TNF treatment.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Inclusion criteria:
1. Diagnosis of malignant melanoma of the skin with locally advanced disease as defined by clinical stage III B and III C according to AJCC 7th Ed, eligible for complete surgical resection.
2. Eligible subjects must have measurable disease and must be candidate for intralesional therapy with at least one injectable cutaneous, subcutaneous, or nodal melanoma lesion (≥ 10 mm in longest diameter) or with multiple injectable lesions that in aggregate have a longest diameter of ≥ 10 mm.
3. Prior anti-tumor treatment for the primary melanoma lesion, including surgery and approved adjuvant treatments (e.g., radiotherapy, immune checkpoint inhibitors, BRAF/MEK inhibitors, etc.) is allowed.
4. Males or females, age ≥ 18 years
5. ECOG Performance Status/WHO Performance Status ≤ 1
6. Life expectancy of at least 24 months (see paragraph 6.3.1)
7. Absolute neutrophil count > 1.5 x 109/L
8. Hemoglobin > 9.0 g/dL
9. Platelets > 100 x 109/L
10. Total bilirubin ≤ 30 µmol/L (or ≤ 2.0 mg/dl)
11. ALT and AST ≤ 2.5 x the upper limit of normal (ULN)
12. Serum creatinine < 1.5 x ULN
13. LDH serum level ≤ 1.5 x ULN
14. Documented negative test for HIV, HBV and HCV.
For HBV serology, the determination of HBsAg and anti-HBcAg Ab is required. In patients with serology documenting previous exposure to HBV (e.g. anti-HBsAg and/or anti-HBc Ab) negative serum HBV-DNA is also required.
15. All acute toxic effects (excluding alopecia) of any prior therapy must have resolved to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) (v4.03) Grade ≤ 1 unless otherwise specified above
16. Negative pregnancy test at screening for Women Of Childbearing Potential (WOCBP*). Pregnant women are not allowed to participate to this study. WOCBP must be using, from the screening to three months following the last study drug administration, highly effective contraception methods, as defined by the "Recommendations for contraception and pregnancy testing in clinical trials" issued by the Head of Medicine Agencies' Clinical Trial Facilitation Group and which include, for instance, progesterone-only or combined (estrogen- and progesterone-containing) hormonal contraception associated with inhibition of ovulation, intrauterine devices, intrauterine hormone-releasing systems, bilateral tubal occlusion, vasectomized partner or sexual abstinence. Pregnancy test will be repeated at the Safety Visit (only WOCBP and only for patients in Arm 1).
17. Male patients with WOCBP partners must agree to use simultaneously two acceptable methods of contraception (i.e., spermicidal gel plus condom) from the screening to three months following the last study drug administration.
18. Evidence of a personally signed and dated informed consent document indicating that the subject has been informed of all pertinent aspects of the study.
19. Willingness and ability to comply with the scheduled visits, treatment plan, laboratory tests and other study procedures.
*Women of childbearing potential are defined as females who have experienced menarche, are not postmenopausal (12 months with no menses without an alternative medical cause) and are not permanently sterilized (e.g., tubal occlusion, hysterectomy, bilateral oophorectomy or bilateral salpingectomy)

E.4

Principal exclusion criteria

Patients exclusion criteria:
1. Uveal melanoma, mucosal melanoma or melanoma with unknown primary.
2. Evidence of distant metastases at screening
3. Previous or concurrent cancer that is distinct in primary site or histology from the cancer being evaluated in this study except cervical carcinoma in situ, treated basal cell carcinoma, superficial bladder tumors (Ta, Tis & T1), second primary melanoma in situ or any cancer curatively treated ≥ 5 years prior to study entry
4. Presence of active infections (e.g. requiring antimicrobial therapy) or other severe concurrent disease, which, in the opinion of the investigator, would place the patient at undue risk or interfere with the study.
5. History within the last year of acute or subacute coronary syndromes including myocardial infarction, unstable or severe stable angina pectoris.
6. Inadequately controlled cardiac arrhythmias including atrial fibrillation
7. Heart insufficiency (> Grade II, New York Heart Association (NYHA) criteria)
8. LVEF ≤ 50% and/or abnormalities observed during baseline ECG and Echocardiogram investigations that are considered as clinically significant by the investigator.
9. Uncontrolled hypertension
10. Ischemic peripheral vascular disease (Grade IIb-IV)
11. Severe diabetic retinopathy
12. Active autoimmune disease
13. History of organ allograft or stem cell transplantation
14. Recovery from major trauma including surgery within 4 weeks prior to enrollment.
15. Known history of allergy to IL2, TNF, or other human proteins/peptides/antibodies or any other constituent of the product.
16. Breast feeding female
17. Anti-tumor therapy (except allowed treatments listed at point 3 of Inclusion criteria) within 4 weeks before enrollment
18. Previous in vivo exposure to monoclonal antibodies for biological therapy (except allowed treatments listed at point 3 of Inclusion criteria) in the 6 weeks before enrollment
19. Planned administration of growth factors or immunomodulatory agents (except allowed treatments listed at point 3 of Inclusion criteria) within 7 days before enrollment
20. Patient requiring or taking corticosteroids or other immunosuppressant drugs on a long-term basis. Limited use of corticosteroids to treat or prevent acute hypersensitivity reactions is not considered an exclusion criterion.
21. Any conditions that in the opinion of the investigator could hamper compliance with the study protocol.
22. Previous enrolment and randomization in this same study.

E.5 End points

E.5.1

Primary end point(s)

Primary endpoint is:
- Recurrence-free survival (RFS) in the treatment arm (L19IL2/L19TNF plus surgery followed by adjuvants; Arm 1) versus control arm (surgery followed by adjuvants; Arm 2).

E.5.1.1

Timepoint(s) of evaluation of this end point

Recurrence is evaluated every 3 months after surgery up to 36 months.

E.5.2

Secondary end point(s)

Secondary endpoints are:
- Overall survival (OS) in the treatment arm (L19IL2/L19TNF plus surgery; Arm 1) versus control arm (surgery; Arm 2).
- Local recurrence-free survival (LRFS) and distant metastasis-free survival (DMFS) in the treatment arm (L19IL2/L19TNF plus surgery - Arm 1) versus control arm (Arm 2).
- Proportion of patients with pathological responses (defined as the proportion of patients with a pathological CR, pathological near-CR, or pathological PR).
- Safety of intratumoral administration of L19IL2/L19TNF.
- Biomarker studies (both arms): immunophenotypic characterization of PBMCs for changes in absolute counts and relative percentages of lymphocytic subpopulations (e.g., Tregs, MDSCs etc.) over time (only for patients recruited in German centers; the data will be collected for at least 50 patients). Study of blood biomarkers.
- Assessment of the formation of human anti-fusion protein antibodies (HAFA) against L19IL2 and L19TNF.

E.5.2.1

Timepoint(s) of evaluation of this end point

- Overall survival (OS): evaluation every 3 months after surgery up to 36 months; at least every 6 months up to 60 months.
- LRFS and DMFS: evaluation every 3 months after surgery up to 36 months.
- Proportion of patients with pathological responses: evaluated after surgery.
- Safety of intratumoral administration of L19IL2/L19TNF: evaluation throughout the entire study for each patient
- Biomarker studies, immunophenotypic characterization of PBMCs: assessment at screening; at surgery visit; at first follow-up fisit
- HAFA assessment will be performed on patients included in Arm 1: on day 1 before drug administration; on day 8 before drug administration; on day 29 at safety visit; at first 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

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

Yes

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)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

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

Yes

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

Yes

E.8.2.3.1

Comparator description

Elective surgical resection of the tumor

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

E.8.6.2

Trial being conducted completely outside of the EEA

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

End of treatment: corresponds to the day of surgery for patients randomized to both Arm 1 and Arm 2.
End of 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

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:

120

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

114

F.4.2

For a multinational trial

F.4.2.1

In the EEA

214

F.4.2.2

In the whole clinical trial

214

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)

n.a.

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

2015-12-16

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-06-02

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

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