Clinical Trials Register

Summary
EudraCT Number:	2021-006041-36
Sponsor's Protocol Code Number:	PH-L19IL2TNFBASK-04/21
National Competent Authority:	France - ANSM
Clinical Trial Type:	EEA CTA
Trial Status:	Trial now transitioned
Date on which this record was first entered in the EudraCT database:	2021-12-03
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

France - ANSM

A.2

EudraCT number

2021-006041-36

A.3

Full title of the trial

A phase II study of L19IL2/L19TNF in patients with skin cancers amenable to intralesional treatment

A.3.1

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

L19IL2/L19TNF in skin cancer patients

A.3.2

Name or abbreviated title of the trial where available

INTRINSIC

A.4.1

Sponsor's protocol code number

PH-L19IL2TNFBASK-04/21

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.3.9.2	Current sponsor code	L19IL2
D.3.9.3	Other descriptive name	Darleukin
D.3.9.4	EV Substance Code	SUB195506
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.3.9.2	Current sponsor code	L19TNF
D.3.9.3	Other descriptive name	Fibromun
D.3.9.4	EV Substance Code	SUB195289
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

Patients with malignant tumors of the skin amenable to intratumoral injection, and in a curative or neoadjuvant or palliative intention, including:
• Basal cell carcinoma (BCC)
• Cutaneous squamous cell carcinoma (cSCC)
• Merkel cell carcinoma (MCC)
• Keratoacanthoma (KA)
• Malignant Adnexal Tumors of the skin (MATS)
• Tumors from Cutaneous T-cell lymphoma (CTCL)
• Kaposi’s sarcoma (KS)

E.1.1.1

Medical condition in easily understood language

Patients with malignant tumors of the skin amenable to intratumoral injection, and in a curative or neoadjuvant or palliative intention

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

Efficacy of L19IL2/L19TNF measured as Confirmed Best Overall Response Rate BORR (Complete Response CR + Partial Response PR) for each tumor type measured according to RECIST v1.1 criteria. Confirmation of CR requires histopathological analysis of exeresis specimens for lesions removed by surgery or of biopsies in all other cases.

E.2.2

Secondary objectives of the trial

Secondary objective of the study is to demonstrate the efficacy of L19IL2/L19TNF measured as:
o Disease control rate DCR (Complete Response CR + Partial Response PR + Stable Disease SD) for each tumor type measured according to RECIST v1.1 criteria.
o Local PFS (LPFS) on the treated tumors only,
o Progression-free survival PFS, assessed separately in patients who are not resected after CR (curative intention) and in patients who undergo secondary surgery (neoadjuvant intention), whatever the RECIST response to treatment, taking into account appearance of new lesions and occurrence of metastases etc.
o Among tumors not initially amenable to surgery, proportion which are finally resected or disappear.
o Effect on non-treated lesions, if any
o Pathological Response for each tumor type in surgical specimens from tumors which are resected after treatment, or in biopsy for the others
In addition, safety of intratumoral administration of L19IL2/L19TNF will be evaluated.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Patient participation to the present study is subjected to the positive evaluation of a local interdisciplinary tumor board, in the context of available treatment alternatives. Whatever the tumor (list of eligible tumors below) the local interdisciplinary tumor board has to consider that a local response to injection of L19IL2/L19TNF may be of benefit for the patient, in the context of this tumor and available therapeutic opportunities, benefit defined by any of the following objectives: (1) to avoid surgery considered difficult or mutilating or (2) as a neoadjuvant treatment with the objective to permit surgery considered initially impossible, or to facilitate surgery considered difficult or mutilating, or to secure surgery considered of uncertain effect or (3) as a salvage treatment to control a tumor proved resistant to treatment alternatives or (4) as a palliative treatment improving patient comfort.
2. Patient must have at least one skin tumor that is amenable to intratumoral injection.
3. All tumors must be histologically confirmed before treatment.
4. Tumors eligible to the present study include:
o Difficult-to-treat lesions BCC: as defined by EADO operational staging system (stages IIa to IIIb) [1].
o Non-metastatic cSCC:
• Either advanced SCC for which a simple surgical excision is difficult or impossible,
• Or common SCC at high risk of recurrence, for which surgery alone is deemed uncertain by the tumor board, according to EADO/EORTC interdisciplinary guidelines [2].
cSCC post-transplantation, or cSCC in patients with concomitant chronic lymphocytic leukemia, or patients after anti PD-1 failure are all eligible to the study, according to the evaluation of the tumor board;
o KA: particularly when surgical excision is considered as too much mutilating for this type of tumor
o MCC: particularly when either primary tumor is considered unresectable, or skin metastases or local relapse are primarily or secondarily resistant to anti-PD1 (progress under anti-PD1)
o CTCL: particularly when skin tumors at tumoral stage of Mycosis fungoides subtypes are resistant to usual systemic treatments
o KS: Classic or endemic, histologically confirmed KS, particularly when local response can be considered of either functional or cosmetic benefit
o MATS: Advanced or refractory MATS.
5. Subjects must have radiographically or clinically measurable disease, defined as at least one injectable lesion that is ≥ 10 mm in diameter in at least 1 dimension, or an aggregate of injectable lesions that measures ≥ 10 mm in diameter in at least 1 dimension.
6. Subjects must be able and willing to undergo serial biopsies of injected lesion(s) and, when applicable and clinically feasible, non-injected lesions.
7. Male or female patients from the age of 18 years.
8. ECOG Performance Status/WHO Performance Status ≤ 1.
9. Hemoglobin > 10.0 g/dL.
10. Platelets > 100 x 109/L.
11. ALT and AST, GGT and Lipase ≤ 1.5 x the upper limit of normal (ULN).
12. Serum creatinine < 1.5 x ULN and GFR > 60 mL/min.
13. 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 v. 5.0) Grade ≤ 1 unless otherwise specified.
14. Women of childbearing potential (WOCBP) must have negative pregnancy test results at screening. WOCBP must be using, from 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, vasectomised partner.
15. 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.
16. Willingness and ability to comply with the scheduled visits, treatment plan, laboratory tests and other study procedures.

E.4

Principal exclusion criteria

1. Previous or concurrent cancer type that is distinct from the cancers being evaluated in this study, exception made for any other cancer curatively treated ≥ 2 years prior to study entry.
2. Previous topical or systemic chemotherapy, immunotherapy or radiation therapy at the tumor sites within 4 weeks prior to study drug administration.
3. Presence of active severe bacterial or viral infections or other severe concurrent disease, which, in the opinion of the investigator, would place the patient at undue risk or interfere with the study. In particular, a documented test for HIV, HBV, HCV and Covid-19 excluding active infection is needed.
4. Impaired cardiocirculatory functions due to any of the following conditions:
a. History within the last year of acute or subacute coronary syndromes including myocardial infarction, unstable or severe stable angina pectoris.
b. Inadequately controlled cardiac arrhythmias including atrial fibrillation.
c. Heart insufficiency (> Grade II, New York Heart Association (NYHA) criteria).
d. Any abnormalities observed during baseline ECG and Echocardiogram investigations that are considered as clinically significant by the investigator.
e. Uncontrolled hypertension.
f. Ischemic peripheral vascular disease (Grade IIb-IV).
5. Known arterial aneurysms.
6. INR > 3.
7. Known uncontrolled coagulopathy or bleeding disorder.
8. Known hepatic cirrhosis or severe pre-existing hepatic impairment.
9. Moderate to severe respiratory failure.
10. Active autoimmune disease.
11. Patient requires or is taking systemic corticosteroids or other immunosuppressant drugs on a long-term basis. Limited use of corticosteroids to treat or prevent acute hypersensitivity reactions and asthma/COPD is not considered an exclusion criterion.
12. Known history of allergy to IL2, TNF, or other human proteins/peptides/antibodies.
13. Pregnancy or breast-feeding.
14. Severe diabetic retinopathy.
15. Recovery from major trauma including surgery within 4 weeks prior to enrollment.
16. Patient with iatrogenic or pathologic severe immune suppression.
17. Any conditions that in the opinion of the investigator could hamper compliance with the study protocol.

E.5 End points

E.5.1

Primary end point(s)

Primary endpoint is the confirmed Best Overall Response Rate BORR (Complete Response CR + Partial Response PR) for each tumor type measured according to RECIST v1.1 criteria. Confirmation of CR requires histopathological analysis of exeresis specimens for lesions removed by surgery or of biopsies in all other cases

E.5.1.1

Timepoint(s) of evaluation of this end point

End of study

E.5.2

Secondary end point(s)

Secondary endpoints are
o Disease control rate DCR (Complete Response CR + Partial Response PR + Stable Disease SD) for each tumor type measured according to RECIST v1.1 criteria.
o Local PFS (LPFS) on the treated tumors only,
o Progression-free survival PFS, assessed separately in patients who are not resected after CR (curative intention) and in patients who undergo secondary surgery (neoadjuvant intention), whatever the RECIST response to treatment, taking into account appearance of new lesions and occurrence of metastases etc.
o Among tumors not initially amenable to surgery, proportion which are finally resected or disappear.
o Effect on non-treated lesions, if any
o Pathological Response for each tumor type in surgical specimens from tumors which are resected after treatment, or in biopsy for the others

E.5.2.1

Timepoint(s) of evaluation of this end point

End of 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

Yes

E.6.13.1

Other scope of the trial description

HAFA assessment

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.8.3

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

Last visit of the last patient 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

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)

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.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

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

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

2022-02-08

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2022-01-04

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

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