Clinical Trials Register

Summary
EudraCT Number:	2018-004104-19
Sponsor's Protocol Code Number:	PH-L19TNFSARC-03/18
National Competent Authority:	Germany - PEI
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2018-12-21
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

2018-004104-19

A.3

Full title of the trial

A randomized study to investigate the efficacy and safety of the tumor-targeting human antibody-cytokine fusion protein L19TNF in previously treated patients with advanced stage or metastatic soft-tissue sarcoma

A.3.1

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

A study to investigate the efficacy and safety of L19TNF in previously treated patients with advanced stage or metastatic soft-tissue sarcoma

A.3.2

Name or abbreviated title of the trial where available

FLASH

A.4.1

Sponsor's protocol code number

PH-L19TNFSARC-03/18

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	Loc. 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	Yes
D.2.5.1	Orphan drug designation number	OD/108/16
D.3 Description of the IMP
D.3.1	Product name	Onfekafusp alfa
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	Intravenous 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	L19TNFALFA
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	up to
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	Yes
D.3.11.13.1	Other medicinal product type	L19TNF is a new agent with potential antitumor activity, similar to another antitumoral drug already available called Tasonermin, Beromun (TNFalpha).
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	Yes
D.2.1.1.1	Trade name	Dacarbazin
D.2.1.1.2	Name of the Marketing Authorisation holder	Medac
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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	Dacarbazin
D.3.4	Pharmaceutical form	Powder for solution for injection/infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
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

Unresectable and/or metastatic soft-tissue sarcoma after failure of at least two prior systemic therapy regimens

E.1.1.1

Medical condition in easily understood language

Soft-tissue sarcoma after failure of at least two prior systemic therapy regimens

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	20.0
E.1.2	Level	PT
E.1.2	Classification code	10075333
E.1.2	Term	Soft tissue sarcoma
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

The primary objective of the trial is to evaluate whether L19TNF in combination with dacarbazine (DTIC) given for unresectable or metastatic soft-tissue sarcoma prolongs progression free survival after at least two lines of systemic therapy, as compared to dacarbazine (DTIC) alone.

E.2.2

Secondary objectives of the trial

The key secondary objective of the study is to demonstrate with statistical superiority that L19TNF in combination with DTIC, given for unresectable or metastatic soft-tissue sarcoma, prolongs OS after at least two lines of systemic therapy for advanced or metastatic disease, as compared to DTIC alone.

The other secondary objectives of the study are as follows:
- Efficacy of L19TNF in combination with DTIC compared to DTIC alone
- Safety of L19TNF in combination with DTIC

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Male or female, 18 to 80 years of age
- Histologically or cytologically confirmed advanced unresectable or metastatic soft tissue sarcoma, grade 2 - 3 according to the FNLCC grading system. Participants with bone sarcomas including Ewing sarcoma, Kaposi's sarcoma and gastrointestinal stromal tumors (GIST) will be excluded.
- Subjects who received at least two prior systemic therapies (e.g., anthracyclines, taxanes, ifosfamide, gemcitabine, trabectedin, pazopanib, eribulin) for advanced or metastatic disease including at least one prior therapy based on anthracyclines as monotherapy or in combination. Neoadjuvant and adjuvant therapies can be considered as a prior line of treatment if the time to recurrence from completion of treatment was ≤ 12 months. Previous therapy with anthracyclines is not compulsory in situations of contraindications to this class of drugs. All previous therapies must have completed ≥ 3 weeks (21 days) prior to study treatment start.
- Evidence of disease progression after prior line of therapy for advanced or metastatic disease.
- Patients must have at least one unidimensionally measurable lesion by computed tomography as defined by RECIST criteria 1.1. If only one lesion is present at screening this lesion should not have been irradiated during previous treatments
- Life expectancy of at least 3 months in the judgment of the investigator
- ECOG ≤ 2
- Documented negative test for HIV-HBV-HCV.
- Female patients: negative serum pregnancy test at screening for women of childbearing potential (WOCBP)*. WOCBP must agree to use, from the screening to six months following the last administration of L19TNF and/or DTIC, 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 (www.hma.eu/ctfg.html). Male patients: Male subjects able to father children must agree to use two acceptable methods of contraception from the screening to six months following the last administration of L19TNF and/or DTIC (e.g. condom with spermicidal gel).
- Evidence of a personally signed and dated informed consent document indicating that the subject has been informed of all pertinent aspects of the study
- Willingness and ability to comply with the scheduled visits, treatment plan, laboratory tests and other study procedures

E.4

Principal exclusion criteria

- Anti-cancer treatment with radiation therapy (with the exception of radiation of single lesions for palliative reasons, e.g. pain management which then are not taken as indicator lesions for iRECIST response), chemotherapy, targeted therapies, immunotherapy, hormones or other antitumor therapies within 3 weeks prior to study treatment start.
- Subjects who participated in an investigational drug or device study within 3 weeks prior to study treatment start.
- Previous treatment with TNF or L19TNF or DTIC
- Known history of allergy to intravenously administered human proteins/peptides/antibodies and any other constituent of the product.
- Absolute neutrophil count (ANC) < 1.5 x 109/L, platelets < 100 x 109/L and hemoglobin (Hb) < 9.0 g/dl, with the exception of values lower than these due to cytologically or histologically proven marrow metastasis, which will not constitute exclusion criteria.
- Chronically impaired renal function as expressed by creatinine clearance < 60 mL/min or serum creatinine > 1.5 ULN.
- Inadequate liver function (ALT or AST ≥ 3 x ULN or ALP or gGT ≥ 2.5 x ULN, or total bilirubin ≥ 1.5 x ULN). For patients with metastatic lesions in the liver ALT, AST, gGT or ALP ≥ 5 x ULN.
- Any severe concomitant condition which in the opinion of investigators makes it undesirable for the patient to participate in the study or which could jeopardize compliance with the protocol.
- History within the last year of cerebrovascular disease and/or acute or subacute coronary syndromes including myocardial infarction, unstable or severe stable angina pectoris.
- Heart insufficiency (> Grade II, New York Heart Association (NYHA) criteria)
- Clinically significant cardiac arrhythmias
- Abnormalities observed during baseline ECG and echocardiogram investigations that are considered as clinically significant by the investigator
- Uncontrolled hypertension
- Ischemic peripheral vascular disease (Grade IIb-IV according to Leriche-Fontaine classification)
- Severe diabetic retinopathy such as severe non-proliferative retinopathy and proliferative retinopathy
- Major trauma including major surgery (such as abdominal/cardiac/thoracic surgery) within 4 weeks of administration of study treatment
- Pregnancy or breast-feeding
- Requirement of chronic administration of corticosteroids or other immunosuppressant drugs. Limited use of corticosteroids to treat or prevent acute hypersensitivity reactions is not considered an exclusion criterion.
- Presence of active and uncontrolled 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
- Known active or latent tuberculosis (TB)
- Concurrent malignancies other than soft-tissue sarcoma, unless the patient has been disease-free for at least 2 years
- Serious, non-healing wound, ulcer or bone fracture
- Allergy to study medication or excipients in study medication
- Deep vein thrombosis, pulmonary embolism or other acute vascular events within 6 months.
- Anticoagulation therapy with P2Y12 antagonists (e.g., clopidogrel, ticagrelor) and vitamin K antagonists (e.g., phenprocoumon, warfarin).
- Concurrent use of other anti-cancer treatments or agents other than study medication
- Protected adults (i.e., persons referred to as adults who are under legal protection measure or unable to express their consent) or persons under the protection of justice.

E.5 End points

E.5.1

Primary end point(s)

The following primary efficacy endpoint will be considered:
- Progression-free survival (PFS) according to RECIST v1.1

E.5.1.1

Timepoint(s) of evaluation of this end point

PFS will be assessed throughout the study

E.5.2

Secondary end point(s)

Key secondary efficacy endpoint:
- Overall survival (OS)

Other secondary endpoints:
Efficacy
- Objective response rate (ORR, consisting of CR and PR; only the non-irradiated lesions are measured) according to RECIST v1.1 between arms.
- Objective response rate (ORR, consisting of iCR and iPR; only the non-irradiated lesions are measured) according to iRECIST in arm 1.
- Progression-free survival (PFS) rate at 3, 6, 9 and 12 months according to RECIST v1.1 between arms.
- Progression-free survival (iPFS) rate at 3, 6, 9 and 12 months according to iRECIST in arm 1.
- Overall survival (OS) rate at 12, 24 and 36 months between arms.
Safety:
- Adverse Events (AEs), Serious Adverse Events (SAE) and Drug Induced Liver Injury (DILI) assessment based on CTCAE v.5.0.
- Standard laboratory (hematology, biochemistry and urinalysis) parameters.
- Physical examination findings including assessment of vital signs and physical measurements.
- Assessment of the formation of human anti-fusion protein antibodies (HAFA) against L19TNF.
- Characterization of pharmacokinetics (PK) of L19TNF, DTIC and AIC
• Quality of life of L19TNF in combination with DTIC compared to DTIC alone as assessed by considering the following endpoints:
- Health-related Quality of life (HRQol)

E.5.2.1

Timepoint(s) of evaluation of this end point

Multiple timepoints throughout and after the end of the study, depending on the specific endpoint (see section E.5.2 for details)

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

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)

Yes

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

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

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

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)

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

2019-06-24

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-02-12

P. End of Trial
P.	End of Trial Status	Ongoing

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