L19IL2/L19TNF in skin cancer patients

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Philogen S.p.A.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

26 Nov 2024 → ongoing

Decision date (initial)

2024-11-18

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2024-518531-10-00

EudraCT number

2021-006041-36

ClinicalTrials.gov

NCT05329792

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy

Efficacy of L19IL2/L19TNF measured as:
o 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.

Secondary objectives 2

1. 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 progression free survival (LPFS) on the treated tumors only. o Progression-free survival (PFS), assessed separately in patients who are not resected after 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, a 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 other types.
2. Safety of intratumoral administration of L19IL2/L19TNF.

Conditions and MedDRA coding

Phase II, open label, multicentric, proof-of-principle basket trial in 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)

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 16

1. 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. 2. Patient must have at least one skin tumor that is amenable to intratumoral injection.
3. 3. All tumors must be histologically confirmed before treatment.
4. 4. Patients with skin tumors eligible to the present study include: o BCC patients with difficult-to-treat lesions: as defined by EADO operational staging system (stages IIa to IIIb) [1]. Patients must either (i) have already received, or (ii) have progressed after, or (iii) be resistant to, or (iv) not be candidate to all possible alternative treatments, including notably use or re-use of surgery, radiotherapy,hedgehog inhibitors. o Non-metastatic cSCC patients: • 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]. Patients must either (i) have already received, or (ii) have progressed after, or (iii) be resistant to, or (iv) not be candidate to all possible alternative treatments, including notably use or re-use of surgery, radiotherapy, cetuximab and/or other anti-PD1 checkpoint inhibitors. 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). Patients must either (i) have already received, or (ii) have progressed after, or (iii) be resistant to, or (iv) not be candidate to all possible alternative treatments, including notably use or re-use of surgery, radiotherapy, and/or any anti-PD1 checkpoint inhibitors. o CTCL: Tumoral stage of Mycosis fungoides subtypes which are resistant to usual systemic treatments. In order to validate the first inclusion criterion of this trial, the tumor board will take into account that the treatment under investigation is intended to be only a palliative local therapy and cannot compete with a general efficacious strategy, if any. o KS: Classic or endemic, histologically confirmed KS, particularly when local response can be considered of either functional or cosmetic benefit. In order to validate the first inclusion criterion of this trial, the tumor board will take into account that the treatment under investigation is intended to be only a palliative local therapy and cannot compete with a general efficacious strategy, if any. o MATS: Advanced or refractory MATS.
5. 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. 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. 7. Male or female patients from the age of 18 years
8. 8. ECOG Performance Status/WHO Performance Status ≤ 1.
9. 9. Hemoglobin > 10.0 g/dL.
10. 10. Platelets > 100 x 109/L.
11. 11. ALT and AST, GGT and Lipase ≤ 1.5 x the upper limit of normal (ULN).
12. 12. Serum creatinine < 1.5 x ULN and GFR > 60 mL/min.
13. 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. 14. A woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile. 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. For any other recommendation patient should follow the Contraception Guidance 2014_09_HMA_CTFG_Contraception_guidance Version 1.1.
15. 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. 16. Willingness and ability to comply with the scheduled visits, treatment plan, laboratory tests and other study procedures.

Exclusion criteria 18

1. 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. Patients suffering from cSCC post-organ transplantation, or cSCC patients with concomitant chronic lymphocytic leukemia are excluded from the study
2. 2. Previous topical or systemic chemotherapy, immunotherapy, or radiation therapy at the tumor sites within 4 weeks prior to study drug administration.
3. 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. 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. 5. Known arterial aneurysms
6. 6. INR > 3.
7. 7. Known uncontrolled coagulopathy or bleeding disorder.
8. 8. Known hepatic cirrhosis or severe pre-existing hepatic impairment.
9. 9. Moderate to severe respiratory failure
10. 10. Active autoimmune disease.
11. 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. 12. Known history of allergy to IL2, TNF, or other human proteins/peptides/antibodies.
13. 13. Pregnancy or breast-feeding.
14. 14. Severe diabetic retinopathy.
15. 15. Recovery from major trauma including surgery within 4 weeks prior to enrollment
16. 16. Patient with iatrogenic or pathologic severe immune suppression.
17. 17. Any conditions that in the opinion of the investigator could hamper compliance with the study protocol.
18. 18. Any known hypersensitivity to the constituents of the vehicle L19IL2 and L19TNF.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. • Efficacy of L19IL2/L19TNF measured as: o 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.

Secondary endpoints 7

1. Efficacy of L19IL2/L19TNF measured as: Disease control rate (DCR) [Complete Response (CR) + Partial Response (PR) + Stable Disease (SD)] for each tumor type measured according to RECIST v1.1 criteria.
2. Efficacy of L19IL2/L19TNF measured as: Local progression free survival (LPFS) on the treated tumors only.
3. Efficacy of L19IL2/L19TNF measured as: Progression-free survival (PFS), assessed separately in patients who are not resected after 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.
4. Efficacy of L19IL2/L19TNF measured as: Among tumors not initially amenable to surgery, a proportion which are finally resected or disappear.
5. Efficacy of L19IL2/L19TNF measured as: Effect on non-treated lesions, if any.
6. Efficacy of L19IL2/L19TNF measured as: Pathological response for each tumor type in surgical specimens from tumors which are resected after treatment, or in biopsy for the other types.
7. Safety of intratumoral administration of L19IL2/L19TNF.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Philogen S.p.A.

Sponsor organisation

Philogen S.p.A.

Address

Piazza La Lizza 7

City

Siena

Postcode

53100

Country

Italy

Scientific contact point

Organisation

Philogen S.p.A.

Contact name

Lisa Nadal

Public contact point

Organisation

Philogen S.p.A.

Contact name

Lisa Nadal

Locations

3 EU/EEA countries · 15 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 16 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

3 submissions — initial application plus substantial / non-substantial modifications