Phase II Evaluation of Intratumoral L19IL2 and L19TNF in High-Risk Locally Advanced Basal Cell and Cutaneous Squamous Cell Carcinoma

Trial ID: 2024-518530-92-00
Protocol: PHL19IL2TNFNMSC04/19
Sponsor: Philogen S.p.A.

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Diseases & Conditions

Squamous cell carcinoma of skin Basal cell carcinoma

Objectives

The primary objective of this Phase II study is to evaluate the **Confirmed Best Overall Response Rate (BORR)**, which includes Complete Response (CR) and Partial Response (PR), for Basal Cell Carcinoma (BCC) tumor type. This is measured according to RECIST v1.1 criteria. The confirmation of CR necessitates histopathological analysis of exeresis specimens for lesions removed by surgery or biopsies in all other cases. This objective is clinically relevant as it aims to determine the efficacy of the treatment in achieving significant tumor reduction or elimination, which is crucial for improving patient outcomes in non-melanoma skin cancer.

Secondary objectives include: - Assessing the **efficacy** of L19IL2/L19TNF-treated lesions by measuring the Disease Control Rate (DCR), which encompasses Complete Response (CR), Partial Response (PR), and Stable Disease (SD) for each tumor type according to RECIST v1.1 criteria. - Evaluating **Progression-Free Survival (PFS)**, separately in patients who are not resected after curative intention and those who undergo secondary surgery, regardless of the RECIST response to treatment, considering the appearance of new lesions and metastases. - Determining the **Pathological Response** for each tumor type in surgical specimens from resected tumors or biopsy samples for other types. - Assessing the **safety** of intratumoral administration of L19IL2/L19TNF. These secondary objectives are important for understanding the broader impact of the treatment on disease progression, surgical outcomes, and patient safety.

Participants

The clinical trial involves a total of **14 participants** diagnosed with high-risk, locally advanced **Basal Cell Carcinoma (BCC)** or cutaneous **Squamous Cell Carcinoma (cSCC)**. The study population includes both male and female subjects, aged between 18 and 100 years, who are not eligible for surgery or radiation therapy, or who have refused such treatments. Participants were selected based on their ability to receive intratumoral injections and their compliance with the European Association of Dermato-Oncology (EADO) operational staging system for BCC and EADO/EORTC guidelines for cSCC. The trial excludes vulnerable populations and requires participants to have an ECOG Performance Status of ≤ 1, ensuring a generally stable health status. Lifestyle considerations such as diet and physical activity are not specified, but participants must adhere to specific contraceptive measures if applicable. The trial does not include individuals with unresolved acute toxic effects from prior therapies, except for alopecia, and requires specific laboratory parameters to be within normal limits.

Plans and Procedures

The clinical trial is designed as a **randomized**, **double-blind**, and **controlled** study to evaluate the efficacy and safety of intratumoral administration of the investigational products **Fibromun** and **Darleukin** in patients with high-risk, locally advanced **Basal Cell Carcinoma (BCC)** or **cutaneous Squamous Cell Carcinoma (cSCC)**. The trial aims to assess the Confirmed Best Overall Response Rate (BORR) for BCC tumor type, measured according to RECIST v1.1 criteria, with histopathological confirmation required for complete responses. The study is expected to run from February 2020 to December 2025, with participant involvement lasting up to four months, depending on individual response and treatment tolerance.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, performance status, and laboratory values. Eligible patients are those with injectable lesions not suitable for surgery or radiation therapy. Women of childbearing potential must have a negative pregnancy test and use effective contraception. The trial includes follow-up visits to monitor treatment response and safety, with assessments of disease control rate and progression-free survival as secondary endpoints. The end-of-study visit will conclude the participant's involvement, with final evaluations of treatment efficacy and safety.

Participants may be withdrawn from the study early if they experience unacceptable toxicity, disease progression, or if they withdraw consent. The trial's primary endpoint is the efficacy of the investigational products, measured by BORR, while secondary endpoints include disease control rate and safety assessments. The study is conducted in accordance with international guidelines and ethical standards, ensuring the safety and well-being of all participants throughout the trial duration.

Treatment

The clinical trial involves the administration of two experimental medications, **Fibromun** and **Darleukin**, both formulated as a **solution for injection/infusion**. **Fibromun** contains the active substance **onfekafusp alfa**, a protein of non-standard origin, and is manufactured by Philogen SPA. The medication is administered via **intratumoral use**. The dosing regimen for **Fibromun** includes a maximum daily dose of 400 µg (micrograms) and a maximum total dose of 1600 µg over a treatment period of up to 4 weeks. The administration schedule is designed to ensure optimal therapeutic exposure while monitoring for any adverse effects.

**Darleukin** is the second investigational product in this study, containing the active substance **bifikafusp alfa**, also a protein of non-standard origin, produced by Philogen SPA. Similar to **Fibromun**, **Darleukin** is administered through **intratumoral use**. The dosing for **Darleukin** is set at a maximum daily dose of 13 million IU (international units) and a maximum total dose of 52 million IU over a 4-week treatment period. The administration of **Darleukin** is carefully monitored to ensure participant safety and adherence to the dosing schedule.

Both investigational products are not formulated for pediatric use and are not classified as orphan drugs. The trial does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments. Participant compliance with the dosing regimen is monitored throughout the study to ensure adherence to the protocol and to evaluate the safety and efficacy of the investigational products in patients with non-melanoma skin cancer presenting injectable lesions.

Efficacy

The efficacy of the investigational products L19IL2 and L19TNF in the treatment of non-melanoma skin cancer will be assessed primarily through the **Confirmed Best Overall Response Rate (BORR)**. This includes the sum of Complete Response (CR) and Partial Response (PR) rates for basal cell carcinoma (BCC) tumor type, evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Confirmation of a CR will necessitate histopathological analysis of exeresis specimens for lesions excised surgically or biopsies in other cases.

Secondary efficacy endpoints will include the **Disease Control Rate (DCR)**, which encompasses CR, PR, and Stable Disease (SD) for each tumor type, also measured according to RECIST v1.1 criteria. Additionally, **Progression-Free Survival (PFS)** will be assessed separately for patients who are not resected after curative intention and those who undergo secondary surgery, regardless of the RECIST response to treatment. This assessment will consider the appearance of new lesions and the occurrence of metastases.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Patients with high-risk, locally advanced (non-metastatic, node negative, single or multifocal), basal cell carcinoma (BCC) or cutaneous squamous cell carcinoma (cSCC) amenable to intratumoral injection, not eligible to surgery or radiation therapy according to the evaluation of a local interdisciplinary tumor board or who refuse surgery or radiation therapy and for whom an histological evaluation is available according to international guidelines. Eligible patients are those as defined by the European Association of Dermato-Oncology (EADO) operational staging system (stages IIa to IIIb) [1] for BCC and by EADO/EORTC (European Organization for Research and Treatment of Cancer) interdisciplinary guidelines [1] for cSCC.
Patients with injectable and measurable regional cutaneous or subcutaneous in-transit or satellite metastasis but without regional nodal involvement are also eligible.
Male or female patients, age 18 - 100 years.
ECOG Performance Status/WHO Performance Status ≤ 1.
Hemoglobin > 10.0 g/dL
Platelets > 100 x 109/L.
ALT and AST, GGT and Lipase ≤ 1.5 x the upper limit of normal (ULN).
Serum creatinine < 1.5 x ULNAn age-calibrated definition of CKD has been proposed to distinguish age-related from disease-related changes in eGFR. For patients younger than 40 years, CKD is defined by eGFR below 75 mL/min/1.73m2. For patients with ages between 40 and 65 years, CKD is defined by 60 mL/min/1.73m2. For subjects older than 65 years without albuminuria or proteinuria, CKD is defined by eGFR below 45 mL/min/1.73m2.
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.
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.
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.
Willingness and ability to comply with the scheduled visits, treatment plan, laboratory tests and other study procedures.

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Exclusion Criteria

Previous or concurrent cancer type that is distinct from the cancers being evaluated in this study, except any cancer curatively treated more than 2 years prior to study entry.
Topical or systemic chemotherapy, immunotherapy or radiation therapy on the tumor sites in the 4 weeks prior to study drug administration.
Patients with node positive BCC/cSCC who are candidate to SHH inhibitor or checkpoint inhibitor therapy.
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 and HCV excluding active infection is needed.
History within the last year of acute or subacute coronary syndromes including myocardial infarction, unstable or severe stable angina pectoris, of inadequately treated cardiac arrhythmias and heart insufficiency (any grade, New York Heart Association (NYHA) criteria).
Any abnormalities observed during baseline ECG investigations that are considered as clinically significant by the investigator.
Known arterial aneurysms.
INR > 3.
Uncontrolled hypertension.
Known uncontrolled coagulopathy or bleeding disorder.
Known hepatic cirrhosis or severe pre-existing hepatic impairment.
Moderate to severe respiratory failure.
Active autoimmune disease.
Patient requires or is taking systemic corticosteroids (>5 mg/day) 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.
Known history of allergy to IL2, TNF, or other human proteins/peptides/antibodies.
Pregnancy or breast-feeding.
Ischemic peripheral vascular disease (Grade IIb-IV).
Severe diabetic retinopathy.
Recovery from major trauma including surgery within 4 weeks prior to enrollment.
Solid organ transplant recipient or patient with iatrogenic or pathologic severe immune suppression.
Any conditions that in the opinion of the investigator could hamper compliance with the study protocol.