L19IL2 or L19TNF or L19IL2/TNF in Patients With Basal Cell Carcinoma (BCC)

A Phase 2 Controlled Randomized Study of the Efficacy of L19IL2 or L19TNF or L19IL2/L19TNF Intralesional Injections for the Treatment of Locally Advanced Basal Cell Carcinoma (LaBCC)

Open label, randomized study in patients with LaBCC not eligible or refusing surgery or radiation therapy according to the evaluation of a local interdisciplinary tumor board. The primary objective of the study is to evaluate the efficacy of L19IL2 or L19TNF or L19IL2/L19TNF, the secondary objectives of this study are to evaluate efficacy, safety and pharmacokinetics of immunocytokines. A minimum of 60 patients and a maximum of 180 evaluable patients will be randomized in a 1:1:1 ratio to one of the three different treatment arms of the study and will receive intralesional injections of: (i) Monotherapy 13 Mio IU (~2.17 mg) L19IL2; or (ii) Monotherapy 0.4 mg L19TNF; or (iii) Combination of 13 Mio IU L19IL2 + 0.4 mg L19TNF, once weekly for 4 consecutive weeks. Patients will be followed for a maximum of 156 weeks after beginning of treatment.

Tumor Assessment (TA) visits will be performed at Week 8 (Day 50 from the beginning of treatment), Week 12 (Day 78), Week 16 (Day 106) and then every 8 weeks for the first year of Follow-up (FU). During second and third years of FU, TA visits will be performed every 12 Weeks. In case a response (CR, PR) or stable disease (SD) is observed, a confirmatory assessment of the tumor response will be performed 4 weeks after the TA visit, when the objective response was first recorded.

Tumor response shall be evaluated according to composite criteria, i.e. BCC-RECIST-like. Measurement of tumor lesions and documentation (photographic documentation with use of a caliper for cutaneous lesions; ultrasound for subcutaneous lesions; imaging techniques as MRI) will be performed at every TA visit.

Confirmation of response or stable disease will be assessed by histopathological analysis of specimens from the treated skin area by multiple punch biopsies. Confirmation of tumor responses will be centrally reviewed by an independent committee (Independent Central Review, ICR).

After the TA visit confirmatory of partial response or stable disease, surgery with a curative intention can be performed if considered appropriate in the judgement of the investigator and if agreed upon by the patient; in these cases, pathological response in the exeresis specimen(s) will be evaluated as described above.

Patients will be followed for overall survival (OS) after a relapse or progression, and any further treatment given will be recorded for three years. Phone contact or any other documented contact with the patient will be recorded every 6 months for OS assessment from treatment start until the death of the patient, withdrawal of consent or until study completion (LPLV).

L19IL2 or L19TNF or L19IL2/L19TNF will be administered to eligible patients under the supervision of the investigator or identified sub-investigator(s). Patients will receive intratumoral administrations of immunocytokines into injectable cutaneous, and subcutaneous tumors once weekly for up to 4 weeks.

On the day of each treatment visit, all tumors to be injected should be measured and recorded (using caliper/ruler for cutaneous lesions and/or ultrasound for subcutaneous lesions). The recommended volume to be injected into the tumor(s) is dependent on the size of the lesion(s). The maximum dose to be administered in a single treatment visit is:

i) 13 MioIU L19IL2, or ii) 0.4 mg L19TNF or iii) 13 MioIU L19IL2 + 0.4 mg L19TNF It is recommended that each lesion should receive the maximum amount possible to inject due to tumor properties at each visit.

Inclusion Criteria:

• Patients with high risk, locally advanced histologically confirmed (non-metastatic, node negative, single or multifocal), BCC and amenable to intratumoral injection, not eligible or refusing surgery or radiation therapy according to the evaluation of a local interdisciplinary tumor board.

• Patients with at least one injectable and measurable cutaneous or subcutaneous lesion.

• Patients must not have received prior HHIs and checkpoint inhibitors systemic treatment.

• Patients may have received prior surgery and/or radiation therapy.

• Radiotherapy must have been previously administered for their locally advanced BCC, unless radiotherapy is contraindicated or inappropriate (e.g., hypersensitivity to radiation due to genetic syndrome such as Gorlin syndrome, limitations because of location of tumor, or cumulative prior radiotherapy dose). For patients whose locally advanced BCC has been irradiated, disease must have progressed after radiation.

• Patients must have a histologically confirmed disease that is considered to be inoperable or medical contraindication to surgery or radiotherapy, in the opinion of a Mohs dermatologic surgeon, head and neck surgeon, plastic surgeon or surgical/medical oncologist. Acceptable medical contraindications to surgery include:

  • BCC that has recurred in the same location after two or more surgical procedures and curative resection is deemed unlikely;
  • Anticipated substantial morbidity and/or deformity from surgery (e.g., removal of all or part of a facial structure, such as nose, ear, eyelid, eye; or requirement for limb amputation);
  • Medical conditions predisposing to poor surgical outcome (e.g., diabetes with history of poor wound healing);
  • Other conditions considered to be medically contraindicating must be discussed with the Medical Monitor before enrolling the patient.

• Prior radiotherapy to the target lesions must be completed at least 4 weeks prior to first study drug administration, with all acute RT-related toxicities resolved to ≤ Grade 1.

• Male or female patients, who are capable of giving consent, age ≥ 18 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).

• 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, vasectomized 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.

Exclusion Criteria:

• Presence of concomitant malignancies, with the exception of any cancer curatively treated more than 3 years prior to study entry and of tumors with a negligible risk for metastasis or death, such as adequately treated squamous-cell carcinoma of the skin (surgically removed 4 weeks prior to study entry), ductal carcinoma in situ of the breast, or carcinoma in situ of the cervix, early-stage asymptomatic CLL and not under active treatment (Rai 0, Binet A) will be eligible for the study.
• Current topical or systemic chemotherapy, targeted therapy immunotherapy.
• Patients with node positive BCC who are candidates for checkpoint inhibitor therapy.
• Chronically impaired renal function as indicated by creatinine clearance < 60 mL/min/1.73m2 or for patients older than 65 years without albuminuria or proteinuria, creatinine clearance < 45 mL/min/1.73m2.
• Presence of active severe bacterial or viral infections or other severe concurrent disease/infection requiring therapy, including positive tests for human immunodeficiency virus (HIV)-1 or HIV-2 serum antibody, hepatitis B virus (HBV), or hepatitis C virus (HCV). For HBV serology, the determination of HBsAg and anti-HBcAg Ab is required. In patients with serology documenting previous exposure to HBV, negative serum HBV-DNA is required. For HCV, HCV-RNA or HCV antibody test is required. Subjects with a positive test for HCV antibody but no detection of HCV-RNA indicating no current infection are eligible.
• History within the last year of acute or subacute coronary syndromes including myocardial infarction, unstable or severe stable angina pectoris, 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 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 that has required systemic treatment in past 2 years.
• Patients have a diagnosis of immunodeficiency or are receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of study drug. 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.
• Patients with a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator.
• Patients who have received a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin, and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist®) are live attenuated vaccines and are not allowed.
• Any conditions that in the opinion of the investigator could hamper compliance with the study protocol.