Malignant melanoma of the skin in patients with locally advanced and fully resectable melanoma with/without prior therapy and presence of injectable cutaneous and/or subcutaneous or nodal lesions. MedDRA version: 21.1 Level: PT Classification code 10025670 Term: Malignant melanoma stage III System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Interventions
Product Name: Darleukin
Product Code: L19IL2
Pharmaceutical Form: Solution for injection
INN or Proposed INN: Bifikafusp alfa
CAS Number: 1957239-90-5
Other descriptive name: Darleukin
Concentration u
Sponsors
Philogen S.p.A.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Inclusion criteria: 1. Diagnosis of malignant melanoma of the skin with locally advanced disease as defined by clinical stage III B and III C according to AJCC 7th Ed, eligible for complete surgical resection. 2. Eligible subjects must have measurable disease and must be candidate for intralesional therapy with at least one injectable cutaneous, subcutaneous, or nodal melanoma lesion (= 10 mm in longest diameter) or with multiple injectable lesions that in aggregate have a longest diameter of = 10 mm. 3. Prior anti-tumor treatment for the primary melanoma lesion, including surgery and approved adjuvant treatments (e.g., radiotherapy, immune checkpoint inhibitors, BRAF/MEK inhibitors, etc.) is allowed. 4. Males or females, age = 18 years 5. ECOG Performance Status/WHO Performance Status = 1 6. Life expectancy of at least 24 months (see paragraph 6.3.1) 7. Absolute neutrophil count > 1.5 x 109/L 8. Hemoglobin > 9.0 g/dL 9. Platelets > 100 x 109/L 10. Total bilirubin = 30 µmol/L (or = 2.0 mg/dl) 11. ALT and AST = 2.5 x the upper limit of normal (ULN) 12. Serum creatinine =65 years) yes F.1.3.1 Number of su
Exclusion criteria
Exclusion criteria: Patients exclusion criteria: 1. Uveal melanoma, mucosal melanoma or melanoma with unknown primary. 2. Evidence of distant metastases at screening 3. Previous or concurrent cancer that is distinct in primary site or histology from the cancer being evaluated in this study except cervical carcinoma in situ, treated basal cell carcinoma, superficial bladder tumors (Ta, Tis & T1), second primary melanoma in situ or any cancer curatively treated = 5 years prior to study entry 4. Presence of active infections (e.g. requiring antimicrobial therapy) or other severe concurrent disease, which, in the opinion of the investigator, would place the patient at undue risk or interfere with the study. 5. History within the last year of acute or subacute coronary syndromes including myocardial infarction, unstable or severe stable angina pectoris. 6. Inadequately controlled cardiac arrhythmias including atrial fibrillation 7. Heart insufficiency (> Grade II, New York Heart Association (NYHA) criteria) 8. LVEF = 50% and/or abnormalities observed during baseline ECG and Echocardiogram investigations that are considered as clinically significant by the investigator. 9. Uncontrolled hypertension 10. Ischemic peripheral vascular disease (Grade IIb-IV) 11. Severe diabetic retinopathy 12. Active autoimmune disease 13. History of organ allograft or stem cell transplantation 14. Recovery from major trauma including surgery within 4 weeks prior to enrollment. 15. Known history of allergy to IL2, TNF, or other human proteins/peptides/antibodies or any other constituent of the product. 16. Breast feeding female 17. Anti-tumor therapy (except allowed treatments listed at point 3 of Inclusion criteria) within 4 weeks before enrollment 18. Previous in vivo exposure to monoclonal antibodies for biological therapy (except allowed treatments listed at point 3 of Inclusion criteria) in the 6 weeks before enrollment 19. Planned administration of growth factors or immunomodulatory agents (except allowed treatments listed at point 3 of Inclusion criteria) within 7 days before enrollment 20. Patient requiring or taking corticosteroids or other immunosuppressant drugs on a long-term basis. Limited use of corticosteroids to treat or prevent acute hypersensitivity reactions is not considered an exclusion criterion. 21. Any conditions that in the opinion of the investigator could hamper compliance with the study protocol. 22. Previous enrolment and randomization in this same study.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Efficacy of L19IL2/L19TNF neoadjuvant treatment followed by surgery to improve in a statistically significant manner the recurrence-free survival (RFS) of patients with locally advanced and fully resectable melanoma with respect to surgery alone: post-surgery adjuvant treatment is allowed in both arms. ;Secondary Objective: Secondary objective of the study is to demonstrate that a neoadjuvant L19IL2/L19TNF treatment followed by surgery improves in a statistically significant manner the overall survival (OS) of patients with fully resectable locally advanced melanoma with respect to surgery. Other secondary objectives include a demonstration of improvement of Local recurrence-free survival (LRFS) and distant metastasis-free survival (DMFS) and, for patients included in Arm 1 only, pathological responses (i.e., pathological Complete Response, pathological near- Complete Response, pathological Partial Response, pathological Non Response) assessed on the surgical specimen after tumor removal, as well as demonstration of safety and tolerability of the L19IL2/L19TNF treatment.;Primary end point(s): Primary endpoint is: - Recurrence-free survival (RFS) in the treatment arm (L19IL2/L19TNF plus surgery followed by adjuvants; Arm 1) versus control arm (surgery followed by adjuvants; Arm 2). ;Timepoint(s) of evaluation of this end point: Recurrence is evaluated every 3 months after surgery up to 36 months. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Secondary endpoints are: - Overall survival (OS) in the treatment arm (L19IL2/L19TNF plus surgery; Arm 1) versus control arm (surgery; Arm 2). - Local recurrence-free survival (LRFS) and distant metastasis-free survival (DMFS) in the treatment arm (L19IL2/L19TNF plus surgery - Arm 1) versus control arm (Arm 2). - Proportion of patients with pathological responses (defined as the proportion of patients with a pathological CR, pathological near-CR, or pathological PR). - Safety of intratumoral administration of L19IL2/L19TNF. - Biomarker studies (both arms): immunophenotypic characterization of PBMCs for changes in absolute counts and relative percentages of lymphocytic subpopulations (e.g., Tregs, MDSCs etc.) over time (only for patients recruited in German centers; the data will be collected for at least 50 patients). Study of blood biomarkers. - Assessment of the formation of human anti-fusion protein antibodies (HAFA) against L19IL2 and L19TNF.;Timepoint(s) of evaluation of this end point: - Overall survival (OS): evaluation every 3 months after surgery up to 36 months; at least every 6 months up to 60 months. - LRFS and DMFS: evaluation every 3 months after surgery up to 36 months. - Proportion of patients with pathological responses: evaluated after surgery. - Safety of intratumoral administration of L19IL2/L19TNF: evaluation throughout the entire study for each patient - Biomarker studies, immunophenotypic characterization of PBMCs: assessment at screening; at surgery visit; at first follow-up visit - HAFA assessment will be performed on patients included in Arm 1: on day 1 before drug administration; on day 8 before drug administration; on day 29 at safety visit; at first follow-up visit | — |
Countries
France, Germany, Italy, Poland
Contacts
Public ContactRegulatory Department
Philogen S.p.A.
Outcome results
None listed