Neoadjuvant L19IL2/L19TNF- Pivotal Study

Study Overview
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Brief Summary
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Phase III, open-label, randomized, controlled multi-center study of the efficacy of L19IL2/L19TNF neoadjuvant intratumoral treatment in Stage III B/C melanoma patients.

Detailed Description
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Phase III, open-label, randomized, controlled multi-center study. In the study, 214 patients will be enrolled and parallel assigned (via automated randomization system) in a 1:1 fashion to one of two different arms: ARM 1: Patients in Arm 1 will receive multiple intratumoral administrations into all injectable cutaneous, subcutaneous, and nodal tumors of a mixture of L19IL2 and L19TNF once weekly for up to 4 weeks (or until all injectable tumors have disappeared, or intolerance to study treatment or in the opinion of the investigator immediate surgical resection or any other treatment for melanoma is warranted, whichever occurs first). The whole volume of L19IL2/L19TNF will be distributed among all injectable lesions. Newly occurring injectable melanoma lesions within the 4 weeks treatment period will also be treated as described. For the new lesions the treatment period will not be extended beyond the pre-defined 4 week- treatment period with a clock start at the time of the first intralesional L19IL2/L19TNF injection. Surgical resection of all existing metastases will follow within 4 weeks after end of treatment. Surgery will be performed after the safety evaluation carried out at week 5 and, if indicated, may be carried out on the same day of the safety evaluation. Post-surgery EMA-approved adjuvant therapy is allowed at discretion of the treating physician. ARM 2: Patients in Arm 2 will receive directly surgical resection of melanoma tumor lesions within 4 weeks after randomization. Post-surgery EMA-approved adjuvant therapy is allowed at discretion of the treating physician. Patients will be followed on a regular basis for the primary outcome until 36 months from randomization and up to 60 months for overall survival. Expected patient enrollment interval: 60 months. Duration of individual patient's participation: up to 60 months. End of treatment corresponds to the day of surgery for patients randomized to both Arm 1 and Arm 2. End of study corresponds to the last patient last visit (LPLV). The final primary efficacy analysis will be conducted when the 95th recurrence event is observed.

Official Title
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A Pivotal Phase III, Open-label, Randomized, Controlled Multi-center Study of the Efficacy of L19IL2/L19TNF Neoadjuvant Intratumoral Treatment Followed by Surgery Versus Surgery Alone in Clinical Stage III B/C Melanoma Patients

Conditions
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Malignant Melanoma

Intervention / Treatment
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* Drug: L19IL2 + L19TNF
* Procedure: Surgery


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: 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. 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. 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. Males or females, age ≥ 18 years. ECOG Performance Status/WHO Performance Status ≤ 1. Life expectancy of at least 24 months (see paragraph 6.3.1). Absolute neutrophil count > 1.5 x 109/L. Hemoglobin > 9.0 g/dL. Platelets > 100 x 109/L. Total bilirubin ≤ 30 µmol/L (or ≤ 2.0 mg/dl). ALT and AST ≤ 2.5 x the upper limit of normal (ULN). Serum creatinine < 1.5 x ULN. LDH serum level ≤ 1.5 x ULN. Documented negative test for HIV, HBV and HCV. For HBV serology, the determination of HBsAg and anti-HBcAg Ab is required. In patients with serology documenting previous exposure to HBV (e.g., anti-HBsAg and/or anti-HBc Ab) negative serum HBV-DNA is also required. 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) (v4.03) Grade ≤ 1 unless otherwise specified above. Negative pregnancy test at screening for Women Of Childbearing Potential (WOCBP*). Pregnant women are not allowed to participate to this study. WOCBP must be using, from the 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 or sexual abstinence. Pregnancy test will be repeated at the Safety Visit (only WOCBP and only for patients in Arm 1). 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. 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. Women of childbearing potential are defined as females who have experienced menarche, are not postmenopausal (12 months with no menses without an alternative medical cause) and are not permanently sterilized (e.g., tubal occlusion, hysterectomy, bilateral oophorectomy or bilateral salpingectomy). Exclusion Criteria: Uveal melanoma, mucosal melanoma or melanoma with unknown primary. Evidence of distant metastases at screening. 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. 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. History within the last year of acute or subacute coronary syndromes including myocardial infarction, unstable or severe stable angina pectoris. Inadequately controlled cardiac arrhythmias including atrial fibrillation. Heart insufficiency (> Grade II, New York Heart Association (NYHA) criteria). LVEF ≤ 50% and/or 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). Severe diabetic retinopathy. Active autoimmune disease. History of organ allograft or stem cell transplantation. Recovery from major trauma including surgery within 4 weeks prior to enrollment. Known history of allergy to IL2, TNF, or other human proteins/peptides/antibodies or any other constituent of the product. Breast feeding female. Anti-tumor therapy (except allowed treatments listed at point 3 of Inclusion criteria) within 4 weeks before enrollment. 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. Planned administration of growth factors or immunomodulatory agents (except allowed treatments listed at point 3 of Inclusion criteria) within 7 days before enrollment. 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. Any conditions that in the opinion of the investigator could hamper compliance with the study protocol. Previous enrolment and randomization in this same study.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1: neoadjuvant + surgery<br>Patients in Arm 1 will receive multiple intratumoral administrations into all injectable cutaneous, subcutaneous, and nodal tumors of a mixture of L19IL2 and L19TNF once weekly for up to 4 weeks (or until all injectable tumors have disappeared, or intolerance to study treatment or in the opinion of the investigator immediate surgical resection or any other treatment for melanoma is warranted, whichever occurs first). Newly occurring injectable melanoma lesions within the 4 weeks treatment period will also be treated as described. Surgical resection of all existing metastases will follow within 4 weeks after end of treatment. Surgery will be performed after the safety evaluation carried out at week 5 and, if indicated, may be carried out on the same day of the safety evaluation. | Drug: L19IL2 + L19TNF<br>* Mixture of L19IL2 and L19TNF once weekly<br>Procedure: Surgery<br>* Surgical resection of melanoma tumor lesions<br>|
| Active Comparator: Arm 2: surgery alone<br>Patients in Arm 2 will receive directly surgical resection of melanoma tumor lesions within 4 weeks after randomization. | Procedure: Surgery<br>* Surgical resection of melanoma tumor lesions<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recurrence-free survival (RFS) rate | Recurrence-free survival (RFS) in the treatment arm (L19IL2/L19TNF plus surgery; Arm 1) versus control arm (Arm 2). | 1 year after randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Local recurrence-free survival (LRFS) |  | 1year, 2years, 3years after randomization and 1year after surgery | 
| Distant metastasis-free survival (DMFS) rate |  | 1year, 2years, 3years after randomization and 1year after surgery | 
| Recurrence-free survival (RFS) rate |  | 2years, 3years after randomization | 
| Overall survival (OS) |  | 1year, 2years, 3years after randomization | 
| Percentage of Participants With On-Study Adverse Events (AEs) and Serious Adverse Events (SAEs) |  | up to 3 years | 
| Percentage of Participants With Worst On-Study Hematological and Chemistry Abnormalities |  | up to 36 months | 
| Clinically Meaningful Changes in Vital Signs and Physical Examinations |  | up to 36 months | 
| Changes in absolute counts and relative percentages of lymphocytic subpopulations over time | 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). | (1) At screening, (2) At Day of surgery: from Day 1 to Day 54, (3) After 3 months from surgery: Day 91 to Day 144 | 
| HAFA | Assessment of the formation of human anti-fusion protein antibodies (HAFA) against L19IL2 and L19TNF. | (1) At Day 1, (2) At Day 29, (3) After 3 months from surgery: Day 119 to Day 144 |