Efficacy of Daromun Neoadjuvant Intratumoral Treatment in Clinical Stage IIIB/C Melanoma Patients

Study Overview
=================
Brief Summary
-----------------
The trial aims to evaluate the efficacy of Daromun neoadjuvant treatment followed by surgery and adjuvant therapy to improve in a statistically significant manner the recurrence-free survival (RFS) of Stage IIIB/C melanoma patients with respect to the standard of care (surgery and adjuvant therapy).

Detailed Description
-----------------
The present study is an open-label, randomized, controlled, two-arm multi-center study of the efficacy of Daromun neoadjuvant intratumoral treatment followed by surgery and adjuvant therapy versus surgery and adjuvant therapy in clinical stage III B/C melanoma patients. 186 patients will be randomized in a 1:1 ratio to receive Daromun treatment followed by surgery and adjuvant therapy (Arm 1) or surgery and adjuvant therapy (Arm 2). In both arms, follow-up for assessing recurrence-free survival will be performed up to five years after randomization. Survival information will also be collected in the following year (up to six years in total after randomization). This is an open-label study, so there is no blinding. Patients who successfully complete the screening evaluations and are eligible for participation in the study will be enrolled and randomly assigned (1:1) to two parallel treatment arms: Daromun plus surgery and adjuvant therapy (Arm 1) or surgery and adjuvant therapy (Arm 2). To ensure a balance across treatment groups, stratified randomization with permuted block will be used and separate randomization list for each subgroup (stratum) will be produced. Patients will be stratified on the basis of the following prognostic factors: Stage of disease (2 levels): Stage IIIB vs. Stage IIIC Planned post-surgical adjuvant therapy (2 levels): anti-PD-1 and other adjuvant therapies. The primary objective of the study is to demonstrate that a neoadjuvant Daromun treatment followed by surgery and adjuvant therapy improves in a statistically significant manner the recurrence-free survival (RFS) of Stage IIIB/C melanoma patients with respect to the standard of care (surgery and adjuvant therapy). Primary endpoint of the study is RFS in a time-to-event analysis in the Daromun plus surgery and adjuvant therapy treatment group (Arm 1) versus the surgery plus adjuvant therapy control group (Arm 2). Analysis will be based on the Intention To Treat population. The key secondary objective of the study is to demonstrate that a neoadjuvant Daromun treatment followed by surgery and adjuvant therapy improves in a statistically significant manner the overall survival (OS) of patients with resectable Stage IIIB/ or C melanoma patients with respect to the standard of care (surgery and adjuvant therapy). For patients enrolled in both arms, local approved post-surgery adjuvant therapies (as part of the standard of care) are allowed and decided at the investigator's discretion. These include high-dose interferon- α2b, anti-CTLA-4 antibodies (e.g. Ipilimumab), anti-PD1 antibodies (e.g. Nivolumab, Pembrolizumab), targeted therapies (e.g. Dabrafenib + Trametinib), or other new local approved treatments.

Official Title
-----------------
An Open-Label, Randomized, Controlled Multi-Center Study of The Efficacy of Daromun (L19IL2 + L19TNF) Neoadjuvant Intratumoral Treatment Followed by Surgery and Adjuvant Therapy Versus Surgery and Adjuvant Therapy in Clinical Stage IIIB/C Melanoma Patients

Conditions
-----------------
Melanoma Stage IIIB/C

Intervention / Treatment
-----------------
* Drug: Daromun
* Procedure: Surgery
* Drug: Adjuvant therapy


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Diagnosis of clinical stage IIIB and IIIC (AJCC v7) metastatic melanoma, eligible for complete surgical resection of all metastases (surgically resectable). 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. Males or females, age ≥ 18 years. ECOG Performance Status/WHO Performance Status ≤ 1. Life expectancy of > 24 months. 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 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. All women of childbearing potential (WOCBP) must have negative pregnancy test results at the screening. WOCBP must be using, from the screening to three months following the last study drug administration, highly effective contraception methods. WOCBP and effective contraception methods are 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. Exclusion Criteria: Uveal melanoma or mucosal melanoma 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 small surgery) within 4 weeks before enrollment. Previous in vivo exposure to monoclonal antibodies for biological therapy in the 6 weeks before enrollment. Planned administration of growth factors or immunomodulatory agents 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 the same study.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Total patients: approximately 186. Daromun plus surgery and adjuvant therapy treatment group (Arm 1): 93 evaluable patients. Surgery and adjuvant therapy (Arm 2): 93 evaluable patients. Patients enrolled will be randomized to the two different arms of the study.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Daromun plus Surgery and Adjuvant therapy (Arm 1)<br>Two-weeks screening period and a 4-weeks open-label treatment period, followed by surgery within a maximum of another 4 weeks and adjuvant therapy (Arm 1). | Drug: Daromun<br>* Patients will receive intratumoral administrations into injectable cutaneous, subcutaneous, and nodal tumors of Daromun once weekly for up to 4 weeks. Surgery will follow within 4 weeks.<br>Procedure: Surgery<br>* Patients in Arm 2 will receive surgery within 4 weeks from randomisation.<br>Drug: Adjuvant therapy<br>* Patients will receive adjuvant therapy at the investigator's discretion following the surgery.<br>|
| Active Comparator: Surgery and adjuvant therapy (Arm 2)<br>Patients in the control arm (Arm 2) will receive direct surgery within 4 weeks from randomization, followed by adjuvant therapy. | Procedure: Surgery<br>* Patients in Arm 2 will receive surgery within 4 weeks from randomisation.<br>Drug: Adjuvant therapy<br>* Patients will receive adjuvant therapy at the investigator's discretion following the surgery.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recurrence Free Survival (RFS) | RFS in the Daromun plus surgery and adjuvant therapy treatment group (Arm 1) versus surgery and adjuvant therapy (Arm 2). RFS is defined as the difference between date of randomization (which represents Day 0 for both arms) and the date of first recurrence (local, regional, distant or new primary melanoma, whichever comes first) or death. | From date of randomization until the date of the first recurrence or date of death from any cause, whichever occurs first assessed up to 60 months. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival (OS) | OS in the Daromun plus surgery and adjuvant therapy treatment group (Arm 1) versus surgery and adjuvant therapy (Arm 2). OS is defined as the difference between date of randomization (which represents Day 0 for both arms) and the date of death. | From date of randomization until the date of the first recurrence or date of death from any cause, whichever occurs first, assessed up to 72 months. | 
| Recurrence free survival (RFS) as determined by the local investigator | RFS after randomization in the Daromun plus surgery and adjuvant therapy treatment group (Arm 1) versus surgery and adjuvant therapy (Arm 2). RFS is defined as the difference between date of randomization (which represents Day 0 for both arms) and the date of first recurrence (local, regional, distant or new primary melanoma, whichever comes first) or death. | From date of randomization until the date of the first recurrence or date of death from any cause, whichever occurs first assessed up to 60 months. | 
| Pathological response (only for patients in Arm 1) | Categorization of pathological response as: p Complete Response, p near-Complete Response, p Partial Response, p None Response | Time Frame: Assessed at the time of surgical resection of the tumor lesions | 
| Adverse Events (AE) | Percentage of Patients in Each Treatment Group with AEs, AEs with CTCAE grade ≥3 | From the inclusion in the study (signature of the informed consent form - ICF) until the first follow-up visit (up to approximately 5 months). | 
| Serious Adverse Event (SAEs) | Percentage of Patients in Each Treatment Group with Drug-Related Adverse Events, Serious Adverse Event (SAEs) | From the inclusion in the study (signature of the informed consent form - ICF) until the end of follow-up (up to approximately 60 months). | 
| Drug-Induced Liver Injury (DILI) | Number of patients with Drug-Induced Liver Injury (DILI) | From the inclusion in the study (signature of the informed consent form - ICF) until the end of follow-up (up to approximately 60 months). | 
| Adverse Events of Special Interest (AESI) | Number of patients with Adverse Events of Special Interest (AESI) | From the inclusion in the study (signature of the informed consent form - ICF) until the end of follow-up (up to approximately 60 months). | 
| Percentage of Subjects with Haematological/chemical Laboratory Abnormalities |  | From the inclusion in the study (signature of the informed consent form - ICF) until the end of follow-up (up to approximately 60 months). | 
| Percentage of participants with Electrocardiogram (ECG) and echocardiogram (ECHO) abnormality findings. | Data about QT/QTc intervals will be collected and analysed for QT/QTc prolongation potentially caused by treatment. | 1) day 0-14 (screening) for both arm; 2) at week 5 (Safety assessment) only for arm 1. | 
| Number of subjects with a clinically significant change from baseline in physical examination |  | From the inclusion in the study (signature of the informed consent form - ICF) until the end of follow-up (up to approximately 60 months) | 
| Concomitant medication | Number of subject with concomitant medication | From the inclusion in the study (signature of the informed consent form - ICF) until the end of follow-up (up to approximately 60 months) | 
| Human anti-fusion protein antibodies (HAFA) | Assessment of the formation of human anti-fusion protein antibodies (HAFA) against L19IL2 and L19TNF | 1) day 0-14 (screening) for arm 1; 2) at week 5 (Safety assessment) for Arm 1; 3) at week 12 (only first follow-up) for Arm 1. | 
| Vital signs (blood pressure) | Number of subjects with a clinically significant change from baseline in vital signs (blood pressure) by visit | From the inclusion in the study (signature of the informed consent form - ICF) until the end of follow-up (up to approximately 60 months). | 
| Number of subjects with a clinically significant change from baseline in vital signs (heart rate) by visit |  | From the inclusion in the study (signature of the informed consent form - ICF) until the end of follow-up (up to approximately 60 months) | 
| Number of subjects with a clinically significant change from baseline in vital signs (body temperature) by visit |  | From the inclusion in the study (signature of the informed consent form - ICF) until the end of follow-up (up to approximately 60 months) |