E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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. |
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E.1.1.1 | Medical condition in easily understood language |
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. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10025670 |
E.1.2 | Term | Malignant melanoma stage III |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
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.
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E.2.2 | Secondary objectives of the trial |
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. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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 < 1.5 x ULN 13. LDH serum level ≤ 1.5 x ULN 14. 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. 15. 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 16. 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 hormonereleasing 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). 17. 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. 18. Evidence of a personally signed and dated informed consent document indicating that the subject has been informed of all pertinent aspects of the study. 19. 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) |
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E.4 | Principal 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. |
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E.5 End points |
E.5.1 | 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).
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Recurrence is evaluated every 3 months after surgery up to 36 months. |
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E.5.2 | 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. |
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E.5.2.1 | 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 |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
Elective surgical resection of the tumor |
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E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 25 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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End of treatment: corresponds to the day of surgery for patients randomized to both Arm 1 and Arm 2. End of trial:LPLV |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 6 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 7 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |