E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Malignant melanoma of the skin in subjects with completely resectable stage IIIB and IIIC disease 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 |
Specific malignant melanoma of the skin in subjects with completely resectable disease 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 measured as recurrence-free survival (RFS) rate in the L19IL2/L19TNF plus surgery treatment group (Arm 1) versus surgery alone (Arm 2), assessed at 1 year after randomization
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E.2.2 | Secondary objectives of the trial |
Efficacy of L19IL2/L19TNF as: - Local recurrence-free survival (LRFS) rate and distant metastasis-free survival (DMFS) rate in the L19IL2/L19TNF plus surgery treatment group (Arm 1) versus surgery alone (Arm 2), assessed at 1 y after randomization. - LRFS rate and DMFS rate in the L19IL2/L19TNF plus surgery treatment group (Arm 1) versus surgery alone (Arm 2), assessed at 1 y after surgery (for both arms). - RFS rate in the L19IL2/L19TNF plus surgery treatment group (Arm 1) versus Arm 2, assessed at 2-y and 3-y after randomization. - Overall survival (OS) in Arm 1 vs Arm 2, assessed at 1y after randomization and at 2y and 3y after randomization. - Safety of intratumoral administration of L19IL2/L19TNF - Biomarker studies: immunophenotyping of PBMCs for changes in absolute counts and relative percentages of lymphocytic subpopulations over time. Study of blood biomarkers - Assessment of the formation of human anti-fusion protein antibodies (HAFA) against L19IL2 and L19TNF
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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 in clinical stage III B and III C, 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. Males or females, age ≥ 18 years 4. ECOG Performance Status/WHO Performance Status ≤ 1 5. Life expectancy of at least 24 months (see paragraph 6.3.1) 6. Absolute neutrophil count > 1.5 x 109/L 7. Hemoglobin > 9.0 g/dL 8. Platelets > 100 x 109/L 9. Total bilirubin ≤ 30 µmol/L (or ≤ 2.0 mg/dl) 10. ALT and AST ≤ 2.5 x the upper limit of normal (ULN) 11. Serum creatinine < 1.5 x ULN 12. LDH serum level ≤ 1.0 x ULN 13. Documented negative test for HIV, HBV and HCV. For HBV serology, the determination of HBsAg, anti-HBsAg Ab and anti-HBcAg Ab is required. In patients with serology documenting previous exposure to HBV (e.g. anti-HBs Ab with no history of vaccination and/or anti-HBc Ab) negative serum HBV-DNA is also required. 14. 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 15. All female subjects must have negative pregnancy test results at the screening. Women of childbearing potential (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 end of treatment visit. 16. 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. 17. Evidence of a personally signed and dated informed consent document indicating that the subject has been informed of all pertinent aspects of the study. 18. Willingness and ability to comply with the scheduled visits, treatment plan, laboratory tests and other study procedures.
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E.4 | Principal exclusion criteria |
Patients exclusion criteria: 1. Uveal melanoma and mucosal melanoma 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 & Ti), 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 small surgery) within 4 weeks before enrollment 18. Previous in vivo exposure to monoclonal antibodies for biological therapy in the 6 weeks before enrollment 19. Planned administration of growth factors or immunomodulatory agents within 7 days before enrollment 20. Patient requires or is 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. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Efficacy of L19IL2/L19TNF measured as recurrence-free survival (RFS) rate in the L19IL2/L19TNF plus surgery treatment group (Arm 1) versus surgery alone (Arm 2), assessed at 1 year after randomization.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
RFS rate in the L19IL2/L19TNF plus surgery treatment group (Arm 1) versus surgery alone (Arm 2), assessed at 1 year after randomization. |
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E.5.2 | Secondary end point(s) |
- Efficacy of L19IL2/L19TNF: --> Local recurrence-free survival (LRFS) rate and distant metastasis-free survival (DMFS) rate in the L19IL2/L19TNF plus surgery treatment group (Arm 1) versus surgery alone (Arm 2), assessed at 1 year after randomization. --> Local recurrence-free survival (LRFS) rate and distant metastasis-free survival (DMFS) rate in the L19IL2/L19TNF plus surgery treatment group (Arm 1) versus surgery alone (Arm 2), assessed at 1 year after surgery (for both arms). ---> Recurrence-free survival (RFS) rate in the L19IL2/L19TNF plus surgery treatment group (Arm 1) versus surgery alone (Arm 2), assessed at 2-y and 3-y after randomization. - Overall survival (OS) in the L19IL2/L19TNF plus surgery treatment group (Arm 1) versus surgery alone (Arm 2), assessed at 1 year after randomization and at 2-y and 3-y after randomization. - 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) . Study of blood biomarkers (e.g., S100b, LDH ratio etc.) - 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 |
- LRFS rate and DMFS rate in Arm 1 vs Arm 2, assessed at 1 y after randomization. - LRFS rate and DMFS rate in Arm 1vs Arm 2, assessed at 1 y after surgery (both arms). - Recurrence-free survival (RFS) rate in Arm 1 vs Arm 2, assessed at 2y and 3y after randomization. - Overall survival (OS) in Arm 1 versus Arm 2, assessed at 1y after randomization and at 2y and 3y after randomization. - Safety of intratumoral administration of L19IL2/L19TNF - Biomarker studies: immunophenotyping of PBMCs for changes in absolute counts and relative percentages of lymphocytic subpopulations over time. Study of blood biomarkers - Assessment of the formation of human anti-fusion protein antibodies (HAFA) against L19IL2 and L19TNF.
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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 | 8 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 20 |
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 | 5 |
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 | 5 |
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 |