Melanoma Stage IIIB, Melanoma Stage IIIC, Melanoma Stage IIID
Conditions
Keywords
Melanoma Stage IIIB, Melanoma Stage IIIC, Melanoma Stage IIID
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/D 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/D 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 (3 levels): Stage IIIB vs. Stage IIIC vs Stage IIID * 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/D 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/C/D 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.
Interventions
DRUGDaromun
Patients will receive intratumoral administrations into injectable cutaneous, subcutaneous, and nodal tumors of Daromun once weekly for up to 4 weeks.
PROCEDURESurgery
Patients will receive surgery.
DRUGAdjuvant therapy
Patients will receive adjuvant therapy at the investigator's discretion following the surgery.
Sponsors
Philogen S.p.A.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention 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.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Histologically or cytologically confirmed diagnosis of clinical stage IIIB, IIIC, and IIID (AJCC 8th edition) locoregional melanoma that is eligible for complete surgical resection of all metastases (surgically resectable). 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. Before enrollment in the study, a wash-out period of 6 weeks is required and toxicities from prior treatments should be resumed to Grade ≤1. 4. Males or females, age ≥ 18 years. 5. ECOG Performance Status/WHO Performance Status ≤ 1. 6. Life expectancy of \> 24 months. 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 (i.e. positive anti-HBsAg with not vaccination and/or positive anti-HBcAg 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. 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). 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.
Exclusion criteria
1. Uveal melanoma or 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, curatively 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 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 requiring or taking corticosteroids or other immunosuppressant drugs on a long-term basis will be evaluated case by case with the Sponsor for inclusion/exclusion in the study. Limited use of corticosteroids to treat or prevent acute hypersensitivity reactions is not considered an
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Recurrence Free Survival (RFS) | 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. | Recurrence Free Survival (RFS) in a time-to-event analysis in the Daromun plus surgery and adjuvant therapy treatment group (Arm 1) versus the surgery and adjuvant therapy control group (Arm 2). Analysis will be performed for the Intention To Treat population. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall survival (OS) | 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. | Overall survival (OS) in the Daromun plus surgery and adjuvant therapy treatment group (Arm 1) versus surgery and adjuvant therapy (Arm 2), which will be evaluated in time to event analysis as key secondary endpoint. |
| Recurrence free survival (RFS) as determined by the local investigator | 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. | A sensitivity analysis to assess ascertainment bias will be performed on recurrence free survival. For this analysis the primary analysis definition of recurrence will be split into its two components and each will be analyzed separately. The first component/definition will be based on the unblinded assessment performed at the site - any new lesion detected by clinical evaluation which is confirmed by histopathology (biopsy or surgical specimen) and the second component/definition will be based on the assessment of a new lesion detected by allowed imaging modalities in a Blinded Independent Central Review and confirmed, wherever possible, by histological analysis. Each of these components will be analyzed separately using the same statistical model as the primary endpoint. Results from the two component analyses will be compared. |
| Event-free survival (EFS) | From date of randomization until the date of the first event as described above, assessed up to 60 months | Event-free survival (EFS) defined as time from randomization to melanoma progression (irresectable stage III or stage IV disease), melanoma recurrence, treatment-related toxicity precluding surgery, treatment-related death, or melanoma-related death, whichever occurs first. |
| Adverse Events (AE) | From the inclusion in the study (signature of the informed consent form - ICF) until the first follow-up visit (up to approximately 5 months). | Percentage of Patients in Each Treatment Group with AEs, AEs with CTCAE grade ≥3 |
| Immune-related Adverse Events (irAEs) | From the inclusion in the study (signature of the informed consent form - ICF) until the end of follow-up (up to approximately 60 months). | Occurrence of immune-related Adverse Events (irAEs) |
| 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). | Number of patients with Drug-Induced Liver Injury (DILI) |
| 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). | Number of patients with Adverse Events of Special Interest (AESI) |
| 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 Subjects with Haematological/chemical Laboratory Abnormalities |
| 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) | Number of subjects with a clinically significant change from baseline in physical examination |
| 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) | Number of subject with concomitant medication |
| Human anti-fusion protein antibodies (HAFA) | 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. | Assessment of the formation of human anti-fusion protein antibodies (HAFA) against L19IL2 and L19TNF |
| Vital signs (blood pressure) | 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 (blood pressure) by visit |
| Vital signals (heart rate) | 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 |
| Vital signals (body temperature) | 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 |
| Pathological responses | Assessed at the time of surgical resection of the tumor lesions. | Pathological responses (categorized into pCR, near-pCR, pPR, pNR, according to INMC criteria) assessed at time of surgical resection. |
| Electrocardiogram (ECG) and echocardiogram (ECHO) abnormalities | 1) day 0-14 (screening) for both arm; 2) at week 5 (Safety assessment) only for arm 1. | 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Local recurrence-free survival (LRFS) and distant metastasis-free survival (DMFS) | 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 | Local recurrence-free survival (LRFS) and distant metastasis-free survival (DMFS) after randomization in the Daromun plus surgery and adjuvant therapy treatment group (Arm 1) versus surgery adjuvant therapy (Arm 2). LRFS is defined as survival free of loco-regional recurrence occurring at any time before systemic recurrence and other events are censored. DMFS is defined as survival free of systemic recurrence, including: 1) systemic recurrence outside the locoregional area at any time before or after locoregional relapse, 2) systemic recurrence with or without loco-regional relapse, or 3) death from cancer with no information on systemic recurrence. |
Countries
Spain, Switzerland, United States
Contacts
Primary ContactSheila Dakhel, PhD
Backup ContactConcetta Aulicino
Outcome results
None listed