Melanoma Stage IIIB/C Clinical Trial
— NeoDREAMOfficial 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
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).
| Status | Recruiting |
| Enrollment | 186 |
| Est. completion date | June 2026 |
| Est. primary completion date | June 2024 |
| Accepts healthy volunteers | No |
| Gender | All |
| Age group | 18 Years and older |
| Eligibility | Inclusion Criteria: 1. Diagnosis of clinical stage IIIB and IIIC (AJCC v7) metastatic melanoma, 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. Males or females, age = 18 years. 4. ECOG Performance Status/WHO Performance Status = 1. 5. Life expectancy of > 24 months. 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 = 1.5 x ULN. 13. 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. 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 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). 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. 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, 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. 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 the same study. |
| Country | Name | City | State |
|---|---|---|---|
| Spain | Hospital Clinic Barcelona | Barcelona | |
| Spain | Hospital de la Santa Creu i Sant Pau | Barcelona | |
| Spain | Hospital Universitari Germans Trias i Pujol | Barcelona | |
| Spain | Hospital Universitari Vall d'Hebron | Barcelona | |
| Spain | Hospital Teresa Herrera | Coruña | |
| Spain | Hospital Universitario Donostia | Donostia | |
| Spain | HU Gran Canaria Doctor Negrin | Las Palmas De Gran Canaria | |
| Spain | Hospital Universitario 12 de Octubre | Madrid | |
| Spain | MD Anderson Madrid | Madrid | |
| Spain | Hospital Universitario Regional de Málaga | Málaga | |
| Spain | Hospital Clínico Universitario Virgen de la Arrixaca | Murcia | |
| Spain | Hospital Universitario Virgen Macarena | Sevilla | |
| Spain | Hospital General Universitario de Valencia | Valencia | |
| Switzerland | Universitätsspital Basel | Basel | |
| Switzerland | Istituto Oncologico della Svizzera Italiana | Bellinzona | |
| Switzerland | Universitätsspital Inselspital Bern | Bern | |
| Switzerland | Hôpitaux Universitaires de Genève | Genève | |
| Switzerland | Kantonsspital St.Gallen | Saint Gallen | |
| Switzerland | Universitätsspital Zürich (USZ) | Zürich | |
| United States | Winship Cancer Institute | Atlanta | Georgia |
| United States | Rush University Cancer Center - - 1750 W. Harrison Street, Jelke 601 | Chicago | Illinois |
| United States | Ohio State University Wexner Medical Center | Columbus | Ohio |
| United States | Duke University Medical Center - Duke Cancer Center | Durham | North Carolina |
| United States | St. Luke's Cancer Center, Clinical Trial, 3rd floor, 1600 St. Luke's Blvd. | Easton | Pennsylvania |
| United States | Penn State Cancer Institute | Hershey | Pennsylvania |
| United States | University of Iowa Hospitals and Clinics | Iowa City | Iowa |
| United States | UC San Diego Moores Cancer Center | La Jolla | California |
| United States | Rutgers Cancer Institute, 195 Little Albany Street | New Brunswick | New Jersey |
| United States | UC Irvine Health-Chao Family Comprehensive Cancer Center | Orange | California |
| United States | Fox Chase Cancer Center 333 Cottman Avenue | Philadelphia | Pennsylvania |
| United States | Mayo Clinic Hospital | Phoenix | Arizona |
| United States | Mayo Clinic | Rochester | Minnesota |
| United States | Huntsman Cancer Institute, University of Utah 2000 Circle of Hope | Salt Lake City | Utah |
| United States | Moffitt Cancer Center | Tampa | Florida |
| Lead Sponsor | Collaborator |
|---|---|
| Philogen S.p.A. |
United States, Spain, Switzerland,
| Type | Measure | Description | Time frame | Safety issue |
|---|---|---|---|---|
| Other | Local recurrence-free survival (LRFS) | LRFS after randomization in the Daromun plus surgery and adjuvant therapy treatment group (Arm 1) versus surgery and 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 | 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 | |
| Other | Distant metastasis-free survival (DMFS) | DMFS after randomization in the Daromun plus surgery and adjuvant therapy treatment group (Arm 1) versus surgery and adjuvant therapy (Arm 2). DMFS is defined as survival free of systemic recurrence, including: 1) systemic recurrence outside the locoregional area at any time before or after loco-regional relapse, 2) systemic recurrence with or without loco-regional relapse, or 3) death from cancer with no information on systemic recurrence | 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 | |
| Primary | 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 | 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. | |
| Secondary | 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. | |
| Secondary | 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 | |
| Secondary | 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). | |
| Secondary | 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). | |
| Secondary | 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). | |
| Secondary | 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). | |
| Secondary | 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). | ||
| Secondary | 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. | |
| Secondary | 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) | ||
| Secondary | 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) | |
| Secondary | 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. | |
| Secondary | 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). | |
| Secondary | 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) | ||
| Secondary | 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) |