Efficacy of Daromun Neoadjuvant Intratumoral Treatment in Clinical Stage IIIB/C/D Melanoma Patients
NCT ID: NCT03567889
Last Updated: 2025-12-17
Study Results
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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RECRUITING
PHASE3
186 participants
INTERVENTIONAL
2018-09-20
2031-12-31
Brief Summary
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Detailed Description
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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.
Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
NONE
Study Groups
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Daromun plus Surgery and Adjuvant therapy
Arm-1 patients will follow these steps:
1. screening period,
2. 4-week open-label treatment period,
3. surgery within a maximum of 4 weeks,
4. adjuvant therapy.
Daromun
Patients will receive intratumoral administrations into injectable cutaneous, subcutaneous, and nodal tumors of Daromun once weekly for up to 4 weeks.
Surgery
Patients will receive surgery.
Adjuvant therapy
Patients will receive adjuvant therapy at the investigator's discretion following the surgery.
Surgery and adjuvant therapy
Arm-2 patients will follow these steps:
1. Screening period,
2. direct surgery within 4 weeks from randomization,
3. adjuvant therapy.
Surgery
Patients will receive surgery.
Adjuvant therapy
Patients will receive adjuvant therapy at the investigator's discretion following the surgery.
Interventions
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Daromun
Patients will receive intratumoral administrations into injectable cutaneous, subcutaneous, and nodal tumors of Daromun once weekly for up to 4 weeks.
Surgery
Patients will receive surgery.
Adjuvant therapy
Patients will receive adjuvant therapy at the investigator's discretion following the surgery.
Eligibility Criteria
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Inclusion Criteria
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
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.
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.
18 Years
ALL
No
Sponsors
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Philogen S.p.A.
INDUSTRY
Responsible Party
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Locations
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Mayo Clinic Hospital
Phoenix, Arizona, United States
UC San Diego Moores Cancer Center
La Jolla, California, United States
UC Irvine Health-Chao Family Comprehensive Cancer Center
Orange, California, United States
Moffitt Cancer Center
Tampa, Florida, United States
Winship Cancer Institute, Emory university
Atlanta, Georgia, United States
Rush University Medical Center
Chicago, Illinois, United States
University of Iowa Hospitals and Clinics
Iowa City, Iowa, United States
Mayo Clinic
Rochester, Minnesota, United States
Rutgers Cancer Institute, 195 Little Albany Street
New Brunswick, New Jersey, United States
Ambulatory Care Center at NYC Langarone Health
New York, New York, United States
Memorial Sloan Kettering Cancer Center - Main Campus
Ney York, New York, United States
Duke University Medical Center - Duke Cancer Center
Durham, North Carolina, United States
Ohio State University Wexner Medical Center
Columbus, Ohio, 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
Fox Chase Cancer Center 333 Cottman Avenue
Philadelphia, Pennsylvania, United States
The University of Texas M.D. Anderson Cancer Center
Houston, Texas, United States
Huntsman Cancer Institute, University of Utah 2000 Circle of Hope
Salt Lake City, UT, Utah, United States
VCU - McGlothlin Medical Education Center
Richmond, Virginia, United States
Hospital Universitari Germans Trias i Pujol
Badalona, Barcelona, Spain
Hospital de la Santa Creu i Sant Pau
Barcelona, Barcelona, Spain
Fir Huvh Fundacio Institut De Recerca Hospital Universitari Vall De Hebron
Barcelona, Barcelona, Spain
Hospital Clinic Barcelona
Barcelona, Barcelona, Spain
El Hospital Universitario De Gran Canaria Dr. Negrin
Las Palmas de Gran Canaria, Canarie, Spain
Fundacion Onkologikoa Fundazioa
Donostia / San Sebastian, Gipuzkoa, Spain
MD Anderson Cancer Center
Madrid, Madrid, Spain
Hospital Universitario 12 de Octubre
Madrid, Madrid, Spain
Hospital Universitario Regional de Málaga
Málaga, Malaga, Spain
Hospital Clínico Universitario Virgen de la Arrixaca
Murcia, Murcia, Spain
Hospital Universitario Virgen De La Macarena
Seville, Sevilla, Spain
Hospital General Universitario de Valencia
Valencia, , Spain
Universitätsspital Basel
Basel, Basel, Switzerland
Istituto Oncologico della Svizzera Italiana
Bellinzona, Bellinzona, Switzerland
Insel Gruppe AG
Bern, Canton of Bern, Switzerland
Hôpitaux Universitaires de Genève
Geneva, Canton of Geneva, Switzerland
Kantonsspital St.Gallen
Sankt Gallen, Canton of St. Gallen, Switzerland
Universitätsspital Zürich (USZ)
Zurich, Canton of Zurich, Switzerland
Countries
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Central Contacts
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Facility Contacts
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Mahesh Seetharam, MD
Role: primary
Jonathan Zager
Role: primary
Michael Lowe
Role: primary
Anastasios Dimou, MD
Role: primary
Adam Berger
Role: primary
Danielle Bello
Role: primary
Georgia Beasley
Role: primary
Claire Verschraegen
Role: primary
Joseph Drabick
Role: primary
Jeffrey Farma
Role: primary
Hussein Tawbi
Role: primary
John Hyngstrom
Role: primary
Andrew Poklepovic
Role: primary
Cristina Mangas
Role: primary
Nikolaus Wagner
Role: primary
Egle Ramelyte
Role: primary
References
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Gorry C, McCullagh L, O'Donnell H, Barrett S, Schmitz S, Barry M, Curtin K, Beausang E, Barry R, Coyne I. Neoadjuvant treatment for stage III and IV cutaneous melanoma. Cochrane Database Syst Rev. 2023 Jan 17;1(1):CD012974. doi: 10.1002/14651858.CD012974.pub2.
Miura JT, Zager JS. Neo-DREAM study investigating Daromun for the treatment of clinical stage IIIB/C melanoma. Future Oncol. 2019 Nov;15(32):3665-3674. doi: 10.2217/fon-2019-0433. Epub 2019 Sep 20.
Other Identifiers
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2023-507119-36-00
Identifier Type: CTIS
Identifier Source: secondary_id
PH-L19IL2TNF-01/18
Identifier Type: -
Identifier Source: org_study_id