Neoadjuvant L19IL2/L19TNF- Pivotal Study

NCT02938299 | Active Not Recruiting Phase 3 DMC

• 1 other identifier: PH-L19IL2TNF-02/15
• Study Type: interventional
• Target: 214
• Locations: 4 countries
• Sites: 22

Brief Summary

Phase III, open-label, randomized, controlled multi-center study of the efficacy of L19IL2/L19TNF neoadjuvant intratumoral treatment in Stage III B/C melanoma patients.

Conditions

Malignant Melanoma

Outcome Measures

Primary Outcomes (1)

• Recurrence-free survival (RFS) rate

  Recurrence-free survival (RFS) in the treatment arm (L19IL2/L19TNF plus surgery; Arm 1) versus control arm (Arm 2).

  1 year after randomization

Secondary Outcomes (9)

• Local recurrence-free survival (LRFS)

  1year, 2years, 3years after randomization and 1year after surgery

• Distant metastasis-free survival (DMFS) rate

  1year, 2years, 3years after randomization and 1year after surgery

• Recurrence-free survival (RFS) rate

  2years, 3years after randomization

• Overall survival (OS)

  1year, 2years, 3years after randomization

• Percentage of Participants With On-Study Adverse Events (AEs) and Serious Adverse Events (SAEs)

  up to 3 years

Study Arms (2)

Arm 1: neoadjuvant + surgery

EXPERIMENTAL

Patients in Arm 1 will receive multiple intratumoral administrations into all injectable cutaneous, subcutaneous, and nodal tumors of a mixture of L19IL2 and L19TNF once weekly for up to 4 weeks (or until all injectable tumors have disappeared, or intolerance to study treatment or in the opinion of the investigator immediate surgical resection or any other treatment for melanoma is warranted, whichever occurs first). Newly occurring injectable melanoma lesions within the 4 weeks treatment period will also be treated as described. Surgical resection of all existing metastases will follow within 4 weeks after end of treatment. Surgery will be performed after the safety evaluation carried out at week 5 and, if indicated, may be carried out on the same day of the safety evaluation.

Drug: L19IL2 + L19TNF; Procedure: Surgery

Arm 2: surgery alone

ACTIVE COMPARATOR

Patients in Arm 2 will receive directly surgical resection of melanoma tumor lesions within 4 weeks after randomization.

Procedure: Surgery

Interventions

L19IL2 + L19TNF DRUG

Mixture of L19IL2 and L19TNF once weekly

Arm 1: neoadjuvant + surgery

Surgery PROCEDURE

Surgical resection of melanoma tumor lesions

Arm 1: neoadjuvant + surgery; Arm 2: surgery alone

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• 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.
• 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.
• Males or females, age ≥ 18 years.
• ECOG Performance Status/WHO Performance Status ≤ 1.
• Life expectancy of at least 24 months (see paragraph 6.3.1).
• Absolute neutrophil count \> 1.5 x 109/L.
• Hemoglobin \> 9.0 g/dL.
• Platelets \> 100 x 109/L.
• Total bilirubin ≤ 30 µmol/L (or ≤ 2.0 mg/dl).
• ALT and AST ≤ 2.5 x the upper limit of normal (ULN).
• Serum creatinine \< 1.5 x ULN.
• LDH serum level ≤ 1.5 x ULN.
• 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.
• 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.

You may not qualify if:

• Uveal melanoma, mucosal melanoma or melanoma with unknown primary.
• Evidence of distant metastases at screening.
• 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.
• 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.
• History within the last year of acute or subacute coronary syndromes including myocardial infarction, unstable or severe stable angina pectoris.
• Inadequately controlled cardiac arrhythmias including atrial fibrillation.
• Heart insufficiency (\> Grade II, New York Heart Association (NYHA) criteria).
• LVEF ≤ 50% and/or abnormalities observed during baseline ECG and Echocardiogram investigations that are considered as clinically significant by the investigator.
• Uncontrolled hypertension.
• Ischemic peripheral vascular disease (Grade IIb-IV).
• Severe diabetic retinopathy.
• Active autoimmune disease.
• History of organ allograft or stem cell transplantation.
• Recovery from major trauma including surgery within 4 weeks prior to enrollment.
• Known history of allergy to IL2, TNF, or other human proteins/peptides/antibodies or any other constituent of the product.

Sponsors & Collaborators

• Philogen S.p.A.: lead

Study Sites (22)

Hôpital de la Timone

Marseille, 13 005, France

Location

Hôpital Universitaire de Nantes

Nantes, 44 093, France

Location

Institut Gustave Roussy

Villejuif, 94 805, France

Location

Universitätsklinikum Carl Gustav Carus an der Technischen Universität Dresden

Dresden, Dresden, D-01307, Germany

Location

Hauttumorzentrum Hannover (HTZH)

Hanover, Hannover, D-30625, Germany

Location

Heidelberg University Hospital

Heidelberg, Heidelberg, D-69120, Germany

Location

Kiel University Hospital

Kiel, Kiel, D-24105, Germany

Location

Leipzig University Hospital

Leipzig, Leipzig, D-04103, Germany

Location

Charité Campus Mitte (CCM)

Berlin, State of Berlin, D-10117, Germany

Location

Tübingen University Hospital

Tübingen, Tübingen, D-72076, Germany

Location

Klinik für Dermatologie und Allergologie, Universitätsklinikum Augsburg

Augsburg, 86156, Germany

Location

Klinik für Dermatologie, Medizinische Fakultät Universitätsklinikum Essen

Essen, 45122, Germany

Location

Klinik und Polyklinik für Dermatologie, Universitätsklinikum Regensburg

Regensburg, 93042, Germany

Location

IRCCS A.O.U. San Martino - IST

Genova, Genova, 16132, Italy

Location

Fondazione IRCCS Istituto Nazionale dei Tumori

Milan, Milan, 20133, Italy

Location

Istituto Oncologico Veneto, IRCCS

Padua, Padova, 35128, Italy

Location

Fondazione IRCCS Istituto Nazionale dei Tumori

Naples, 80131, Italy

Location

AOU Senese

Siena, 53100, Italy

Location

ASUGI Trieste

Trieste, 34128, Italy

Location

AOU Città della Salute e della Scienza

Turin, 10126, Italy

Location

Medgart Centrum Medyczne

Gdansk, 80-980, Poland

Location

Centrum Onkologii-Instytut im. Marii Skłodowskiej-Curie Warszawa

Warsaw, 02-781, Poland

Location

Related Publications (2)

• Kahler KC, Hassel JC, Ziemer M, Rutkowski P, Meier F, Flatz L, Gaudy-Marqueste C, Zimmer L, Santinami M, Russano F, von Wasielewski I, Eigentler TK, Maio M, Zalaudek I, Haferkamp S, Quaglino P, Welzel J, Rocken C, Enk A, Simon JC, Switaj T, Garzarolli M, Amaral T, Malissen N, Livingstone E, Elia G, Covelli A, Lorizzo K, Neri D, Mulatto S, Parca A, Pizzichi B, Ascierto PA, Garbe C, Robert C, Schadendorf D, Hauschild A. Neoadjuvant intralesional targeted immunocytokines (daromun) in stage III melanoma. Ann Oncol. 2025 Oct;36(10):1166-1177. doi: 10.1016/j.annonc.2025.06.014. Epub 2025 Jul 7.

  PMID: 40633690 DERIVED

• 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.

  PMID: 36648215 DERIVED

MeSH Terms

Conditions

Melanoma

Interventions

daromun; Surgical Procedures, Operative

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases

Study Officials

• Katharina C. Kähler, MD

  University Hospital Schleswig-Holstein

  PRINCIPAL INVESTIGATOR

• Mario Santinami, MD

  Istituto Nazionale Tumori Milano

  PRINCIPAL INVESTIGATOR

• Piotr Rutkowski, MD

  Centrum Onkologii-Instytut im. Marii Skłodowskiej-Curie Warszawa

  PRINCIPAL INVESTIGATOR

• Caroline Robert, MD

  Gustave Roussy, Cancer Campus, Grand Paris

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 11, 2016
• First Posted: October 19, 2016
• Study Start: July 1, 2016
• Primary Completion: October 1, 2024
• Study Completion (Estimated): December 1, 2028
• Last Updated: September 19, 2024

Record last verified: 2024-09

Data Sharing

• IPD Sharing: Will not share

Locations

FR (3); PL (2); IT (7); DE (10)