Neoadjuvant L19IL2/L19TNF- Pivotal Study

NCT ID: NCT02938299

Last Updated: 2024-09-19

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE3
• Total Enrollment: 214 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-07-01
• Study Completion Date: 2028-12-31

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.

Detailed Description

Phase III, open-label, randomized, controlled multi-center study. In the study, 214 patients will be enrolled and parallel assigned (via automated randomization system) in a 1:1 fashion to one of two different arms:

ARM 1:

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). The whole volume of L19IL2/L19TNF will be distributed among all injectable lesions.

Newly occurring injectable melanoma lesions within the 4 weeks treatment period will also be treated as described. For the new lesions the treatment period will not be extended beyond the pre-defined 4 week- treatment period with a clock start at the time of the first intralesional L19IL2/L19TNF injection. 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.

Post-surgery EMA-approved adjuvant therapy is allowed at discretion of the treating physician.

ARM 2:

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

Post-surgery EMA-approved adjuvant therapy is allowed at discretion of the treating physician.

Patients will be followed on a regular basis for the primary outcome until 36 months from randomization and up to 60 months for overall survival.

Expected patient enrollment interval: 60 months. Duration of individual patient's participation: up to 60 months. End of treatment corresponds to the day of surgery for patients randomized to both Arm 1 and Arm 2.

End of study corresponds to the last patient last visit (LPLV). The final primary efficacy analysis will be conducted when the 95th recurrence event is observed.

Conditions

Malignant Melanoma

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Arm 1: neoadjuvant + surgery

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.

Group Type: EXPERIMENTAL

L19IL2 + L19TNF

Intervention Type: DRUG

Mixture of L19IL2 and L19TNF once weekly

Surgery

Intervention Type: PROCEDURE

Surgical resection of melanoma tumor lesions

Arm 2: surgery alone

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

Group Type: ACTIVE_COMPARATOR

Surgery

Intervention Type: PROCEDURE

Surgical resection of melanoma tumor lesions

Interventions

L19IL2 + L19TNF

Mixture of L19IL2 and L19TNF once weekly

Intervention Type: DRUG

Surgery

Surgical resection of melanoma tumor lesions

Intervention Type: PROCEDURE

Eligibility Criteria

Inclusion Criteria

1. 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.

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.

4. Males or females, age ≥ 18 years.

5. ECOG Performance Status/WHO Performance Status ≤ 1.

6. Life expectancy of at least 24 months (see paragraph 6.3.1).

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 (e.g., anti-HBsAg and/or anti-HBc 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. Negative pregnancy test at screening for Women Of Childbearing Potential (WOCBP*). Pregnant women are not allowed to participate to this study. 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 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.

• Women of childbearing potential are defined as females who have experienced menarche, are not postmenopausal (12 months with no menses without an alternative medical cause) and are not permanently sterilized (e.g., tubal occlusion, hysterectomy, bilateral oophorectomy or bilateral salpingectomy).

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 this same study.

Exclusion Criteria

1. Uveal melanoma, mucosal melanoma or melanoma with unknown primary.

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Philogen S.p.A.

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Katharina C. Kähler, MD

Role: PRINCIPAL_INVESTIGATOR

University Hospital Schleswig-Holstein

Mario Santinami, MD

Role: PRINCIPAL_INVESTIGATOR

Istituto Nazionale Tumori Milano

Piotr Rutkowski, MD

Role: PRINCIPAL_INVESTIGATOR

Centrum Onkologii-Instytut im. Marii Skłodowskiej-Curie Warszawa

Caroline Robert, MD

Role: PRINCIPAL_INVESTIGATOR

Gustave Roussy, Cancer Campus, Grand Paris

Locations

Hôpital de la Timone

Marseille, , France

Hôpital Universitaire de Nantes

Nantes, , France

Institut Gustave Roussy

Villejuif, , France

Universitätsklinikum Carl Gustav Carus an der Technischen Universität Dresden

Dresden, Dresden, Germany

Hauttumorzentrum Hannover (HTZH)

Hanover, Hannover, Germany

Heidelberg University Hospital

Heidelberg, Heidelberg, Germany

Kiel University Hospital

Kiel, Kiel, Germany

Leipzig University Hospital

Leipzig, Leipzig, Germany

Charité Campus Mitte (CCM)

Berlin, State of Berlin, Germany

Tübingen University Hospital

Tübingen, Tübingen, Germany

Klinik für Dermatologie und Allergologie, Universitätsklinikum Augsburg

Augsburg, , Germany

Klinik für Dermatologie, Medizinische Fakultät Universitätsklinikum Essen

Essen, , Germany

Klinik und Polyklinik für Dermatologie, Universitätsklinikum Regensburg

Regensburg, , Germany

IRCCS A.O.U. San Martino - IST

Genova, Genova, Italy

Fondazione IRCCS Istituto Nazionale dei Tumori

Milan, Milan, Italy

Istituto Oncologico Veneto, IRCCS

Padua, Padova, Italy

Fondazione IRCCS Istituto Nazionale dei Tumori

Naples, , Italy

AOU Senese

Siena, , Italy

ASUGI Trieste

Trieste, , Italy

AOU Città della Salute e della Scienza

Turin, , Italy

Medgart Centrum Medyczne

Gdansk, , Poland

Centrum Onkologii-Instytut im. Marii Skłodowskiej-Curie Warszawa

Warsaw, , Poland

Countries

France; Germany; Italy; Poland

References

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.

Reference Type: DERIVED

PMID: 40633690 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 36648215 (View on PubMed)

Other Identifiers

PH-L19IL2TNF-02/15

Identifier Type: -

Identifier Source: org_study_id