Neoadjuvant L19IL2/L19TNF- Pivotal study

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Philogen S.p.A.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

25 Feb 2016 → ongoing

Decision date (initial)

2024-08-05

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Philogen S.p.A.

External identifiers

EU CT number

2024-515749-40-00

EudraCT number

2015-002549-72

ClinicalTrials.gov

NCT02938299

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy

Efficacy of L19IL2/L19TNF neoadjuvant treatment followed by surgery to improve in a statistically significant manner the recurrence-free survival (RFS) of patients with locally advanced and fully resectable melanoma with respect to surgery alone: post-surgery adjuvant treatment is allowed in both arms.

Secondary objectives 3

1. Secondary objective of the study is to demonstrate that a neoadjuvant L19IL2/L19TNF treatment followed by surgery improves in a statistically significant manner the overall survival (OS) of patients with fully resectable locally advanced melanoma with respect to surgery.
2. Demonstration of improvement of local recurrence-free survival (LRFS) and distant metastasis-free survival (DMFS)
3. For patients included in Arm 1 only, pathological responses (i.e., pathological Complete Response, pathological near-Complete Response, pathological Partial Response, pathological Non Response) assessed on the surgical specimen after tumor removal, as well as demonstration of safety and tolerability of the L19IL2/L19TNF treatment

Conditions and MedDRA coding

Malignant melanoma of the skin in patients with locally advanced and fully resectable melanoma with/without prior therapy and presence of injectable cutaneous and/or subcutaneous or nodal lesions

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 19

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
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). 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).
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 22

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
17. Anti-tumor therapy (except allowed treatments listed at point 3 of Inclusion criteria) within 4 weeks before enrollment
18. Previous in vivo exposure to monoclonal antibodies for biological therapy (except allowed treatments listed at point 3 of Inclusion criteria) in the 6 weeks before enrollment
19. Planned administration of growth factors or immunomodulatory agents (except allowed treatments listed at point 3 of Inclusion criteria) 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 this same study

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

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

Secondary endpoints 6

1. Overall survival (OS) in the treatment arm (L19IL2/L19TNF plus surgery; Arm 1) versus control arm (surgery; Arm 2)
2. Local recurrence-free survival (LRFS) and distant metastasis-free survival (DMFS) in the treatment arm (L19IL2/L19TNF plus surgery - Arm 1) versus control arm (Arm 2)
3. Proportion of patients with pathological responses (defined as the proportion of patients with a pathological CR, pathological near-CR, or pathological PR)
4. Safety of intratumoral administration of L19IL2/L19TNF
5. Biomarker studies (both arms): immunophenotypic characterization of PBMCs for changes in absolute counts and relative percentages of lymphocytic subpopulations (e.g., Tregs, MDSCs etc.) over time (only for patients recruited in German centers; the data will be collected for at least 50 patients). Study of blood biomarkers
6. Assessment of the formation of human anti-fusion protein antibodies (HAFA) against L19IL2 and L19TNF

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Philogen S.p.A.

Sponsor organisation

Philogen S.p.A.

Address

Piazza La Lizza 7

City

Siena

Postcode

53100

Country

Italy

Scientific contact point

Organisation

Philogen S.p.A.

Contact name

Giuliano Elia

Public contact point

Organisation

Philogen S.p.A.

Contact name

Giuliano Elia

Third parties 6

Locations

4 EU/EEA countries · 22 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 24 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

5 submissions — initial application plus substantial / non-substantial modifications