PEMBROLIZUMAB for Unresectable stage III/IV metastatic melanoma

Inclusion criteria

• {"criterion_text":"- 1. >18 years of age on day of signing informed consent; 2. 3.\tParticipant with histologically or cytologically confirmed diagnosis of unresectable metastatic melanoma at stage III B, C, D or IV M1a (AJCC 8th ed.). Patients with Stage IVM1b, M1c and M1d oligometastatic disease [up to 10 visceral lesions in aggregate including lung, liver, bone or brain, with or without lymph node involvement], are eligible. However, patients with symptomatic or rapidly enlarging/bleeding brain lesions are excluded. Patients with acral lentiginous melanoma are eligible as well. Detailed information about prior therapies and burden of disease at study entry must be available."}
• {"criterion_text":"- 13.\tAll acute toxic effects (excluding alopecia and vitiligo) of any prior therapy must have resolved to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) (v. 5.0) Grade ≤ 1 or baseline unless otherwise specified above. Note: Participants with ≤Grade 2 neuropathy may be eligible. Participants with endocrine-related AEs Grade ≤2 requiring treatment or hormone replacement may be eligible. Note: If the participant had major surgery, the participant must have recovered adequately from the procedure and/or any complications from the surgery before starting study intervention"}
• {"criterion_text":"- 14.\tFull resolution of checkpoint blockade therapy-related adverse effects (including immune-related adverse effects) and no treatment for these AEs for at least 4 weeks before the time of enrollment."}
• {"criterion_text":"- 15.\tNo history of severe immune related adverse effects from prior given immune checkpoint blockade therapy (CTCAE Grade 4; CTCAE Grade 3 requiring treatment >4 weeks)."}
• {"criterion_text":"- 16.\tMale 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. In addition, male participant must refrain from sperm donation during the treatment period."}
• {"criterion_text":"- 17.\tWillingness and ability to comply with the scheduled visits, treatment plan, laboratory tests and other study procedures"}
• {"criterion_text":"- 4.\tPatients must have confirmed primary resistance to or acquired resistance on treatment with an anti-PD1/L1 monoclonal antibody (mAb) administered either as monotherapy, or in combination with other checkpoint inhibitors or other therapies. PD-1 treatment progression is defined by meeting all of the following criteria: a.\tHas received at least 2 doses of an approved anti-PD-1/L1 mAb. b.\tHas demonstrated disease progression (PD) after PD-1/L1 as defined by RECIST v1.1. The initial evidence of PD is to be confirmed by a second assessment no less than four weeks from the date of the first documented PD, in the absence of rapid clinical progression. c.\tProgressive disease has been documented within 12 weeks from the last dose of anti-PD-1/L1 mAb. i.\tProgressive disease is determined according to iRECIST. ii.\tThis determination is made by the investigator. Once PD is confirmed, the initial date of PD documentation will be considered the date of disease progression. Primary resistance is defined in Table 4 (reproduced from [2]. Recommendations of the Society for Immunotherapy of Cancer - Immunotherapy Resistance Taskforce)"}
• {"criterion_text":"- 5.\tPatients harboring the BRAF mutation who received BRAF/MEK inhibition (or declined BRAF/MEK inhibitors) and received thereafter anti-PD1 therapy showing resistance to such immunotherapy are eligible to the study"}
• {"criterion_text":"- 6.\tEligible subjects must have measurable disease (according to RECIST v1.1) as assessed by the local site investigator/radiology. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions. Eligible subjects must be candidates for intralesional therapy with at least one injectable cutaneous, subcutaneous, or nodal metastatic melanoma lesion (≥ 5 mm in longest diameter) or multiple injectable lesions that in aggregate have a diameter of ≥ 5 mm"}
• {"criterion_text":"- 9.\tHave an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1."}
• {"criterion_text":"- 10.\tHave adequate organ function as defined in table (Table 5). Specimens must be collected within 14 days prior to the start of study treatment"}
• {"criterion_text":"- 11.\tBe able to provide a core or excisional lymph node biopsy for biomarker analysis from an archival or newly obtained biopsy at Screening. In addition, participants may provide additional biopsy at Week 18 and at the time of discontinuation due to progression."}
• {"criterion_text":"- 12.\tDocumented 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) a negative serum HBV-DNA test is also required."}
• {"criterion_text":"- 7.\tA female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies: a.) Not a woman of childbearing potential (WOCBP) b.) A WOCBP who agrees to follow contraceptive guidance during the treatment period and for at least 120 days after the last dose of study treatment. WOCBP must be using for the time period indicated 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 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)"}

Exclusion criteria

• {"criterion_text":"- 1.\tPatients with more than 10 distant melanoma lesions in lung, liver, bone or brain combined. Patients with symptomatic or rapidly enlarging/bleeding brain lesions are excluded"}
• {"criterion_text":"- 12.\tHas known active CNS metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable, i.e., without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of study treatment."}
• {"criterion_text":"- 13.\tHas severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients, or to (immuno)cytokines IL2, TNF and/or any of its excipients"}
• {"criterion_text":"- 14.\tHas an active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed. 15.\tHas a history of (non-infectious) pneumonitis / interstitial lung disease that required steroids or has current pneumonitis / interstitial lung disease"}
• {"criterion_text":"- 16.\tHas an active infection requiring systemic therapy. 17.\tHas a history or current evidence of any condition, therapy, or laboratory abnormality, or other circumstance that might confound the results of the study or interfere with the participant's participation for the full duration of the study, such that it is not in the best interest of the participant to participate, in the opinion of the treating investigator. 18.\tHas a known psychiatric or substance abuse disorder that would interfere with the participant’s ability to cooperate with the requirements of the study. 19.\tPrevious enrolment and randomization in this same study"}
• {"criterion_text":"- 2.\tUveal melanoma or mucosal melanoma or melanoma with unknown primary"}
• {"criterion_text":"- 3.\tA WOCBP who has a positive urine pregnancy test (within 72 hours) prior to treatment. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required."}
• {"criterion_text":"- 4.\tHas received prior therapy with an anti-PD-1, anti-PD-L1, and was discontinued from that treatment due to a Grade 3 or higher irAE"}
• {"criterion_text":"- 5.\tHas received prior systemic anti-cancer therapy including investigational agents or has used an investigational device within 4 weeks prior to the first dose of study treatment"}
• {"criterion_text":"- 6.\tHas received prior radiotherapy within 2 weeks of start of study treatment or have had a history of radiation pneumonitis. Note: Participants must have recovered from all radiation-related toxicities and not require corticosteroids. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease"}
• {"criterion_text":"- 7.\tHas undergone prior allogeneic hematopoietic stem cell transplantation within the last 5 years. (Participants who have had a transplant greater than 5 years ago are eligible as long as there are no symptoms of GVHD). 8.\tHas had an allogeneic tissue/solid organ transplant. 9.\tHas received live or live attenuated vaccines within 30 days prior to the first dose of study treatment and while participating in the study. Note: Killed vaccines are allowed"}
• {"criterion_text":"- 10.\tHas a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of study drug."}
• {"criterion_text":"- 11.\tHas a known additional malignancy that is progressing or has required active treatment within the past two (2) years. Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, superficial bladder tumors (Ta, Tis & T1), second primary melanoma in situ, or carcinoma in situ, that have undergone potentially curative therapy are not excluded."}

Primary endpoints

• {"endpoint_text":"- Primary endpoint of the study is the Confirmed Objective Response Rate (ORR = CR + PR) over a period of up to 2 years after first intralesional treatment, according to RECIST v1.1 criteria in each arm of the study. The primary analysis will be performed in the Intention-to-Treat population (ITT).","definition_or_measurement_approach":"Confirmed Objective Response Rate (ORR = CR + PR) assessed according to RECIST v1.1 over up to 2 years after first intralesional treatment; primary analysis in the Intention-to-Treat (ITT) population."}

Germany

Earliest CTIS Part Ii Submission Date

15-12-2025

Latest Decision Or Authorization Date

15-01-2026

Processing Time Days

31

Number Of Sites

4

Number Of Participants

40

Italy

Earliest CTIS Part Ii Submission Date

23-10-2025

Latest Decision Or Authorization Date

14-01-2026

Processing Time Days

83

Number Of Sites

1

Number Of Participants

25

Primary sponsor

Full Name

Philogen S.p.A.

Organisation Type

Pharmaceutical company

Country Of Registered Address

Italy