The trial aims to evaluate the efficacy of single agent L19IL2, single agent L19TNF, and combination L19IL2+L19TNF given concurrently with anti-PD1 therapy compared to historical control of anti-PD-1 re-challenge alone for anti-PD1 refractory unresectable stage III-IV melanoma.
The participant (or legally acceptable representative if applicable) provides written informed consent for the trial.
Be > or = 18 years of age on day of signing informed consent.
Participant 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.
Has received at least 2 doses of an approved anti-PD-1/L1 mAb.
Patients 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.
Uveal melanoma or mucosal melanoma or melanoma with unknown primary.
A WOCBP who has a positive urine pregnancy test (within 72 hours) prior to treatment.
Has 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.
Parallel
L19IL2
DrugArm 1: The amount of L19IL2 that is intratumorally administered into injectable cutaneous, subcutaneous, and nodal tumors once weekly for up to 4 weeks is dependent on the size of the tumor. The maximum dose to be administered in a single treatment visit is 13 MioIU/1 mL of L19IL2.
L19TNF
DrugArm 2: The amount of L19TNF that is intratumorally administered into injectable cutaneous, subcutaneous, and nodal tumors once weekly for up to 4 weeks is dependent on the size of the tumor. The maximum dose to be administered in a single treatment visit is 400 μg/1 mL of L19TNF.
L19IL2/L19TNF
DrugArm 3: The amount of L19IL2/L19TNF that is intratumorally administered into injectable cutaneous, subcutaneous, and nodal tumors once weekly for up to 4 weeks is dependent on the size of the tumor. The maximum dose to be administered in a single treatment visit is 13MioIU L19IL2 + 400 μg L19TNF in a combined total volume of approximate 2 mL. In case that study drug-related, grade ≥ γ AEs are recorded after the first L19IL2/L19TNF dose administration, the L19TNF dose is reduced to 200 μg for the following administrations.
KEYTRUDA®
DrugKEYTRUDA® will be administered by i.v. infusion as a dose of 200 mg on the first day of intralesional treatment with ICKs and will continue every 3 weeks for approximately 2 years, 35 cycles, 2 year cap or until disease progression or unacceptable toxicity, whichever comes first. ICKs intralesional treatment will be administered 30-60 minutes post administration of KEYTRUDA®.
Confirmed Objective Response Rate (ORR)
Objective Response Rate (ORR = CR + PR) in all three arms to demonstrate the efficacy of intralesional treatment with immunocytokines (L19IL2, or L19TNF, or L19IL2/L19TNF), in combination with the systemic anti-PD1 pembrolizumab, to induce objective responses in advanced melanoma patients with resistance to or progressing upon anti-PD1 checkpoint inhibitors. The primary analysis will be performed in the Intention-to-Treat population (ITT). Assessed during Tumor Assessment (TA) visits.
Best overall response (BOR)
Best response recorded from the start of the treatment until disease progression/recurrence after first treatment according to RECIST v1.1 criteria
Duration of Response (DoR)
Time from first documented evidence of CR or PR until first documented disease progression or death due to any cause. DoR will be summarized descriptively using Kaplan-Meier medians and quartiles.
Pathological response
Histopathological analysis will be performed on biopsies obtained at baseline and at Week 18 for one target injected lesions. This is to determine: * Confirmation of melanoma metastasis( Biopsy at baseline) * Presence of residual tumor cells (%, biopsy at week 18), * Presence of Necrosis % (biopsy at week 18), * Presence of melanosis/fibrosis % (biopsy at weeks 18 after first treatment)
Confirmed ORR
Confirmed ORR over a period of up to 2 years after first intralesional treatment according to iRECIST and itRECIST criteria in each arm of the study
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Philogen S.p.A.
Lead sponsor
Merck Sharp & Dohme LLC
Collaborator
