A Phase II Study of Intratumoral Injection of LTX-315 in Combination With Pembrolizumab in Patients With Percutaneously Accessible Lesions With Advanced Melanoma Refractory to Pembrolizumab

Including patients who meet these criteria:

• Have 1 of the following confirmed histologically:

• Patients with Stage III A, B, C, or Stage IVm1a unresectable metastatic melanoma who have received an FDA approved anti-PD/PD-L1 therapy and have progressed after prior anti-PD-1 or anti-PD-L1 therapy, alone or in combination with systemic therapy.
• For patients who have refused prior standard-of-care treatment as indicated for their specific tumor type, the patient's reason for refusing standard therapy for their disease shall be clearly documented in the study electronic case report form prior to study participation.
• All patients must have received anti-PD-1 or anti-PD-L1 in addition to complying with the relevant criteria below (anti-PD-1 or anti-PD-L1 need not be the most recent line of therapy). Melanoma patients with BRAF (v-raf murine sarcoma viral oncogene homolog B1) mutation who are eligible and suitable for BRAF inhibitor therapy should have received specific BRAF inhibitor therapy before enrolling in this study. Patients who have refused BRAF inhibitor therapy are also eligible for the study.
• The patients should have had radiologically progressive disease after the most recent line of systemic therapy (no more than 3 prior lines).

Anti-PD-1 or anti-PD-L1 does not need to be the most recent line of therapy prior to study entry.

• Disease that is not amenable to further radiotherapy or surgery for cancer treatment.
• Have at least 1 superficial, nonvisceral tumor lesion accessible for injection via cutaneous, subcutaneous, or intramuscular route. Note, lymph nodes with metastatic disease may be selected for injection if they are superficial, but not if deep-seated; visceral lesions must not be selected for injection. The lesion must not be located close to airways, defined as close enough to jeopardize the patient's safety, in the opinion of the investigator, in the event of a local reaction to LTX-315 injection (for example, if such a reaction has the potential to interfere with swallowing or result in hemorrhaging into the airways). The size of the lesion(s) selected for injection must be ≥0.5 cm, and preferably ≤3 cm in the longest diameter. For larger lesions, approval from the sponsor and medical monitor is needed prior to enrollment.
• At least 1 measurable tumor lesion evaluable with a longest diameter ≥1.0 cm according to RECIST version 1.1 that is not planned to be injected with LTX-315. The location of this noninjected tumor may be superficial, deep-seated, or visceral.
• Have a life expectancy ≥3 months.
• Are males or females aged 18 years or older.
• Have an ECOG performance status of 0 or 1.
• Resolution of all disease or prior treatment-related toxicities to Grade <1, with the exception of alopecia, Grade 2 neuropathy and laboratory abnormalities (parameters below apply). If subject underwent major surgery or received radiation therapy, they must have recovered from the toxicity and/or complications from the intervention.
• Have a left ventricular ejection fraction that is above the institution's lower limit of normal (by echo scan assessment).
• Meet the following laboratory requirements:
• Are willing and able to comply with the protocol and agree to return to the clinical site for Follow up visits and examinations.
• Are willing to undergo tumor biopsy procedures.
• Are fully informed about the study and have signed the informed consent form.
• Are willing to use contraceptive measures as prescribed by the protocol. Female patients of childbearing potential and their partners who are sexually active must agree to the use of 2 highly effective forms of contraception starting from the screening visit, throughout their participation in the study, and for at least 120 days after their last dose of pembrolizumab or at least 180 days after their last dose of LTX-315, whichever is longer. Male patients with partners who are pregnant or of childbearing potential must use a barrier method of contraception starting from the screening visit, throughout their participation in the study and for at least 120 days after their last dose of pembrolizumab or at least 180 days after their last dose of LTX 315, whichever is longer. A woman is considered of childbearing potential, that is, fertile, following menarche and until becoming postmenopausal unless permanently sterile.
• Female patients must not be pregnant or breastfeeding. Female patients of childbearing potential must have a negative pregnancy test result during screening and at Day 1.

• Absolute neutrophil count ≥1.00 × 109/L
• Absolute lymphocyte count that is >0.5 k/µL or equivalent
• Platelet count ≥75.0 × 109/L
• Hemoglobin ≥9.0 g/dL
• Prothrombin time/partial thromboplastin time ≤ 1.5 x upper limit of normal (ULN), if the patient is receiving oral anticoagulation international normalized ratio ≤ 1.5 x ULN
• Total bilirubin ≤1.5 x ULN (≤2 x ULN if associated with hepatobiliary metastases or Gilbert's syndrome) AND associated to the aspartate aminotransferase (AST) and alanine aminotransferase (ALT) 2.5 x ULN (≤5 x ULN if liver metastases are present)
• AST and ALT ≤2.5 × ULN (≤5 × ULN if liver metastasis present or in case of hepatocellular carcinoma)
• Calculated creatinine clearance ≥30 mL/min using Cockcroft-Gault formula.

Excluding patients who meet these criteria:

• Subjects with primary ocular melanoma or mucosal melanoma are not eligible
• Excessive tumor burden, in the opinion of the investigator.
• Known bone-only or active central nervous system metastases and/or carcinomatous meningitis.
• Subjects with untreated brain metastases ≤3 mm that are asymptomatic, do not have significant edema, and do not require steroids or anti-seizure medications are eligible after discussion with the medical monitor. Subjects with previously treated brain metastases may participate provided they are stable after treatment and without evidence of progression by imaging for at least 4 weeks prior to the first dose of study drug administration, and are not using corticosteroids for at least 7 days prior to study drug administration
• Have a history of cerebrovascular or cardiac disorders (eg, Class III or IV New York Heart Association cardiac failure) and in the investigators' opinion the patient would be at particular risk of sequelae following a short hypotensive episode.
• Have a marked baseline prolongation of QT interval corrected for heart rate using Fridericia's formula (eg, repeated demonstration of a QTc interval >480 ms [National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Grade 1]).
• Are currently taking immunosuppressive agents or use of systemic corticosteroids or other systemic immunosuppressive drugs within 28 days prior to study drug administration (see Appendix 4 for examples). Patients who require corticosteroids should have been on a stable dose (up to 10 mg daily prednisone or equivalent) for at least 2 weeks prior to study drug administration. Topical and inhaled corticosteroids are also permitted.
• Have a history of systemic autoimmune disease requiring anti-inflammatory or immunosuppressive therapy within 3 months prior to Day 1, with the following exceptions:
• Patients with a history of autoimmune thyroiditis are eligible provided the patient requires only thyroid hormone replacement therapy and disease has been stable for ≥1 year.
• Patients with well-controlled type I diabetes (in the opinion of the investigator) are eligible.
• Patients with a history of chronic disease, who have been stable for the preceding 6 months without treatment
• Patients who are allergic or have hypersensitivity to chlorpheniramine or equivalent H1 antagonist, cimetidine or equivalent H2 antagonist, or montelukast.
• Have a history of severe hypersensitivity to another monoclonal antibody; are receiving immunosuppressive therapy; have a history of severe immune-related adverse reaction from treatment with a monoclonal antibody, defined as any Grade ≥3 toxicity requiring corticosteroid treatment (>10 mg/day prednisone or equivalent) for >12 weeks.
• Have had (non-infectious) pneumonitis Grade ≥3 in the past or current pneumonitis.
• History of interstitial lung disease.
• Have a known hypersensitivity to pembrolizumab or LTX-315 or any of their excipients (for pembrolizumab those listed in the SmPC).
• Have any other serious illness or medical condition, such as, but not limited to:
• Have received external radiotherapy or cytotoxic chemotherapy within 4 weeks prior to Day 1 or have not recovered (to NCI-CTCAE Grade ≤1; alopecia of any grade is allowed, and peripheral neuropathy of up to Grade 2 is allowed) from adverse events (AEs) due to such agents being administered more than 4 weeks prior to Day 1. Palliative radiotherapy to nontarget lesions within 4 weeks prior to Day 1 is allowed.
• Have received cancer immunotherapy within 4 weeks prior to Day 1 or have not recovered from AEs (to NCI-CTCAE Grade ≤1) due to such agents being administered more than 4 weeks prior to Day 1.
• Have received an investigational drug within 4 weeks prior to Day 1 or are scheduled to receive 1 during the treatment or post-treatment periods.
• Are expected to need any other anticancer therapy or immunotherapy to be initiated during the study period.

• Uncontrolled infection or infection requiring systemic antibiotics
• Uncontrolled cardiac failure: Class III or IV New York Heart Association
• Uncontrolled hypertension > or risk factors for uncontrolled hypertension (>160 mmHg systolic and/or >100 mmHg diastolic), despite appropriate antihypertensive medication
• Uncontrolled systemic or gastrointestinal inflammatory conditions
• Known bone marrow dysplasia
• History of positive tests for HIV/acquired immunodeficiency syndrome or active hepatitis B or C (based on serology); positive serology will be confirmed by a viral load test. Patients with treated HIV and a viral load test result consistent with treated HIV, as well as patients with treated hepatitis B or C with an undetectable viral load test result, are eligible.
• History of or current mastocytosis.