Phase 1b/2 Clinical Trial to Evaluate the Safety and Efficacy of Combination Therapy With Pembrolizumab and Irinotecan in Patients With Metastatic or Recurrent Malignant Melanoma

Inclusion Criteria:

1. Patients with histologically confirmed non-uveal melanoma, diagnosed as Stage IV or unresectable Stage III melanoma.
2. Age ≥19 years at the time of signing the informed consent form.
3. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
4. Patients must be treatment-naïve in the metastatic or unresectable setting (first-line setting) and meet at least one of the following criteria:

   A. No prior systemic therapy in the metastatic or unresectable setting. B. Patients who previously received pembrolizumab or other immune checkpoint inhibitors (ICIs) as adjuvant therapy, and subsequently experienced relapse or metastasis ≥6 months (180 days) after the last dose, provided that no additional systemic therapy was administered after recurrence in the metastatic setting.
5. Patients with CNS metastases must have stable neurological function without evidence of CNS progression within 4 weeks prior to enrollment (i.e., treated/controlled or asymptomatic CNS metastases, or resected CNS metastases without radiographic evidence of disease).
6. Female subjects of childbearing potential must have a negative serum or urine pregnancy test during the screening period. If the urine test result is positive or inconclusive, a serum pregnancy test must be performed.
7. Patients must have measurable disease per RECIST v1.1 (lesions previously irradiated may be considered measurable if disease progression at the site is documented).
8. Adequate organ function as defined below:

Table 2. Organ Function Requirements Hematological Absolute neutrophil count (ANC) ≥1,500/μL Platelets ≥100,000/μL Hemoglobin ≥9.0 g/dL or ≥5.6 mmol/L Renal Serum creatinine ≤1.5 × ULN or If creatinine \>1.5 × ULN: creatinine clearance (CrCl) ≥40 mL/min (GFR may be used in place of creatinine or CrCl) Hepatic Total bilirubin ≤1.5 × ULN or If total bilirubin \>1.5 × ULN: direct bilirubin ≤ ULN (Exception: Gilbert's syndrome - total bilirubin \<3 × ULN and ALT \<3 × ULN) AST (SGOT) and ALT (SGPT) ≤2.5 × ULN (≤5 × ULN in patients with hepatic metastasis) Coagulation International normalized ratio (INR) or prothrombin time (PT), and activated partial thromboplastin time (aPTT) ≤1.5 × ULN, unless the subject is receiving anticoagulant therapy, in which case PT or aPTT must be within the therapeutic range of intended anticoagulation.

Exclusion Criteria:

1. Female subjects of childbearing potential (WOCBP) with a positive urine pregnancy test within 72 hours prior to study enrollment (see Appendix 3). If the urine test is positive or inconclusive, a serum pregnancy test must be performed.
2. Receipt of radiotherapy within 2 weeks prior to initiation of study intervention. Subjects must have recovered from all radiation-related toxicities, not require corticosteroids, and have no evidence of radiation pneumonitis. For palliative radiotherapy to non-CNS disease (\<2 weeks duration), a 1-week washout period is permitted.
3. Receipt of a live or live-attenuated vaccine within 30 days prior to the first dose of study drug. Inactivated vaccines are allowed.
4. Participation in another clinical study or receipt of systemic therapy (e.g., cytotoxic chemotherapy, immunotherapy, or investigational agents) within 4 weeks prior to the first dose of study intervention.
5. Diagnosis of immunodeficiency, or receipt of chronic systemic steroid therapy (\>10 mg/day prednisone equivalent) or other immunosuppressive therapy within 7 days prior to the first dose.

   In addition, subjects with a history of autoimmune disease requiring systemic treatment (e.g., disease-modifying agents, corticosteroids, immunosuppressants) within the past 2 years are excluded.

   Exceptions include physiologic replacement therapy (e.g., thyroxine, insulin, or corticosteroid replacement for adrenal or pituitary insufficiency), which are permitted.
6. Presence of another active malignancy or malignancy requiring treatment within the past 3 years.

   Exceptions include adequately treated basal cell carcinoma, squamous cell carcinoma of the skin, or carcinoma in situ (except carcinoma in situ of the bladder).
7. Symptomatic CNS metastases or carcinomatous meningitis. Subjects with previously treated CNS metastases may participate if they are radiographically stable (no progression for ≥4 weeks on repeat imaging during screening), clinically stable, and do not require steroid treatment for at least 14 days prior to the first dose.
8. Known severe hypersensitivity (≥ Grade 3) to pembrolizumab.
9. History of (non-infectious) pneumonitis/interstitial lung disease requiring steroids, or current pneumonitis/interstitial lung disease.
10. Active infection requiring systemic therapy.
11. Active hepatitis B (HBsAg positive and/or detectable HBV DNA) or hepatitis C infection (anti-HCV positive with detectable HCV RNA).
12. Any medical condition or evidence of disease that may confound study results or interfere with study participation, as judged by the investigator.
13. Psychiatric or substance abuse disorders that would interfere with compliance with study requirements.
14. Subjects who are pregnant, breastfeeding, or planning to become pregnant or father a child during the study period, from screening through 120 days after the last dose of study treatment.
15. History of allogeneic tissue or solid organ transplantation.
16. Concomitant use of strong CYP3A4 inducers (e.g., rifampin, phenytoin, carbamazepine, phenobarbital, St. John's Wort) or strong CYP3A4 inhibitors (e.g., clarithromycin, grapefruit juice, itraconazole, ketoconazole, posaconazole, telithromycin, voriconazole).
17. QTc interval \>450 ms (male) or \>470 ms (female), or history of congenital long QT syndrome or Torsades de pointes (TdP).
18. Patients with UGT1A1 poor metabolizer genotype (e.g., \*28/\*28, \*6/\*6, \*6/\*28) or other clinically significant reduced-function UGT1A1 variants identified at screening (based on medical records or external test results) will be excluded in this study.