• Age 18 years or older

• Patients must have a histologically or cytologically confirmed diagnosis of locally advanced unresectable or metastatic disease that is relapsed/refractory to standard therapy or for which no effective standard therapy is available, including

∙ Malignant Melanoma (MM)

⁃ Patients who have progressed after a minimum of 2 doses of a PD-1/PD-L1 treatment. Study enrollment (C1D1) must be within 12 weeks of the last dose of the anti-PD-1/PD-L1 blocking antibody

• Patients must have had prior testing for BRAF V600 mutations. Patients with BRAF V600 activating mutation must have received prior therapy with a BRAF/MEK inhibitor

• Uveal and mucosal melanoma are excluded

‣ Head and Neck squamous cell carcinoma (HNSCC)

⁃ HNSCC of oral cavity, oropharynx, hypopharynx, or larynx

• Patients who have progressed after a minimum of 2 doses of a PD-1/PD-L1 treatment. Study enrollment (C1D1) must be within 12 weeks of the last dose of the anti-PD-1/PD-L1 blocking antibody

• Patients must have received prior treatment with platinum-based chemotherapy

‣ Non-Small Cell Lung Cancer (NSCLC)

⁃ Patients who have progressed after a minimum of 2 doses of a PD-1/PD-L1 treatment. Study enrollment (C1D1) must be within 12 weeks of the last dose of the anti-PD-1/PD-L1 blocking antibody

• Patients must have received prior treatment with platinum-based chemotherapy

‣ Triple Negative Breast Cancer (TNBC)

⁃ ER/PR and HER2 status should be defined by ASCO/CAP guidelines (JCO Allison et al 2020)

• Patients with HER2-low cancers (HER2 IHC 1+ or 2+/ISH negative) are excluded

• Patients must have received prior sacituzumab govitecan and if PD-L1 ≥10% by CPS pembrolizumab with chemotherapy

‣ Classical Hodgkin Lymphoma (HL)

⁃ Patients must have received at least two prior systemic therapies including brentuximab vedotin (if eligible) and a prior PD-1 inhibitor

• Patients must have experienced less than a CR (according to Lugano criteria) to anti- PD-1 treatment

‣ (Cohort 2 Dose Expansion): Non-Small Cell Lung Cancer (NSCLC)

⁃ Patients who have progressed after a minimum of 2 doses of a PD-1/PD-L1 treatment

• Patients must have received prior treatment with platinum-based chemotherapy

‣ (Cohort 2 Dose Expansion) Triple Negative Breast Cancer (TNBC)

⁃ ER/PR and HER2 status should be defined by ASCO/CAP guidelines (JCO Allison et al 2020)

• Patients must have received prior sacituzumab govitecan and if PD-L1 ≥10% by CPS pembrolizumab with chemotherapy

• Patients with HER2-low tumors need to have received fam-trastuzumab deruxtecan (Enhertu)

• Patients with NSCLC, MM, TNBC, and HNSCC must have measurable disease per RECIST 1.1. Patients with HL must have at least one measurable lesion \> 1.5 cm for nodal, \> 1.0 cm for extranodal FDG-avid disease by the Lugano (2014) response criteria. Tumor sites that are considered measurable must not have received prior radiation

• Eastern Cooperative Oncology Group (ECOG) performance status 0-1

• Adequate bone marrow function defined by absolute neutrophil (ANC) of ≥ 1.5×109/L, platelet count of ≥ 100.0×109/L, and hemoglobin of ≥ 9.0 g/dL (with or without transfusion)

• a. (Cohort 2 Dose Expansion) Adequate bone marrow function defined by absolute neutrophil (ANC) of ≥ 1.5×109/L, platelet count of ≥ 100.0×109/L, and hemoglobin of ≥ 9.0 g/dL (with or without transfusion) within 2 weeks from the first dose of CTX-8371.

• \- Blood transfusion is not allowed within 2 weeks from the first dose of CTX-8371

• Adequate hepatic function defined as serum total bilirubin ≤ 1.5 × ULN, AST/ALT ≤ 2.5 × ULN (or ≤ 5 × ULN in patients with liver metastases)

• Adequate renal function defined as creatinine clearance ≥ 30mL/min by Cockcroft-Gault equation

• Female patients must be surgically sterile (or have a monogamous partner who is surgically sterile) or be at least 2 years postmenopausal or commits to use 2 acceptable forms of birth control (defined as the use of an intrauterine device (IUD), a barrier method with spermicide, condoms, any form of hormonal contraceptives) or abstinence for the duration of the study and for 4 months following the last dose of study treatment. Male patients must be sterile (biologically or surgically) or commit to the use of a reliable method of birth control (condoms with spermicide) for the duration of the study and for 4 months following the last dose of study treatment

• Female patients who are women of childbearing potential (WOCBP) must have a negative serum pregnancy test at Screening within 7 days of dosing with CTX-8371

⁃ Last dose of previous PD-1 or PD-L1 therapy ≥ 28 days, other anticancer therapy \> 21 days (or 2 half-lives for proteins, whichever is longer), radiotherapy \>21 days (concurrent localized palliative radiotherapy is allowed during CTX-8371 treatment), or surgical intervention \>21 days prior to the first dose of CTX-8371

⁃ Resolution of all prior anti-cancer therapy toxicities ≤ Grade 2

⁃ Life expectancy ≥ 12 weeks

⁃ Capable of understanding and complying with protocol requirements

⁃ Signed and dated institutional review board (IRB)/independent ethics committee (IEC)-approved informed consent form (ICF) before any protocol-directed screening procedures are performed