A Phase 1 of CTX-8371 in Patients With Advanced Malignancies

This Phase 1, open-label, first-in-human study will evaluate the safety, tolerability, immunogenicity, and pharmacokinetic profile of CTX-8371 monotherapy. Preliminary anti-tumor activity of CTX-8371 will also be assessed. The study will be conducted in 2 cohorts: Dose escalation and Dose expansion. The Dose Escalation Cohort will utilize a 3+3 design to evaluate five dose levels (0.1-10.0 mg/kg) of CTX-8371 given as an IV infusion once every 2 weeks. Patients in the Dose Expansion Cohort will receive CTX-8371 as an IV infusion at 3.0 mg/kg or 10.0 mg/kg at a 1:1 allocation.

Inclusion criteria

• 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 (HER2 IHC 1+ or 2+/ISH negative) need to have received fam-trastuzumab deruxtecan (Enhertu)
• (Cohort 2 Dose Expansion) Classical Hodgkin's 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 received at least 12 weeks of treatment with a PD-1/PD-L1 inhibitor as a monotherapy or in combination and had at least stable disease or progressive disease (PD) with overall clinical benefit.
• 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

Exclusion criteria

• Developed clinically significant adverse reaction to PD-1 or PD-L1 therapy, including immune related adverse reactions, which led to discontinuation of treatment
• Systemic therapy with immunosuppressive agents within 7 days before the start of CTX-8371 treatment. Topical, intranasal, intraocular, or inhaled corticosteroids and physiologic replacement for patients with adrenal insufficiency are allowed
• Patient is a pregnant or lactating WOCBP
• Prior organ transplantation
• Patients with evidence of active hepatitis B virus (HBV), hepatitis C virus (HCV) or human immunodeficiency virus (HIV) infection. Patients with positive HBsAg and/or detectable HBV DNA are eligible only if adequately controlled on antiviral therapy according to institutional standards and liver function eligibility criteria are also met. HCV patients showing sustained viral response or patients with immunity to HBV infection may enroll.
• Active autoimmune disease or medical conditions requiring chronic steroid (i.e., > 10 mg/day prednisone or equivalent) or immunosuppressive therapy. Patients with a prior history of autoimmune disease may be eligible following discussion with the Medical Monitor
• History of primary malignancy other than the malignancy under study will be excluded, except for malignancies with a negligible risk of metastasis or death (e.g., 5-year OS rate >90%). Prior malignancy history will be evaluated on a case-by-case basis by the Sponsor Medical Monitor.
• Symptomatic or uncontrolled central nervous system and brain metastasis or active leptomeningeal disease. Patients with equivocal findings or with confirmed brain metastases are eligible for the study provided that they are asymptomatic and radiologically and neurologically stable without the need for corticosteroid treatment or seizure prophylaxis for ≥4 weeks before the first dose of study drug. Prior treatment with either surgery or radiation is permitted and all patients with a history of CNS or brain lesions require imaging during screening to confirm stability.
• Other medical condition that in the opinion of the Investigator and/or Sponsor Medical Monitor may interfere with the conduct and/or interpretation of the current study, including:

• Congestive heart failure (> New York Heart Association Class II), active coronary artery disease, unevaluated new onset angina within 3 months or unstable angina (angina symptoms at rest) or clinically significant cardiac arrhythmias
• QTc interval (using Fridericia correction calculation) > 480 msec