This study will enroll patients with central lab confirmed NCAM (CD56 IHC) positive metastatic neuroendocrine neoplasms that have progressed after standard of care treatment. CTX-471 to be administered as an intravenous (IV) infusion at either 0.3 mg/kg or 0.6 mg/kg every 2 weeks until disease progression or unacceptable toxicity. The study will be conducted in two stages. In Stage 1, 18 patients will be accrued for each dose level. If there are less than 2 objective responses in these 18 patients at either dose level, the dose level will be stopped. Otherwise, an additional 22 patients will be accrued in Stage 2 with 11 patients for each dose level.

Inclusion Criteria:

1. Age 18 years or older.

2. Positive immunohistochemical staining for NCAM (defined as ≥ 1% of malignant cells with membranous/cytoplasmic staining of any intensity) on an archived (≤ 3 months) or freshly taken biopsy specimen (centrally tested) with histologically confirmed diagnosis of metastatic tumors.

3. Locally advanced unresectable or metastatic neuroendocrine neoplasm (NEN) defined by World Health Organization (WHO) (Rindi et al 2022) Grade 3 neuroendocrine tumor (NET) or neuroendocrine carcinoma (NEC) (Ki-67 > 20% and/or > 20 mitoses/10 hpf) and confirmed by histopathology or cytology (eg, gastroentero-pancreatic NECs (GEP-NEC) and lung NEC, other rare sites of origin such as genitourinary, gynecological, larynx, thyroid, or unknown origin).

4. Patients must have received at least one prior line of chemotherapy and must have exhausted any other standard-of-care treatment option.

   a. Patients with histologically confirmed prostate NEC are not required to have received prior androgen deprivation therapy (ADT) or castrated levels of testosterone.

5. A washout period of 4 weeks or at least 5-fold half-life of the last dose (whichever is shorter) of prior systemic therapy prior to receiving the first dose of CTX-471.

   • The eligibility of patients who received unapproved drugs will be determined by discussion with the Sponsor Medical Monitor.

6. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.

7. At least one measurable lesion definable by MRI or CT scan per RECIST version 1.1 criteria.

8. All toxicities related to previous anti-cancer therapies have resolved to (CTCAE) Grade 1 prior to trial treatment administration (except for alopecia, peripheral neuropathy, fatigue and endocrinopathies controlled by replacement therapy which must be CTCAE Grade 2 and amenorrhea/menstrual disorders which can be any grade).

9. Adequate organ function and laboratory values:

   • 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).
   • Adequate hepatic function defined as serum total bilirubin ≤ 1.5 × ULN, AST/ALT ≤ 2.5 × ULN (or ≤ 5 × ULN in patients with liver metastases or ≤3 x ULN for patients with Gilbert's syndrome).
   • Adequate renal function defined as creatinine clearance ≥ 30 mL/min by Cockcroft-Gault equation.

10. Females of childbearing potential (FOCBP) should have a negative serum pregnancy within 72 hours prior to receiving the first dose of study medication.

11. FOCBP must agree to use adequate contraception as outlined in study documentation, starting with the first dose of study medication through 120 days after the last dose of study medication.

12. Male patients of childbearing potential must agree to use an adequate method of contraception as outlined in study documentation, starting with the first dose of study medication through 120 days after the last dose of study medication.

13. Capable of understanding and complying with protocol requirements.

14. Signed and dated institutional review board (IRB) approved informed consent form (ICF) before any protocol-directed screening procedures are performed.

Exclusion Criteria:

1. Diagnosis of well differentiated G1/G2 neuroendocrine neoplasm.

2. Prior history of interstitial lung disease.

3. Prior treatment of CD137 targeted therapy (investigational and approved).

4. 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 central nervous system (CNS) or brain lesions require imaging during screening to confirm stability.

5. Prior solid organ transplantation and/ or an allogeneic tissue transplant.

6. Active hepatitis B virus (HBV), hepatitis C virus (HCV) or human immunodeficiency virus (HIV) infection or a positive serological test at Screening within 35 days of dosing with CTX-471.

   • Hepatitis B surface antigen (HBsAg) positive patients are eligible if they have received HBV antiviral therapy for at least 4 weeks and have undetectable HBV viral load prior to randomization.
   • HBV+ patients should remain on anti-viral therapy throughout study intervention and follow local guidelines for HBV anti-viral therapy post completion of study intervention.
   • History of HCV infection is eligible if HCV viral load is undetectable at screening.
   • HCV+ patients must have completed curative anti-viral therapy at least 4 weeks prior to randomization.

7. HIV-infected patients must be on anti-retroviral therapy (ART) and have a well-controlled HIV infection/disease defined as:

   • Patients on ART must have a CD4+ T-cell count < 350 cells/mm3 at time of screening.
   • Patients on ART must have achieved and maintained virologic suppression defined as confirmed HIV RNA level below 50 copies/mL or the lower limit of qualification (below the limit of detection) using the locally available assay at the time of screening and for at least 12 weeks prior to screening.
   • Patients on ART must have been on a stable regimen, without changes in drugs or dose modification, for at least 4 weeks prior to study entry (Day 1).

8. Active autoimmune disease or medical conditions requiring chronic steroid (ie, > 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.

9. Systemic therapy with immunosuppressive agents within 7 days before the start of CTX-471 treatment. Topical, intranasal, intraocular, or inhaled corticosteroids and physiologic replacement for patients with adrenal insufficiency are allowed (≤ 10 mg/day prednisone or equivalent).

10. 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.

11. Other systemic conditions or organ abnormalities that in the opinion of the Investigator may interfere with the conduct and/or interpretation of the current study.

12. Has received prior radiotherapy within 2 weeks of start of study treatment.

    • Patients must have recovered from all radiation-related toxicities and not require corticosteroids.

13. Has received a live or live-attenuated vaccine within 30 days prior to the first dose of study medication.

    • Administration of killed vaccines are allowed.

14. Has a known additional malignancy that is progressing or has required active treatment within the past 3 years.

    • Patients with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ, excluding carcinoma in situ of bladder, that have undergone potentially curative therapy are not excluded.