This is a multicenter, Phase II, open-label, single-dose-level (6 mg/kg) study of PRL3-zumab monotherapy in patients with unresectable or metastatic solid tumors. PRL3-zumab will be administered via intravenous (IV) infusion until discontinuation criteria are met (e.g., disease progression per RECIST v1.1/iRECIST, intolerable toxicity, or withdrawal of consent).

Study Periods and Duration

The study is divided into the following phases:

• Screening Period: Day -21 to Day -1; all assessments must be completed prior to the first dose.
• Treatment Period: One cycle is defined as 4 weeks, consisting of two infusions administered 2 weeks apart.
• End-of-Treatment (EOT) Visit: To be conducted within 14 days of the last dose or treatment discontinuation.
• Safety Follow-Up: A visit scheduled 30 days after the last dose.
• Survival Follow-Up: Conducted every 3 months post-discontinuation via telephone or other appropriate methods until the data cutoff date.

Assessments

• Safety & QoL: Safety assessments (including laboratory tests) will be performed prior to each infusion. Quality of Life (QoL) will be assessed at screening and every 8 weeks during treatment.
• Tumor Imaging: Assessments will be performed at baseline and every 8 weeks following the initiation of study treatment, according to RECIST v1.1 and iRECIST.
• Immunogenicity: Assessments will be performed pre-dose on Cycle 1 Day 1, and prior to infusions in Cycles 2, 4, and 6. For patients remaining on treatment, assessments will continue every 3 cycles thereafter.

Pharmacokinetic (PK) profiles will be evaluated in two distinct subgroups of 10 patients each. For the intensive PK sampling subgroup, assessments are concentrated in the first three cycles: Cycle 1 monitoring includes Day 1 (pre-dose, end of infusion, 2, and 6 hours post-infusion), Day 2 (24 hours), Day 6 (120 hours), Day 10 (216 hours), and Day 15 (pre-dose). Following pre-dose samples on Cycle 2 (Days 1 and 15) and Cycle 3 (Day 1), a second intensive window occurs on Cycle 3 Day 15 (pre-dose, end of infusion, 2, and 6 hours post-infusion) and continues through Days 16, 20, and 24. Subsequent samples are taken pre-dose on Day 1 of Cycles 4, 5, and 6, concluding at the EOT visit. In contrast, the sparse PK sampling subgroup will undergo limited assessments at Cycle 1 Day 1 (pre-dose and end of infusion), Cycle 1 Day 15 (pre-dose), and the first day of Cycles 2 and 3 (pre-dose and end of infusion), with a final sample collected at the EOT visit.

Study Assessments

Efficacy:

Efficacy will be evaluated by the investigator using RECIST v1.1 and iRECIST criteria. Tumor evaluations, including contrast-enhanced computed tomography (CT) scans, will be performed at baseline (within 14 days prior to Cycle 1 Day 1) and every 56 days thereafter. Magnetic resonance imaging (MRI) may be used if a patient is ineligible for CT scans; however, the same imaging modality must be used consistently throughout the study.

Safety:

Patient safety will be assessed on an ongoing basis during each cycle. Evaluations include physical examinations, vital signs (systolic/diastolic blood pressure, heart rate, respiratory rate, and temperature), and clinical laboratory tests (hematology, clinical chemistry, and coagulation). Adverse events (AEs) will be graded according to CTCAE v5.0.

Pharmacokinetics (PK):

Blood samples for PK analysis will be collected as follows:

• Intensive Sampling Group (N=10): C1D1 (pre-dose, EOI, 2h, and 6h post-infusion), C1D2 (24h), C1D6 (120h), C1D10 (216h), C1D15 (pre-dose); C2D1 and C2D15 (pre-dose); C3D1 (pre-dose), C3D15 (pre-dose, EOI, 2h, and 6h post-infusion), C3D16 (24h), C3D20 (120h), C3D24 (216h); C4D1, C5D1, C6D1 (pre-dose), and at End of Treatment (EOT).
• Sparse Sampling Group: C1D1 (pre-dose, EOI), C1D15 (pre-dose); C2D1 and C3D1 (pre-dose and EOI), and at EOT.

Immunogenicity & Quality of Life (QoL) Anti-drug antibody (ADA) samples will be collected prior to infusion on C1D1 and Cycles 2, 4, and 6. Thereafter, samples will be collected every three months. Neutralizing antibody assessments will be performed for any patient testing positive for ADA.

Quality of Life (QoL) will be measured using EQ-5D and EORTC-QLQ-C30 questionnaires at screening and every 2 cycles (8 weeks ± 2 days for C1-C4; 8 weeks ± 7 days thereafter).

Study Duration and Periods

• Cycle Period: One cycle is 28 days (two infusions administered 2 weeks apart).
• Treatment Period: Treatment continues until disease progression (per RECIST 1.1/iRECIST or clinical criteria), intolerable toxicity, or withdrawal of consent.
• Follow-up Period: Includes a Safety Follow-up (30 ± 7 days after the last dose or prior to new therapy) and a Survival Follow-up (every 3 months via telephone until the data cutoff date, which is 24 weeks after the last subject's enrollment).

Statistical Considerations

Sample Size and Populations:

This is an exploratory trial; thus, the sample size is not based on formal hypothesis testing. A total of 50 subjects will be enrolled, with approximately 30 evaluable subjects expected for PFS and TTP assessments. Patients receiving fewer than 4 doses or lacking at least one post-baseline assessment will be replaced.

Analysis Sets:

• Safety Set (SS): All patients receiving dose of study treatment.
• Full Analysis Set (FAS): All patients receiving dose with measurable lesions at baseline.
• Per Protocol Set (PPS): A subset of the FAS excluding those with major protocol deviations.
• Evaluable Population Set (EPS): FAS patients with evaluable post-baseline tumor assessment.
• PK/ADA Sets: Patients with dose and valid post-baseline PK/ADA measurements.

Statistical Methods:

Analyses will be performed using SAS® v9.4 or later. Categorical variables will be summarized by frequency/percentage, and continuous variables by descriptive statistics (mean, SD, median, range).

• Efficacy: The primary endpoints, Progression-Free Survival (PFS) and Time to Progression (TTP), will be analyzed using Kaplan-Meier methods. Secondary endpoints (ORR, CBR) will include 95% confidence intervals (Clopper-Pearson).
• Pharmacokinetics: PK parameters will be summarized descriptively. A population PK model will be developed.
• Safety: TEAEs and treatment-related AEs (TRAEs) will be summarized by System Organ Class (SOC) and Preferred Term (PT). Laboratory and vital sign changes from baseline will be summarized descriptively.

Inclusion Criteria:

1. Men and women aged 18 or older with unresectable or metastatic solid tumors

2. Patients with locally advanced or metastatic solid tumors who have failed standard therapy or for whom no standard therapy is available. Treatment failure is defined as disease progression during or after systemic antitumor therapy (including but not limited to chemotherapy, radiotherapy, biologic therapy, immunotherapy, and endocrine therapy), or intolerance to treatment-related toxicities. Disease progression must be documented by radiographic evidence or clinical evidence. For patients who have received adjuvant or neoadjuvant therapy (radiotherapy or chemoradiotherapy), disease progression occurring during treatment or after completion of such therapy will be considered treatment failure.

3. Willing to provide written informed consent for the study.

4. Histopathological diagnosis and metastatic status cancer at study entry.

5. Must have received no more than 3 prior lines of treatment for metastatic disease.

6. Life expectancy of more than 6 months

7. Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of 0 or 1.

8. Patient should have recovered from toxicity of prior treatment regimen to Grade 1 level except for alopecia or peripheral neuropathy or fatigue as defined by Common Terminology Criteria for Adverse Events (CTCAE version 5.

9. Women of childbearing potential (WOCBP) must have a negative serum pregnancy test at study entry and must follow highly effective contraception

   1. WOCBP must be willing to use highly effective methods of birth control (i.e., a hormonal contraceptive, intra-uterine device, diaphragm with spermicide, or condom with spermicide,) for the duration of the study and 90 days thereafter.
   2. Male participants should take precaution to avoid pregnancy in sexual partner during the study and 90 days thereafter.

10. Adequate organ and hematological function as evidenced by the following laboratory studies within 10 days of treatment:

    • Absolute neutrophil count ≥ 1.0 x 109/L to 8.0 × 10⁹/L.
    • Lymphocyte count ≥ 0.9 × 10⁹/L
    • Platelet count ≥ 75 x 109/L.
    • Hemoglobin ≥ 9 g/dL.
    • Prothrombin time and activated partial thromboplastin time ≤ 1.5 x upper limit of normal (ULN) per institutional laboratory normal range.
    • Total bilirubin ≤ 1.5x ULN.
    • Aspartate aminotransferase and alanine aminotransferase ≤ 2.5 x upper limit of normal (ULN) (≤ 5 x ULN in the presence of liver metastases).
    • For patients with hepatocellular carcinoma (HCC) Child Pugh score of ≤ B7.
    • Creatinine < 1.5x ULN. Creatinine clearance (according to Cockcroft-Gault Equation or by 24-hour urine collection) of > 60 mL/min at study entry.

11. According to RECIST 1.1 and iRECIST, patients mush have at least one measurable lesion that meets the following criteria: Accurately measureable at baseline. Longest diameter ≥10mm at baseline (for lymph nodes, short axis ≥ 15mm). Measurable by a reproducible imaging method such as computed tomography (CT) or magnetic resonance imaging (MRI). If only one measurable lesion is present, it must not have been previously treated with local therapy such as radiotherapy.

Exclusion Criteria:

1. Patient has known untreated or symptomatic central nervous system metastasis.

2. Female patient is pregnant, breastfeeding, or expecting to conceive children while receiving study treatment and for 150 days (for pregnancy or conception) or 30 days (for breastfeeding) after the last dose of study treatment.

3. Patient with any of the following virologic findings:

   • Positive hepatitis B surface antigen (HBsAg) and positive HBV DNA
   • Positive anti-HIV antibody and positive HCV RNA
   • Positive HIV antibody

4. Patients with active autoimmune disease requiring systemic treatment, or with a history of autoimmune disease that may recur (e.g., systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, autoimmune thyroid disease, multiple sclerosis, vasculitis, glomerulonephritis), or patients at high risk (e.g., prior organ transplantation requiring immunosuppressive therapy).

5. Patient is receiving systemic glucocorticoids (only if higher than 10 mg or equivalent of prednisolone daily) or other immunosuppressive treatment for autoimmune disease or any other medical condition.

6. Patient has experienced a severe hypersensitivity reaction to another monoclonal antibody.

7. Patient has received treatment with any systemic anti-cancer therapies within 3 weeks prior to starting study treatment.

8. Patient has undergone radiotherapy ≤ 4 weeks or limited field radiation for palliation ≤ 2 weeks prior to starting study treatment.

9. Patient has received > 3 lines of prior systemic chemotherapy for metastatic disease (adjuvant or neoadjuvant chemotherapy treatment completed at least 1-year prior is not to be included in this).

10. Patient is unable to provide informed consent.

11. Patient has a history of another active cancer (which requires treatment and not considered cured by the investigator) within the last 2 years.

12. Patient has received a prior stem cell or bone marrow transplant.

13. Patient has received a live vaccine within 12 weeks of the first dose of PRL3-zumab. (Seasonal influenza vaccines that do not contain live virus are permitted).

14. Patient is currently participating in a treatment study or has participated in a study of an investigational agent within 4 weeks prior to the anticipated first dose of study treatment in this study.

15. Patients with spinal cord compression caused by tumor, unless the condition has been treated and clinically stable for more than 1 month.

16. Patients with any unstable medical condition or any other disease that may compromise their safety or compliance with the study, including any severe or uncontrolled systemic disease such as uncontrolled hypertension, uncontrolled diabetes mellitus, or active bleeding.

17. Patients with alcohol dependence or a history of drug abuse or substance abuse within 1 year prior to study entry.

18. Patients with any other severe, acute, or chronic medical or psychiatric condition, or laboratory abnormality, that may increase the risk associated with study participation or investigational product administration, or may interfere with the interpretation of study results.

19. Patients who, in the investigator's judgment, are not suitable for participation in this study.

Requests for IPD can be submitted by email to min.thura@intra-immusg.com