包括肝細胞癌之晚期實體腫瘤

本試驗的目的是評估 ZW251 的安全性和耐受性，並確定第 1 部分（劑量遞增）的 MTD 和／或 RD。此外，本試驗也希望進一步評估第 2 部分（劑量最佳化）已確定之 RD 的安全性和潛在抗腫瘤活性。

ZW251

ZW251

靜脈輸注液

240 mg/ 8 ml

第 1 部分：劑量遞增
•描述 ZW251 的安全性和耐受性
•確認 ZW251 的 MTD
•確認 ZW251 劑量最佳化的 RD
第 2 部分：劑量最佳化
•確定 ZW251 的最佳劑量
•評估 ZW251 用於晚期 HCC 的抗腫瘤活性
•持續監測 ZW251 的安全性和耐受性

1.All participants must be able to understand and willing to comply with the study procedures, understand the risks involved in the study, and provide written informed consent before study-specific procedures are performed, including screening evaluations.
For participants below the legal age of adulthood per country specific regulations, a written informed assent form (participant), when appropriate, and a written informed consent form (parent or guardian), as applicable, must be obtained ([Note] Taiwan will not be enrolling adolescents.).
2.Male and female participants ≥18 years of age (or the legal age of adulthood per country/region-specific requirements) on the day of signing the ICF. In Part 1, adolescent participants (≥ 12 to < 18 years of age) may be enrolled in backfill cohorts once approved by the Safety Monitoring Committee (SMC) (Note] Taiwan will not be enrolling adolescents.).
3.Minimum life expectancy of 12 weeks in the opinion of the investigator.
4.HCC: Pathologically or cytologically confirmed diagnosis of HCC with evidence of locally advanced (unresectable, and ineligible for transplant) and/or metastatic disease. Noninvasive methods may be used to confirm diagnosis as described below:
•Focal lesion > 1 cm with arterial hypervascularity and venous or delayed phase washout on a 4-phase multi-detector computed tomography (CT) or dynamic contrast-enhanced magnetic resonance imaging (MRI).
Germ cell (yolk sac or choriocarcinoma) tumors (Part 1 backfill only): Pathologically or cytologically confirmed diagnosis of germ cell (yolk sac or choriocarcinoma) tumors with evidence of locally advanced (unresectable) and/or metastatic disease.
5.Liver function status should be Child-Pugh Class A (assessed for HCC only).
6.For participants with HCC:
•Part 1 (dose escalation): Participants with HCC must have either progressed on at least 1 first-line therapy, or are intolerant to, or refused treatment with approved and available immunotherapy (or immunotherapy combination), or approved and available TKI. Adolescent participants with HCC must have progressed on approved and available standard of care (SOC) therapies. Participants with HCC must not be amenable to locoregional treatment (e.g., transplant, surgery, radiofrequency ablation, trans arterial chemoembolization, selective internal radiotherapy) ([Note] Taiwan will not be enrolling adolescents.).
•Part 2 (dose optimization): Participants with HCC (adults ≥18 years of age [or the legal age of adulthood per country/region-specific requirements]) must have progressed on at least 1 treatment regimen, including an approved and available PD-L1 inhibitor.
For participants with germ cell tumor (GCT):
•Part 1 (dose escalation backfill): Participants with GCTs must have advanced (unresectable) and/or metastatic disease that is not amenable to locoregional treatment and/or that has progressed on, or participant is intolerant to, or has refused treatment with, an approved and available SOC therapy of at least 2 platinum-containing chemotherapy regimens.
7.A new/fresh biopsy, or archival FFPE tumor tissue sample should be collected from participants to determine GPC3 expression (to be performed retrospectively by a centralized laboratory). A new/fresh biopsy is preferred where clinically feasible and safe; however, this is not mandatory. When a new/fresh biopsy is not clinically feasible, an archival tumor tissue is permitted. Archival FFPE tumor tissue samples must have been collected within ≤ 5 years of the screening visit. Fine needle aspirates (cytology samples) and biopsies from sites of bone metastases may not be used for eligibility assessment. When collection of tissue by biopsy is not clinically feasible, and archival tissue is not available, exceptions for inclusion are allowed with the study medical monitor’s approval.
8.Participants ≥ 16 years of age must have Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1, or Karnofsky performance status score of ≥ 50%. Participants < 16 years of age must have a Lansky performance status score of ≥ 50%. Performance status must be assessed during screening ([Note] Taiwan will not be enrolling adolescents.).
9.Participants must have measurable disease as per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 as assessed by the local site investigator/radiology.
10.Participants must have a washout period (≥ 3 weeks or 5 half-lives, whichever is shorter) from prior anticancer therapies before the first dose of ZW251. Sponsor approval is required for molecules with very long half-lives. Participants treated with radiation therapy must have a washout period of ≥ 2 weeks before the first dose of ZW251.
Note: Participants must have recovered from all AEs due to previous therapies to Grade ≤ 1 or baseline. Participants with endocrine-related AEs Grade ≤ 2 requiring treatment or hormone replacement may be eligible. If the participant had major surgery, the participant must have recovered adequately from the procedure (minimum of 3 weeks) and/or any complications from the surgery prior to starting study treatment.
11.Adequate organ function as defined in the following table:
SystemLaboratory Value
Hematological
Result Values and Normal Range Must be Reported with the Same Units of Measurement
ANC≥ 1,500/µL and not requiring growth factor support within 14 days of receiving study treatment.
Platelets≥ 75,000/µL and not requiring transfusion support within 14 days of receiving study treatment.
Hemoglobin≥ 8.0 g/dL or ≥ 4.9 mmol/L. Criteria must be met without packed red blood cell transfusion within the prior 2 weeks. Participants with chronic anemia that is supported by intermittent red blood cell transfusions are eligible. Participants can be on stable dose of erythropoietin (≥ approximately 3 months).
Renal
CrCl
Adequate renal function,
For participants ≥ 18 years: creatinine clearance (CrCl) ≥ 50 mL/min calculated using the Cockcroft-Gault equation, or measured CrCl ≥ 50 mL/min
For participants < 18 years: eGFR ≥ 60 mL/min/1.73 m² calculated using the revised Schwartz formula

Cockcroft-Gault CrCl = [(140 – age in years) × (Wt in kg) × (0.85 if female)] / (72 × serum creatinine in mg/dL ) or measured creatinine clearance ≥ 50 mL/min
Hepatic (for HCC)
Total bilirubin≤ 3 mg/dL
Albumin≥ 2.8 g/dL
AST (SGOT) and ALT (SGPT)≤ 5 × ULN per institutional values

Hepatic (for non-HCC)
Total bilirubin≤1.5 × ULN OR direct bilirubin ≤ULN for participants with total bilirubin levels >1.5 × ULN (participants with known Gilbert’s syndrome may enroll with a value of 2.5 × ULN provided direct bilirubin is ≤1.5 mg/dL)
(if liver metastases are present, ≤2.0 × ULN)
AST (SGOT) and ALT (SGPT)≤ 3 × ULN per institutional values
(if liver metastases are present, ≤5.0 × ULN)
Coagulation (for HCC)
INR or PT and
PTT or aPTT≤ 1.7 × ULN unless on medication known to alter the INR or PTT or participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants.
Coagulation (for non-HCC)
INR or PT and PTT or aPTT≤1.5 × ULN unless on medication known to alter the INR or PTT or participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants.
Abbreviations: ALT = alanine aminotransferase; ANC = absolute neutrophil count; aPTT = activated partial thromboplastin time; AST = aspartate aminotransferase; CrCl = creatinine clearance; HCC = hepatocellular carcinoma; INR = international normalized ratio; PT = prothrombin time; PTT = partial thromboplastin time; SGOT = serum glutamic oxaloacetic transaminase; SGPT = serum glutamic pyruvic transaminase; ULN = upper limit of normal; Wt = weight.
Note: Re-testing(s) of abnormal safety laboratory values may be performed, and results confirmed by the investigator prior to overall eligibility confirmation. The overall eligibility results must be communicated to the study medical monitor 48 hours before the start of study treatment.
12.Human immunodeficiency virus (HIV) infected participants must be on anti-retroviral therapy (ART) and have a well-controlled HIV infection/disease defined as follows:
•Participants on ART must have a CD4+ T-cell count > 350 cells/mm3 at the time of screening.
•Participants on ART must have achieved and maintained virologic suppression defined as confirmed by an 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 before screening.
•Participants on ART must have been on a stable regimen, without changes in drugs or dose modification, for at least 4 weeks before the first dose of ZW251.
•Participants with active or past history of HIV do not have a history of pulmonary Kaposi’s sarcoma or multicentric Castleman disease.
13.Participants who are hepatitis B surface antigen (HBsAg) positive and/or anti-HBcAb, with HBV DNA, are eligible if they have received HBV antiviral therapy for at least 2 weeks before the first dose of ZW251. Note: Participants should remain on antiviral therapy throughout study treatment and follow local guidelines for HBV antiviral therapy post completion of study treatment. Participants who test positive for anti-HBcAb with undetectable HBV DNA (e.g., <10 IU/mL) do not require anti-viral therapy prior to enrollment. These participants will be tested as per local guidelines to monitor HBV DNA levels and initiate antiviral therapy if HBV DNA is detected (e.g., ≥10 IU/mL). HBV DNA detectable participants must initiate and remain on antiviral therapy for the study duration.
14.Participants with hepatitis C virus (HCV) infection must have confirmed diagnosis of HCV characterized by the presence of detectable HCV RNA or anti-HCV antibody upon enrollment (management of this disease is per local institutional practice). Note: Participants must be on antiviral therapy prior to initiating the study treatment.
15.Participants with other hepatitis viruses, such as hepatitis D virus (HDV) or co-infection, require study medical monitor approval. These cases require confirmed diagnosis by the presence of detectable HDV RNA or anti-HDV antibody upon enrollment (management of this disease is per local institutional practice). Note: Participants must be on antiviral therapy prior to initiating the study treatment.
16.Female participants must not be pregnant. Woman of childbearing potential (WOCBP) must have a negative serum beta-human chorionic gonadotropin (βhCG) pregnancy test result at the screening visit to assess eligibility. This test must be repeated within 1 week (7 days) before the first dose of study treatment. WOCBP and male participants with a WOCBP partner must agree to use a highly effective method of birth control in combination with a barrier method following the first negative screening serum pregnancy test throughout the study and for up to 10 months after the last dose of ZW251. Female participants must agree not to breastfeed or donate oocytes, and male participants must agree to not donate sperm starting at screening and throughout the study period and for at least 10 months after the last dose of ZW251.

1.Known additional malignancy that is progressing or that has required active treatment within the last year. Exceptions include cancers with a very low likelihood of recurrence (i.e., treatments administered have a reported > 95% cure rate or < 5% recurrence rate), including earlystage cancers (carcinoma in situ or Stage I [excluding carcinoma in situ of bladder]), basal cell carcinoma of the skin, and squamous cell carcinoma of the skin that have undergone potentially curative therapy.
2.Hypersensitivity or contraindications to ZW251, excipients of the drug product, or other components of the study treatment regimen.
3.Life-threatening illness, significant organ system dysfunction, or other condition that, in the investigator’s opinion, could compromise participant’s safety or integrity of the study outcomes or interfere with the absorption or metabolism of ZW251.
4.Ongoing, clinically significant toxicity associated with prior cancer therapies, with the exception of alopecia, as assessed by the investigator.
5.History of hepatic encephalopathy within the past 6 months or requirement for medications to control encephalopathy (e.g., no lactulose, rifaximin, etc. if used for purposes of hepatic encephalopathy). Note: Prophylactic medications for hepatic encephalopathy are allowed.
6.Participants with HCC experiencing main portal vein thrombosis (VP4), as documented on imaging, require sponsor approval prior to enrollment. (VP4 is defined as portal vein thrombosis in the main trunk of the portal vein or a portal vein branch contralateral to the primarily involved lobe [or both]). Participants with newly diagnosed portal vein thrombosis within 3 months prior to Cycle 1 Day 1 that require coagulation therapy or is not stable in the opinion of the investigator.
7.Known gastrointestinal (GI) bleeding (e.g., esophageal varices or ulcer bleeding) within 3 months. Note: For participants with a history of GI bleeding for more than 3 months or assessed as high risk for esophageal variceal by the investigator, adequate endoscopic therapy according to institutional standards is required.
8.Cardiology: Any history of, or at risk for, as evidence by one or more of the following cardiac conditions within the last 3 months:
•Abnormal left ventricular ejection fraction (LVEF) (< 50%), ECHO, or MUGA.
•Congestive heart failure of Grade > 2 severity according to New York Heart Association (NYHA) functional classification defined as participants with marked limitation of activity and who are comfortable only at rest.
•History of acute cardiac arrest, myocardial infarction, unstable angina or uncontrolled hypertension as defined by the need for an overnight hospital admission.
•Concurrent treatment with any medication that prolongs QT interval may induce torsades de pointes, and which cannot be discontinued at least 1 week before treatment with ZW251.
•History of long corrected QT interval for heart rate (QTc) syndrome or clinically significant arrythmias.
Confirmed manually over-read QTc corrected according to Fridericia’s method (QTcF) > 480 ms on screening Electrocardiogram (ECG) or known history of congenital long QT syndrome. Note: For participants with longer QTcF on initial ECG, additional ECG maybe performed in triplicate to determine eligibility.
9.Neurology:
•Grade ≥ 2 neuropathy.
•Leptomeningeal carcinomatosis.
•Known symptomatic brain metastasis, unless stable, previously treated or resected. Note: Participants with brain metastases may participate provided they are radiologically stable and asymptomatic (i.e., without evidence of progression for at least 14 days by repeat imaging; note that the repeat imaging should be performed during study screening), clinically stable, and without requirement of escalating steroid treatment for at least 14 days prior to the first dose of study treatment. Brain metastases discovered incidentally during screening must be asymptomatic prior to enrollment.
•Previous cerebrovascular accident, transient ischemic attack, or sub-arachnoids hemorrhage within 3 months prior to first dose.
•Primary intracranial germ cell tumor. Note: Participants with brain metastases may participate provided they are radiologically stable and asymptomatic, clinically stable, and without requirement of escalating steroid treatment for at least 14 days prior to the first dose of study treatment.
10.Pulmonary function:
•Baseline oxygen saturation < 93%, or on supplemental oxygen regardless of saturation level.
•Clinically significant, Grade ≥ 3, preexisting pleural effusion requiring > 1 thoracocentesis for therapeutic purposes (i.e., not for diagnosis) within 14 days prior to Cycle 1 Day 1. However, participants with a permanent drainage catheter may be enrolled once approved by the study medical monitor.
•History of clinically significant interstitial lung disease (ILD), pneumonitis (including radiation pneumonitis), or non-infectious pulmonary toxicity (NIPT), or imaging at screening consistent with such pulmonary disease, or participants with severe dyspnea at rest or requiring supplementary oxygen therapy and/or corticosteroids.
11.Known significant mental illness or other condition such as active alcohol, or other substance abuse that, in the opinion of investigator, predisposes the participant to high risk of non-compliance with the protocol treatment and assessment. Known clinically significant psychiatric or substance abuse disorder or any other medical, social, or psychosocial factors that, in the opinion of the investigator, would interfere with the participant’s ability to cooperate with the requirements of the study.
12.Undergone prior allogenic tissue (e.g., hematopoietic stem cell) or solid organ transplantation within the last 5 years. Note: Participants who have had a transplant more than 5 years ago are eligible as long as there are no symptoms of graft versus-host disease. Participants who have had an autologous transplant more than 90 days prior to Cycle 1 Day 1 are eligible.
13.Advanced/metastatic, symptomatic, visceral spread, at risk of life-threatening complications in the short-term (including participants with massive uncontrolled effusion [pleural, pericardial], pulmonary lymphangitis, and active unresolved bowel obstruction).
14.Acute or chronic uncontrolled renal disease, pancreatitis, or non-malignant liver disease (with exception of participants with Gilbert’s syndrome, asymptomatic gall stones, liver metastases, or stable chronic liver disease per investigator assessment).
15.Active and clinically significant bacterial, fungal, or viral infection that is not controlled or requires IV therapy (participants requiring oral therapy must complete the planned course of treatment before administration of the study treatment, except for HIV infected participants who must be on ART and have a well controlled HIV infection [as described in inclusion criterion #12]).
16.Received a live or live-attenuated vaccine within 30 days before the first dose of ZW251. Note: Administration of inactivated vaccines is allowed.