Clinical Trials List
Protocol NumberTPST-1120-301
Not yet recruiting
2025-02-03 - 2029-12-23
Recruiting6
ICD-10C22.0
Liver cell carcinoma
ICD-10C22.2
Hepatoblastoma
ICD-10C22.3
Angiosarcoma of liver
ICD-10C22.4
Other sarcomas of liver
ICD-10C22.7
Other specified carcinomas of liver
ICD-10C22.8
Malignant neoplasm of liver, primary, unspecified as to type
ICD-10Z51.12
Encounter for antineoplastic immunotherapy
ICD-9155.0
Malignant neoplasm of liver, primary
A phase 3 randomized, double-blind, placebo-controlled trial compared TPST-1120 with Atezolizumab plus Bevacizumab to placebo plus Atezolizumab plus Bevacizumab in patients with unresectable or metastatic hepatocellular carcinoma (HCC) who had not received systemic therapy.
-
Trial Applicant
-
Sponsor
Novotech Clinical Research Taiwan Pty Ltd.
-
Trial scale
Multi-Regional Multi-Center
-
Update
2026/08/25
Investigators and Locations
The Actual Total Number of Participants Enrolled
0 Recruiting
Co-Principal Investigator
The Actual Total Number of Participants Enrolled
0 Recruiting
Co-Principal Investigator
The Actual Total Number of Participants Enrolled
0 Recruiting
Co-Principal Investigator
- 林昶廷 無
- Yu-Li Su 無
- 郭明濬 無
- 吳佳哲 無
- 劉建廷 無
- Shau-Hsuan Li 無
- 黃詩喻 無
- 曾亮節 無
- 陳彥豪 無
- Tai-Jan Chiu 無
The Actual Total Number of Participants Enrolled
0 Recruiting
Co-Principal Investigator
- 劉奕廷 無
- Chih-Chieh Yen 無
- 邱彥程 無
- Chiu Hung Chiu 無
- Yih-Jyh Lin 無
The Actual Total Number of Participants Enrolled
0 Recruiting
Principal Investigator
Shi-Ming Lin
Co-Principal Investigator
The Actual Total Number of Participants Enrolled
0 Recruiting
Condition/Disease
● Overall survival (OS) is defined as the time elapsed from random assignment until death from any cause.
Objectives
Primary Objectives:
● To evaluate the efficacy of TPST-AB compared to Pbo-AB
Secondary Objectives:
● To evaluate the efficacy of TPST-AB compared to Pbo-AB
● To evaluate the correlation between predetermined biomarkers and the efficacy of TPST-AB compared to Pbo-AB
● To evaluate patient-reported outcomes (PROs), such as disease/treatment-related symptoms, health-related quality of life (HRQoL)/overall health score (GHS), and function, in patients receiving TPST-AB compared to those receiving Pbo-AB
● To investigate population pharmacokinetics (PK) of TPST-1120 using sparse pharmacokinetic (PK) sampling
Safety:
● To evaluate the safety of TPST-AB compared to Pbo-AB
Test Drug
TPST-1120
Active Ingredient
TPST-1120
Dosage Form
Tablets
Dosage
200 mg
Endpoints
● Overall survival (OS) is defined as the time elapsed from random assignment until death from any cause.
Inclution Criteria
Inclusion Criteria
To be eligible to participate in this trial, patients must meet all of the following criteria:
Informed Consent
1. Willing and able to provide written informed consent. However, if a patient is unable to read, understand, and sign the Informed Consent Form (ICF), the patient's legally authorized representative (LAR) may provide consent on behalf of the patient, subject to the permission of the Institutional Review Board (IRB) or the Independent Ethics Committee (IEC).
Age
2. Age ≥ 18 years at the time of signing the ICF
Patient Type and Disease Characteristics
3. The diagnosis of hepatocellular carcinoma (HCC) must be histologically/cytologically confirmed, or clinically diagnosed in patients with cirrhosis according to the American Association for the Study of Liver Diseases (AASLD) criteria.
a) Patients without cirrhosis must have a histologically confirmed diagnosis.
4. Unresectable or metastatic disease unsuitable for curative surgery and/or localized treatment
a) Patients who have progressed after HCC surgery and/or localized treatment are eligible.
5. No prior systemic therapy for HCC (including investigational systemic drugs)
a) Prior use of herbal remedies/traditional Chinese medicines labeled with anticancer activity is permitted, provided these medications were discontinued within 14 days prior to the start of the trial treatment.
6. At least one measurable untreated lesion according to the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1
a) Patients who have previously received local therapy (e.g., radiofrequency ablation, percutaneous ethanol or acetic acid injection, cryoablation, high-intensity focused ultrasound, transarterial chemoembolization, transarterial embolization, etc.) are eligible, provided that the target lesion has not previously received local therapy, or that the target lesion within the scope of the local therapy has subsequently progressed according to RECIST v1.1.
7. Prior to trial entry, any acute, clinically significant treatment-related toxicities from previous treatments have resolved to ≤ Grade 1 (excluding hair loss).
Diagnostic Assessment
8. Performance status of 0 or 1 according to the Eastern Cooperative Oncology Group (ECOG) within 7 days prior to randomization.
9. Child-Turcotte-Pugh (Child-Pugh) functional classification of cirrhosis of grade A within 7 days prior to randomization.
10. Adequate organ and bone marrow function, as defined by the following laboratory test results (unless otherwise specified, must be obtained within 7 days prior to randomization):
a) Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L (1500/μL) without the use of granulocyte colony-stimulating factor.
b) Lymphocyte count ≥ 0.5 x 10^9/L (500/μL).
c) Platelet count ≥ d) Heme ≥ 90 g/L (9 g/dL) (This condition can be met through blood transfusion)
e) Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) ≤ 5 times the upper limit of normal (ULN)
f) Total bilirubin ≤ 3 times ULN
g) Creatinine clearance ≥ 50 mL/min calculated using the Cockcroft-Gault formula, unless otherwise specified by the testing facility. h) Albumin ≥ 28 g/L (2.8 g/dL) without blood transfusion
i) For patients not receiving anticoagulation therapy: International Normalized Ratio (INR) or Activated Partial Thromboplastin Time (aPTT) ≤ 2 times ULN
j) Urine test strip shows proteinuria < 2+ (within 7 days prior to the start of the intervention)
k) If a 24-hour urine collection shows protein < 1 g within 24 hours, then patients with ≥ 2+ proteinuria on baseline urine test strip analysis are eligible.
1) Cholesterol ≤ 400 mg/dL (or 10.34 mmol/L) and triglycerides ≤ 400 mg/dL (or 4.52 mmol/L) within 28 days prior to randomization (antilipid therapy [excluding fibrate derivatives] is permitted to achieve this threshold).
11. Negative for Human Immunodeficiency Virus (HIV) at screening.
12. Documented hepatitis virological status confirmed by screening tests for Hepatitis B Virus (HBV) and Hepatitis C Virus (HCV).
a) For patients with active HBV: HBV deoxyribonucleic acid (DNA) levels during screening.
< 500 IU/mL, and having started anti-HBV treatment at least 14 days prior to randomization, and willing to continue receiving anti-HBV treatment (according to local standard of care; e.g., nucleoside (acid) analogs) during the trial.
Sexual Behavior and Reproduction
13. For women of fertility: Agree to abstain from sexual intercourse (avoiding heterosexual intercourse) or use two effective methods of contraception (at least one with an annual failure rate < 1%) during treatment, and for at least 5 months after the last dose of atezolizumab, 6 months after the last dose of bevacizumab, or 3 months after the last dose of TPST-1120/placebo (whichever occurs latest).
a) Women of fertility must have a negative serum pregnancy test result within 7 days prior to the start of the trial intervention.
14. For men: Agree to abstain from sexual intercourse (avoiding heterosexual intercourse) or use contraception during treatment and for 6 months after the last dose of bevacizumab or 3 months after the last dose of TPST-1120/placebo (whichever occurs latest), and agree not to donate sperm during this period.
Other: 15. Agree to submit and provide mandatory tumor specimens for central determination of PD-L1 status. This can be stocked tumor specimens (collected ≤ 3 years ago) or fresh tumor sections (if no stocked tissue is available). The quantity and quality of the tissue specimens must be sufficient to define the tumor's PD-L1 status.
To be eligible to participate in this trial, patients must meet all of the following criteria:
Informed Consent
1. Willing and able to provide written informed consent. However, if a patient is unable to read, understand, and sign the Informed Consent Form (ICF), the patient's legally authorized representative (LAR) may provide consent on behalf of the patient, subject to the permission of the Institutional Review Board (IRB) or the Independent Ethics Committee (IEC).
Age
2. Age ≥ 18 years at the time of signing the ICF
Patient Type and Disease Characteristics
3. The diagnosis of hepatocellular carcinoma (HCC) must be histologically/cytologically confirmed, or clinically diagnosed in patients with cirrhosis according to the American Association for the Study of Liver Diseases (AASLD) criteria.
a) Patients without cirrhosis must have a histologically confirmed diagnosis.
4. Unresectable or metastatic disease unsuitable for curative surgery and/or localized treatment
a) Patients who have progressed after HCC surgery and/or localized treatment are eligible.
5. No prior systemic therapy for HCC (including investigational systemic drugs)
a) Prior use of herbal remedies/traditional Chinese medicines labeled with anticancer activity is permitted, provided these medications were discontinued within 14 days prior to the start of the trial treatment.
6. At least one measurable untreated lesion according to the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1
a) Patients who have previously received local therapy (e.g., radiofrequency ablation, percutaneous ethanol or acetic acid injection, cryoablation, high-intensity focused ultrasound, transarterial chemoembolization, transarterial embolization, etc.) are eligible, provided that the target lesion has not previously received local therapy, or that the target lesion within the scope of the local therapy has subsequently progressed according to RECIST v1.1.
7. Prior to trial entry, any acute, clinically significant treatment-related toxicities from previous treatments have resolved to ≤ Grade 1 (excluding hair loss).
Diagnostic Assessment
8. Performance status of 0 or 1 according to the Eastern Cooperative Oncology Group (ECOG) within 7 days prior to randomization.
9. Child-Turcotte-Pugh (Child-Pugh) functional classification of cirrhosis of grade A within 7 days prior to randomization.
10. Adequate organ and bone marrow function, as defined by the following laboratory test results (unless otherwise specified, must be obtained within 7 days prior to randomization):
a) Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L (1500/μL) without the use of granulocyte colony-stimulating factor.
b) Lymphocyte count ≥ 0.5 x 10^9/L (500/μL).
c) Platelet count ≥ d) Heme ≥ 90 g/L (9 g/dL) (This condition can be met through blood transfusion)
e) Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) ≤ 5 times the upper limit of normal (ULN)
f) Total bilirubin ≤ 3 times ULN
g) Creatinine clearance ≥ 50 mL/min calculated using the Cockcroft-Gault formula, unless otherwise specified by the testing facility. h) Albumin ≥ 28 g/L (2.8 g/dL) without blood transfusion
i) For patients not receiving anticoagulation therapy: International Normalized Ratio (INR) or Activated Partial Thromboplastin Time (aPTT) ≤ 2 times ULN
j) Urine test strip shows proteinuria < 2+ (within 7 days prior to the start of the intervention)
k) If a 24-hour urine collection shows protein < 1 g within 24 hours, then patients with ≥ 2+ proteinuria on baseline urine test strip analysis are eligible.
1) Cholesterol ≤ 400 mg/dL (or 10.34 mmol/L) and triglycerides ≤ 400 mg/dL (or 4.52 mmol/L) within 28 days prior to randomization (antilipid therapy [excluding fibrate derivatives] is permitted to achieve this threshold).
11. Negative for Human Immunodeficiency Virus (HIV) at screening.
12. Documented hepatitis virological status confirmed by screening tests for Hepatitis B Virus (HBV) and Hepatitis C Virus (HCV).
a) For patients with active HBV: HBV deoxyribonucleic acid (DNA) levels during screening.
< 500 IU/mL, and having started anti-HBV treatment at least 14 days prior to randomization, and willing to continue receiving anti-HBV treatment (according to local standard of care; e.g., nucleoside (acid) analogs) during the trial.
Sexual Behavior and Reproduction
13. For women of fertility: Agree to abstain from sexual intercourse (avoiding heterosexual intercourse) or use two effective methods of contraception (at least one with an annual failure rate < 1%) during treatment, and for at least 5 months after the last dose of atezolizumab, 6 months after the last dose of bevacizumab, or 3 months after the last dose of TPST-1120/placebo (whichever occurs latest).
a) Women of fertility must have a negative serum pregnancy test result within 7 days prior to the start of the trial intervention.
14. For men: Agree to abstain from sexual intercourse (avoiding heterosexual intercourse) or use contraception during treatment and for 6 months after the last dose of bevacizumab or 3 months after the last dose of TPST-1120/placebo (whichever occurs latest), and agree not to donate sperm during this period.
Other: 15. Agree to submit and provide mandatory tumor specimens for central determination of PD-L1 status. This can be stocked tumor specimens (collected ≤ 3 years ago) or fresh tumor sections (if no stocked tissue is available). The quantity and quality of the tissue specimens must be sufficient to define the tumor's PD-L1 status.
Exclusion Criteria
Exclusion Criteria
Patients meeting any of the following criteria are ineligible to participate in this trial:
Disease
1. Known fibrolamellar hepatocellular carcinoma (HCC), sarcomatoid HCC, or a mixed type of cholangiocarcinoma and HCC.
2. History of malignancy other than HCC within the 5 years prior to screening, except for malignancies with negligible risk of metastasis or death (e.g., 5-year overall survival > 90%), such as well-treated cervical carcinoma in situ, non-melanoma skin cancer, low-grade prostate cancer, ductal carcinoma in situ, or stage I uterine cancer.
3. Patients with symptomatic, untreated, or actively progressive central nervous system (CNS) metastases, or a history of any leptomeningeal carcinoma, are ineligible. a) Patients with previously treated CNS lesions are still eligible if they meet all of the following criteria:
i) Measurable lesions outside the CNS are required according to RECIST v1.1.
ii) Baseline contrast-enhanced brain imaging (MRI) must be obtained during screening (MRI is preferred, but CT is also acceptable).
iii) All metastases are confined to the cerebellum or supratentorial region (i.e., no metastases to the midbrain, pons, medulla oblongata, or spinal cord).
iv) All metastases have been treated with definitive therapy, including stereotactic radiotherapy (at least 7 days prior to the start of the trial intervention) or neurosurgical resection (at least 28 days prior to the start of the trial intervention).
v) The patient has no symptoms associated with CNS cancer and has not used corticosteroids for CNS cancer. Stable doses of antiepileptic drugs are permitted.
vi) There is no evidence of CNS disease progression between completion of definitive therapy and randomization. vii) The patient has no history of intracranial or spinal cord hemorrhage.
4. Patients with metastatic disease involving major airways or blood vessels, or mediastinal tumors located centrally (<30 mm from the carina).
a) Patients with involvement of the portal or hepatic veins may be included.
5. Untreated or incompletely treated esophageal and/or gastric venous aneurysms.
a) Patients must undergo esophagogastroduodenoscopy (EGD), and all sizes of venous aneurysms (small to large) must have received definitive treatment (e.g., banding surgery) according to local standards of care prior to trial inclusion.
b) Screening for EGD is not required if EGD and definitive venous aneurysm treatment were completed within 6 months prior to the start of the trial intervention.
6. Bleeding or bleeding events of grade 3 or higher within 8 weeks prior to the start of the trial intervention.
7. History of hemoptysis (coughing up ≥ 2.5 mL of bright red blood per episode) within 1 month prior to the start of the trial intervention.
8. Evidence of bleeding disorder or significant coagulation dysfunction (in the absence of anticoagulant therapy).
9. Poorly controlled hypertension, defined as systolic blood pressure (BP) > 150 mmHg and/or diastolic blood pressure > 100 mmHg, based on the average of at least three measurements taken at two or more different time points.
a) Antihypertensive therapy to achieve these parameters is permitted.
10. History of hypertensive crisis or hypertensive encephalopathy
11. History of hepatic encephalopathy
12. Major vascular disease (e.g., aortic aneurysm requiring surgical repair, or recent peripheral artery thrombosis) within 6 months prior to the start of the trial intervention
13. History of abdominal or tracheoesophageal fistula, gastrointestinal (GI) perforation, or intra-abdominal abscess within 6 months prior to the start of the trial intervention
14. History of intestinal obstruction and/or GI obstruction symptoms before the start of the trial intervention, including sub-occlusive or obstructive syndrome associated with pre-existing conditions, or requiring routine parenteral fluid replacement, parenteral nutrition, or tube feeding
a) Patients with signs or symptoms of sub-occlusive or obstructive syndrome/intestinal obstruction at initial diagnosis who have received decisive (surgical) treatment to relieve symptoms may be included in the trial.
15. Evidence of free air in the abdominal cavity that cannot be explained by paracentesis or recent surgery.
16. Severe unhealed or dehiscent wounds, active ulcers, or untreated fractures.
17. History of a clinically significant intra-abdominal inflammatory process within 6 months prior to the start of the trial intervention, including but not limited to peptic ulcers, diverticulitis, or colitis.
18. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring repeated drainage (≥ once a month).
a) Patients with indwelling catheters (e.g., PleurX®) are permitted.
19. Underwent a core needle biopsy or other minor surgical procedure within 3 days prior to the start of the trial intervention, excluding the placement of vascular access devices.
20. Underwent major surgery, open biopsy, or severe trauma within 28 days prior to the start of the trial intervention; or underwent abdominal surgery, abdominal intervention, or severe abdominal trauma within 60 days prior to the start of the trial intervention; or is expected to require major surgery during the trial, or is unable to recover from any side effects of such surgery.
21. Known active tuberculosis (TB)
a) Patients with a positive tuberculin skin test (PPD) or TB blood test, but subsequently a negative chest X-ray or chest CT scan, are eligible.
22. Uncontrolled tumor-related pain
a) Patients requiring analgesia must have a stable course of treatment at the time of entry into the trial.
b) For symptomatic lesions (e.g., bone metastases or metastases causing nerve compression) suitable for palliative radiation therapy, treatment should be received prior to randomization (see exclusion criterion #33 for clearance period). c) For asymptomatic metastatic lesions that may lead to functional impairment or intractable pain if further growth occurs (e.g., epidural metastases without current spinal cord compression), localized regional therapy should be considered prior to inclusion, if appropriate.
23. Uncontrolled or symptomatic hypercalcemia (ionized calcium > 1.5 mmol/L, calcium > 12 mg/dL, or corrected calcium > ULN)
24. Serum potassium, calcium, or magnesium concentrations that cannot be corrected to > LLN by supplementation
25. Having or having a history of active autoimmune disease or immunodeficiency, including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid syndrome, Wegener's granulomatosis, Shoegrange syndrome, Guillain-Barré syndrome, or multiple sclerosis, except in the following cases:
a) Patients with a history of controlled hypothyroidism or controlled type 1 diabetes who are currently on stable treatment are eligible.
b) Patients with eczema, psoriasis, chronic simple lichen simplex, or vitiligo with only skin manifestations (e.g., excluding patients with psoriatic arthritis) are eligible for this trial if all of the following criteria are met:
i) The rash must cover <10% of the body surface area.
ii) The disease was well controlled at baseline and requires only low-potency topical corticosteroids (US Topical Corticosteroid Grade 6 or 7 or equivalent intensity).
iii) There has been no acute exacerbation of pre-existing disease requiring treatment with psoralen plus UVA, methotrexate, retinoids, biologics, oral calcineurin inhibitors, or high-potency or oral corticosteroids within the past 12 months.
26. History of idiopathic pulmonary fibrosis, organic pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonia, or idiopathic pneumonia, or evidence of active pneumonia on chest CT scan at screening time.
a) History of radiation-induced fibrosis is permitted.
27. Major cardiovascular disease (e.g., New York Heart Association Class II or higher heart disease, myocardial infarction, or cerebrovascular accident), unstable arrhythmia, or unstable angina within 3 months prior to the start of the trial intervention, within 4 weeks prior to the start of the trial intervention, including but not limited to hospitalization due to complications from infection, bacteremia, or severe pneumonia, or any active infection deemed by the trial administrator to potentially affect patient safety.
29. Any other disease, metabolic disorder, physical examination result, or clinical laboratory result that would preclude the use of the investigational drug, potentially affect the interpretation of results, or potentially place the patient at high risk of treatment complications.
30. QTc interval (calculated using the Fridricia method) > 470 ms at screening.
Previous/concomitant therapies:
31. Prior treatment with CD137 agonists or immune checkpoint blockade therapy, including therapeutic antibodies against cytotoxic T-lymphocyte antigen 4 (CTLA-4), anti-programmed cell death protein 1 (PD-1), and anti-PD-L1.
32. Localized liver treatments, including radiofrequency ablation, percutaneous ethanol or acetic acid injection, cryoablation, high-intensity focused ultrasound, transarterial chemoembolization, transarterial yttrium-90 embolization, and transarterial mild embolization, are not permitted within 28 days prior to the start of the trial intervention. (Note that localized liver treatments prior to 28 days are permissible.)
33. External beam radiation therapy is not permitted within 28 days prior to the start of the trial intervention, except in the following circumstances: (i) whole abdominal/pelvic radiation therapy is not permitted within 60 days prior to the start of the trial intervention; (ii) mild radiation therapy to the bone is not permitted within 7 days prior to the start of the trial intervention; and (iii) stereotactic radiation therapy to CNS lesions is not permitted within 7 days prior to the start of the trial intervention.
a) According to exclusion criterion #33, the clearance period for transarterial yttrium-90 embolization of the liver is 28 days.
34. Received a live attenuated vaccine within 4 weeks prior to the start of the trial intervention, or is expected to receive such a vaccine during atezolizumab treatment or within 5 months after the last dose of atezolizumab.
35. Received fibrates (such as gemfibrozil or fenofibrate) within 28 days prior to the start of the trial intervention.
36. Used a potent CYP3A4 inhibitor (such as atazanavir, clarithromycin, grapefruit juice, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, or voriconazole) within 7 days of the start of the trial intervention. ), or potent CYP3A4 inducers (e.g., barbiturates, efavirenz, nevirapine, ritonavir, and topiramate) (30 days for enzalutamide and apalutamide)
37. Current or recent (no more than 10 days prior to the start of the trial intervention) use
a) Daily aspirin ≥ 325 mg or treatment with clopidogrel, dipyridamole, ticlopidine, or cilostazol
b) Use of a full dose of oral or parenteral anticoagulants or thrombolytic agents for therapeutic (not prophylactic) purposes
i) Prophylactic anticoagulation is permitted to maintain patency of the intravenous access device, provided that the drug activity within 14 days prior to the start of the trial intervention results in an INR < 1.5 times the ULN, and aPTT falls within the normal range.
ii) For prophylactic use of anticoagulants or thrombolytic therapy, the locally approved dosage may be used.
38. Use of therapeutic oral or intravenous (IV) antibiotics within 2 weeks prior to the start of the trial intervention to treat any systemic infection:
a) Patients currently receiving prophylactic antibiotic therapy (e.g., to prevent urinary tract infections or exacerbations of chronic obstructive pulmonary disease (COPD)) are still eligible.
39. Treatment with systemic immunostimulants (including, but not limited to, interferon and interleukin (IL)-2) within 4 weeks or 5 drug clearance half-lives (whichever is longer) prior to the start of the trial intervention.
40. Treatment with systemic immunosuppressive drugs (including, but not limited to, more than 10 doses daily) within 2 weeks prior to the start of the trial intervention. Patients receiving an equivalent dose of prednisone (mg) of corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, or anti-tumor necrosis factor (TNF)-α drugs, or who are expected to require systemic immunosuppressants during the trial treatment, are eligible to participate in this trial, except in the following circumstances:
a) Patients receiving acute, low-dose systemic immunosuppressants or a single-pulse dose of systemic immunosuppressants (e.g., 48-hour corticosteroids for contrast agent allergy) are eligible to participate in this trial upon confirmation by a medical monitor.
b) Patients receiving mineralogypsum (such as fludrocortisone) or corticosteroids for COPD or asthma, or low-dose corticosteroids for postural hypotension or adrenal insufficiency, are still eligible.
41. Previous allogeneic stem cell or solid organ transplantation
Previous/concurrent clinical trial experience
42. Received investigational therapy within 28 days prior to the start of the investigational intervention
Other exclusion criteria
43. Known hypersensitivity or allergy to any investigational intervention or any excipient used in the investigational intervention
44. Inability to take the investigational drug orally in its complete dosage form, or any condition that may impair adequate absorption of the investigational drug orally, including refractory nausea and vomiting, uncontrolled diarrhea, malabsorption, major small bowel resection or gastric bypass surgery, or use of an enema tube
45. Pregnancy or breastfeeding female patients
Patients meeting any of the following criteria are ineligible to participate in this trial:
Disease
1. Known fibrolamellar hepatocellular carcinoma (HCC), sarcomatoid HCC, or a mixed type of cholangiocarcinoma and HCC.
2. History of malignancy other than HCC within the 5 years prior to screening, except for malignancies with negligible risk of metastasis or death (e.g., 5-year overall survival > 90%), such as well-treated cervical carcinoma in situ, non-melanoma skin cancer, low-grade prostate cancer, ductal carcinoma in situ, or stage I uterine cancer.
3. Patients with symptomatic, untreated, or actively progressive central nervous system (CNS) metastases, or a history of any leptomeningeal carcinoma, are ineligible. a) Patients with previously treated CNS lesions are still eligible if they meet all of the following criteria:
i) Measurable lesions outside the CNS are required according to RECIST v1.1.
ii) Baseline contrast-enhanced brain imaging (MRI) must be obtained during screening (MRI is preferred, but CT is also acceptable).
iii) All metastases are confined to the cerebellum or supratentorial region (i.e., no metastases to the midbrain, pons, medulla oblongata, or spinal cord).
iv) All metastases have been treated with definitive therapy, including stereotactic radiotherapy (at least 7 days prior to the start of the trial intervention) or neurosurgical resection (at least 28 days prior to the start of the trial intervention).
v) The patient has no symptoms associated with CNS cancer and has not used corticosteroids for CNS cancer. Stable doses of antiepileptic drugs are permitted.
vi) There is no evidence of CNS disease progression between completion of definitive therapy and randomization. vii) The patient has no history of intracranial or spinal cord hemorrhage.
4. Patients with metastatic disease involving major airways or blood vessels, or mediastinal tumors located centrally (<30 mm from the carina).
a) Patients with involvement of the portal or hepatic veins may be included.
5. Untreated or incompletely treated esophageal and/or gastric venous aneurysms.
a) Patients must undergo esophagogastroduodenoscopy (EGD), and all sizes of venous aneurysms (small to large) must have received definitive treatment (e.g., banding surgery) according to local standards of care prior to trial inclusion.
b) Screening for EGD is not required if EGD and definitive venous aneurysm treatment were completed within 6 months prior to the start of the trial intervention.
6. Bleeding or bleeding events of grade 3 or higher within 8 weeks prior to the start of the trial intervention.
7. History of hemoptysis (coughing up ≥ 2.5 mL of bright red blood per episode) within 1 month prior to the start of the trial intervention.
8. Evidence of bleeding disorder or significant coagulation dysfunction (in the absence of anticoagulant therapy).
9. Poorly controlled hypertension, defined as systolic blood pressure (BP) > 150 mmHg and/or diastolic blood pressure > 100 mmHg, based on the average of at least three measurements taken at two or more different time points.
a) Antihypertensive therapy to achieve these parameters is permitted.
10. History of hypertensive crisis or hypertensive encephalopathy
11. History of hepatic encephalopathy
12. Major vascular disease (e.g., aortic aneurysm requiring surgical repair, or recent peripheral artery thrombosis) within 6 months prior to the start of the trial intervention
13. History of abdominal or tracheoesophageal fistula, gastrointestinal (GI) perforation, or intra-abdominal abscess within 6 months prior to the start of the trial intervention
14. History of intestinal obstruction and/or GI obstruction symptoms before the start of the trial intervention, including sub-occlusive or obstructive syndrome associated with pre-existing conditions, or requiring routine parenteral fluid replacement, parenteral nutrition, or tube feeding
a) Patients with signs or symptoms of sub-occlusive or obstructive syndrome/intestinal obstruction at initial diagnosis who have received decisive (surgical) treatment to relieve symptoms may be included in the trial.
15. Evidence of free air in the abdominal cavity that cannot be explained by paracentesis or recent surgery.
16. Severe unhealed or dehiscent wounds, active ulcers, or untreated fractures.
17. History of a clinically significant intra-abdominal inflammatory process within 6 months prior to the start of the trial intervention, including but not limited to peptic ulcers, diverticulitis, or colitis.
18. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring repeated drainage (≥ once a month).
a) Patients with indwelling catheters (e.g., PleurX®) are permitted.
19. Underwent a core needle biopsy or other minor surgical procedure within 3 days prior to the start of the trial intervention, excluding the placement of vascular access devices.
20. Underwent major surgery, open biopsy, or severe trauma within 28 days prior to the start of the trial intervention; or underwent abdominal surgery, abdominal intervention, or severe abdominal trauma within 60 days prior to the start of the trial intervention; or is expected to require major surgery during the trial, or is unable to recover from any side effects of such surgery.
21. Known active tuberculosis (TB)
a) Patients with a positive tuberculin skin test (PPD) or TB blood test, but subsequently a negative chest X-ray or chest CT scan, are eligible.
22. Uncontrolled tumor-related pain
a) Patients requiring analgesia must have a stable course of treatment at the time of entry into the trial.
b) For symptomatic lesions (e.g., bone metastases or metastases causing nerve compression) suitable for palliative radiation therapy, treatment should be received prior to randomization (see exclusion criterion #33 for clearance period). c) For asymptomatic metastatic lesions that may lead to functional impairment or intractable pain if further growth occurs (e.g., epidural metastases without current spinal cord compression), localized regional therapy should be considered prior to inclusion, if appropriate.
23. Uncontrolled or symptomatic hypercalcemia (ionized calcium > 1.5 mmol/L, calcium > 12 mg/dL, or corrected calcium > ULN)
24. Serum potassium, calcium, or magnesium concentrations that cannot be corrected to > LLN by supplementation
25. Having or having a history of active autoimmune disease or immunodeficiency, including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid syndrome, Wegener's granulomatosis, Shoegrange syndrome, Guillain-Barré syndrome, or multiple sclerosis, except in the following cases:
a) Patients with a history of controlled hypothyroidism or controlled type 1 diabetes who are currently on stable treatment are eligible.
b) Patients with eczema, psoriasis, chronic simple lichen simplex, or vitiligo with only skin manifestations (e.g., excluding patients with psoriatic arthritis) are eligible for this trial if all of the following criteria are met:
i) The rash must cover <10% of the body surface area.
ii) The disease was well controlled at baseline and requires only low-potency topical corticosteroids (US Topical Corticosteroid Grade 6 or 7 or equivalent intensity).
iii) There has been no acute exacerbation of pre-existing disease requiring treatment with psoralen plus UVA, methotrexate, retinoids, biologics, oral calcineurin inhibitors, or high-potency or oral corticosteroids within the past 12 months.
26. History of idiopathic pulmonary fibrosis, organic pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonia, or idiopathic pneumonia, or evidence of active pneumonia on chest CT scan at screening time.
a) History of radiation-induced fibrosis is permitted.
27. Major cardiovascular disease (e.g., New York Heart Association Class II or higher heart disease, myocardial infarction, or cerebrovascular accident), unstable arrhythmia, or unstable angina within 3 months prior to the start of the trial intervention, within 4 weeks prior to the start of the trial intervention, including but not limited to hospitalization due to complications from infection, bacteremia, or severe pneumonia, or any active infection deemed by the trial administrator to potentially affect patient safety.
29. Any other disease, metabolic disorder, physical examination result, or clinical laboratory result that would preclude the use of the investigational drug, potentially affect the interpretation of results, or potentially place the patient at high risk of treatment complications.
30. QTc interval (calculated using the Fridricia method) > 470 ms at screening.
Previous/concomitant therapies:
31. Prior treatment with CD137 agonists or immune checkpoint blockade therapy, including therapeutic antibodies against cytotoxic T-lymphocyte antigen 4 (CTLA-4), anti-programmed cell death protein 1 (PD-1), and anti-PD-L1.
32. Localized liver treatments, including radiofrequency ablation, percutaneous ethanol or acetic acid injection, cryoablation, high-intensity focused ultrasound, transarterial chemoembolization, transarterial yttrium-90 embolization, and transarterial mild embolization, are not permitted within 28 days prior to the start of the trial intervention. (Note that localized liver treatments prior to 28 days are permissible.)
33. External beam radiation therapy is not permitted within 28 days prior to the start of the trial intervention, except in the following circumstances: (i) whole abdominal/pelvic radiation therapy is not permitted within 60 days prior to the start of the trial intervention; (ii) mild radiation therapy to the bone is not permitted within 7 days prior to the start of the trial intervention; and (iii) stereotactic radiation therapy to CNS lesions is not permitted within 7 days prior to the start of the trial intervention.
a) According to exclusion criterion #33, the clearance period for transarterial yttrium-90 embolization of the liver is 28 days.
34. Received a live attenuated vaccine within 4 weeks prior to the start of the trial intervention, or is expected to receive such a vaccine during atezolizumab treatment or within 5 months after the last dose of atezolizumab.
35. Received fibrates (such as gemfibrozil or fenofibrate) within 28 days prior to the start of the trial intervention.
36. Used a potent CYP3A4 inhibitor (such as atazanavir, clarithromycin, grapefruit juice, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, or voriconazole) within 7 days of the start of the trial intervention. ), or potent CYP3A4 inducers (e.g., barbiturates, efavirenz, nevirapine, ritonavir, and topiramate) (30 days for enzalutamide and apalutamide)
37. Current or recent (no more than 10 days prior to the start of the trial intervention) use
a) Daily aspirin ≥ 325 mg or treatment with clopidogrel, dipyridamole, ticlopidine, or cilostazol
b) Use of a full dose of oral or parenteral anticoagulants or thrombolytic agents for therapeutic (not prophylactic) purposes
i) Prophylactic anticoagulation is permitted to maintain patency of the intravenous access device, provided that the drug activity within 14 days prior to the start of the trial intervention results in an INR < 1.5 times the ULN, and aPTT falls within the normal range.
ii) For prophylactic use of anticoagulants or thrombolytic therapy, the locally approved dosage may be used.
38. Use of therapeutic oral or intravenous (IV) antibiotics within 2 weeks prior to the start of the trial intervention to treat any systemic infection:
a) Patients currently receiving prophylactic antibiotic therapy (e.g., to prevent urinary tract infections or exacerbations of chronic obstructive pulmonary disease (COPD)) are still eligible.
39. Treatment with systemic immunostimulants (including, but not limited to, interferon and interleukin (IL)-2) within 4 weeks or 5 drug clearance half-lives (whichever is longer) prior to the start of the trial intervention.
40. Treatment with systemic immunosuppressive drugs (including, but not limited to, more than 10 doses daily) within 2 weeks prior to the start of the trial intervention. Patients receiving an equivalent dose of prednisone (mg) of corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, or anti-tumor necrosis factor (TNF)-α drugs, or who are expected to require systemic immunosuppressants during the trial treatment, are eligible to participate in this trial, except in the following circumstances:
a) Patients receiving acute, low-dose systemic immunosuppressants or a single-pulse dose of systemic immunosuppressants (e.g., 48-hour corticosteroids for contrast agent allergy) are eligible to participate in this trial upon confirmation by a medical monitor.
b) Patients receiving mineralogypsum (such as fludrocortisone) or corticosteroids for COPD or asthma, or low-dose corticosteroids for postural hypotension or adrenal insufficiency, are still eligible.
41. Previous allogeneic stem cell or solid organ transplantation
Previous/concurrent clinical trial experience
42. Received investigational therapy within 28 days prior to the start of the investigational intervention
Other exclusion criteria
43. Known hypersensitivity or allergy to any investigational intervention or any excipient used in the investigational intervention
44. Inability to take the investigational drug orally in its complete dosage form, or any condition that may impair adequate absorption of the investigational drug orally, including refractory nausea and vomiting, uncontrolled diarrhea, malabsorption, major small bowel resection or gastric bypass surgery, or use of an enema tube
45. Pregnancy or breastfeeding female patients
The Estimated Number of Participants
-
Taiwan
40 participants
-
Global
740 participants
