Clinical Trials List
Protocol NumberTPST-1120-301
Not yet recruiting
2025-02-03 - 2029-12-23
Phase III
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 Study of TPST-1120 in Combination with Atezolizumab plus Bevacizumab Compared with Placebo plus Atezolizumab plus Bevacizumab in Patients with Unresectable or Metastatic Hepatocellular Carcinoma (HCC) Not Previously Treated with Systemic Therapy
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Trial Applicant
-
Sponsor
Novotech Clinical Research Taiwan PTY LTD.
-
Trial scale
Multi-Regional Multi-Center
-
Update
2026/02/01
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
- 林伯庭 無
- Wei-Chen Lee 無
- 呂嘉偉 無
- 鄭志軒 無
- 王瑜肇 無
- 吳宗翰 無
- Chia-Hsun Hsieh 無
- Kun-Ming Chan 無
- 周宏學 無
- 李勁樵 無
- 李兆偉 無
- 洪豪謙 無
- Yi-Chung Hsieh 無
- 吳庭榕 無
The Actual Total Number of Participants Enrolled
0 Recruiting
Co-Principal Investigator
- Yu-Li Su 無
- Shau-Hsuan Li 無
- 陳彥豪 無
- 郭明濬 無
- 黃詩喻 無
- Tai-Jan Chiu 無
- 林昶廷 無
- 劉建廷 無
- 曾亮節 無
- 吳佳哲 無
The Actual Total Number of Participants Enrolled
0 Recruiting
Co-Principal Investigator
- 邱彥程 無
- 顏志傑 無
- Yih-Jyh Lin 無
- 劉奕廷 無
- Chiu Hung Chiu 無
The Actual Total Number of Participants Enrolled
0 Recruiting
Principal Investigator
Jee-Fu Huang
Co-Principal Investigator
The Actual Total Number of Participants Enrolled
0 Recruiting
Condition/Disease
HCC
Objectives
Primary Objective:
● To evaluate the efficacy of TPST-AB compared with placebo antibody (Pbo-AB).
Secondary Objectives:
● To further evaluate the efficacy of TPST-AB compared with Pbo-AB.
● To assess the correlation between predefined biomarkers and the efficacy of TPST-AB compared with Pbo-AB.
● To evaluate patient-reported outcomes (PROs), including disease- and treatment-related symptoms, health-related quality of life (HRQoL), global health status (GHS), and functional domains, in patients receiving TPST-AB versus Pbo-AB.
● To characterize the population pharmacokinetics (PK) of TPST-1120 using sparse PK sampling.
Safety Objective:
● To evaluate the safety of TPST-AB compared with Pbo-AB.
Test Drug
TPST-1120
Active Ingredient
TPST-1120
Dosage Form
110
Dosage
200 mg
Endpoints
● Overall Survival (OS): Defined as the time from randomization to death from any cause.
Inclution Criteria
Inclusion Criteria
To be eligible for participation in this study, patients must meet all of the following criteria:
Informed Consent
Willing and able to provide written informed consent. If a patient is unable to read, understand, and sign the informed consent form (ICF), a Legally Authorized Representative (LAR) may provide consent on the patient’s behalf, if permitted by the Institutional Review Board (IRB) or Independent Ethics Committee (IEC).
Age
2. Age ≥18 years at the time of signing the ICF.
Patient Type and Disease Characteristics
3. Diagnosis of hepatocellular carcinoma (HCC) confirmed histologically or cytologically, or clinical diagnosis in cirrhotic patients according to the American Association for the Study of Liver Diseases (AASLD) criteria.
a) For patients without cirrhosis, histologic confirmation of HCC is required.
Unresectable or metastatic disease not amenable to curative surgery and/or locoregional therapy.
a) Patients with disease progression following prior surgical and/or locoregional therapy for HCC are eligible.
No prior systemic therapy for HCC (including investigational systemic agents).
a) Prior use of herbal or traditional Chinese medicines with claimed antineoplastic activity is allowed, provided these agents were discontinued at least 14 days before initiation of study treatment.
At least one measurable, untreated lesion per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
a) Patients with prior locoregional therapy (e.g., radiofrequency ablation, percutaneous ethanol or acetic acid injection, cryoablation, high-intensity focused ultrasound, transarterial chemoembolization, or transarterial embolization) are eligible, provided that:
The target lesion has not been previously treated, or
If treated, the lesion shows progression within or adjacent to the treated area as per RECIST v1.1.
Any clinically significant acute toxicities from prior therapy must have resolved to ≤ Grade 1 (except for alopecia) before study entry.
Diagnostic Assessment
8. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 within 7 days before randomization.
9. Child–Turcotte–Pugh (Child–Pugh) class A liver function within 7 days before randomization.
10. Adequate organ and bone marrow function, as defined by the following laboratory parameters (unless otherwise specified, obtained within 7 days before randomization):
a) Absolute neutrophil count (ANC) ≥ 1.5 × 10⁹/L (1,500/μL), without granulocyte colony-stimulating factor.
b) Lymphocyte count ≥ 0.5 × 10⁹/L (500/μL).
c) Platelet count ≥ 75 × 10⁹/L (75,000/μL), without transfusion.
d) Hemoglobin ≥ 90 g/L (9 g/dL) (transfusions allowed to meet this criterion).
e) AST, ALT, and alkaline phosphatase (ALP) ≤ 5 × upper limit of normal (ULN).
f) Total bilirubin ≤ 3 × ULN.
g) Creatinine clearance ≥ 50 mL/min (by Cockcroft–Gault formula or per institutional standard).
h) Serum albumin ≥ 28 g/L (2.8 g/dL), without albumin transfusion.
i) For patients not receiving anticoagulant therapy: international normalized ratio (INR) or activated partial thromboplastin time (aPTT) ≤ 2 × ULN.
j) Urinalysis by dipstick showing proteinuria < 2+ within 7 days before study intervention.
k) If dipstick shows ≥ 2+ proteinuria, eligibility may be met if 24-hour urine protein < 1 g.
l) Total cholesterol ≤ 400 mg/dL (10.34 mmol/L) and triglycerides ≤ 400 mg/dL (4.52 mmol/L) within 28 days before randomization (lipid-lowering therapy permitted, excluding fibrates).
Negative test result for human immunodeficiency virus (HIV) at screening.
Documented hepatitis viral status confirmed by screening for hepatitis B virus (HBV) and hepatitis C virus (HCV):
a) For participants with active HBV infection: HBV DNA < 500 IU/mL at screening, on antiviral therapy for at least 14 days prior to randomization, and willing to continue antiviral treatment during the study (per local standard of care, e.g., nucleos[t]ide analogs).
Reproductive and Sexual Health
13. Females of childbearing potential: must agree to remain abstinent (refrain from heterosexual intercourse) or use two effective methods of contraception (at least one with <1% annual failure rate) 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 is longer).
In addition, they must not donate eggs during this period.
a) A negative serum pregnancy test is required within 7 days before the start of study intervention.
Males: must agree to remain abstinent (refrain from heterosexual intercourse) or use contraception during treatment and for at least:
6 months after the last dose of bevacizumab, or
3 months after the last dose of TPST-1120/placebo (whichever is longer),
and must not donate sperm during this period.
Other Requirements
15. Willing to submit and provide a mandatory tumor tissue sample for central assessment of PD-L1 status. The specimen may be an archival tumor sample (collected within ≤3 years) or a fresh tumor biopsy if archival tissue is unavailable. The quantity and quality of the sample must be sufficient to determine PD-L1 status.
To be eligible for participation in this study, patients must meet all of the following criteria:
Informed Consent
Willing and able to provide written informed consent. If a patient is unable to read, understand, and sign the informed consent form (ICF), a Legally Authorized Representative (LAR) may provide consent on the patient’s behalf, if permitted by the Institutional Review Board (IRB) or Independent Ethics Committee (IEC).
Age
2. Age ≥18 years at the time of signing the ICF.
Patient Type and Disease Characteristics
3. Diagnosis of hepatocellular carcinoma (HCC) confirmed histologically or cytologically, or clinical diagnosis in cirrhotic patients according to the American Association for the Study of Liver Diseases (AASLD) criteria.
a) For patients without cirrhosis, histologic confirmation of HCC is required.
Unresectable or metastatic disease not amenable to curative surgery and/or locoregional therapy.
a) Patients with disease progression following prior surgical and/or locoregional therapy for HCC are eligible.
No prior systemic therapy for HCC (including investigational systemic agents).
a) Prior use of herbal or traditional Chinese medicines with claimed antineoplastic activity is allowed, provided these agents were discontinued at least 14 days before initiation of study treatment.
At least one measurable, untreated lesion per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
a) Patients with prior locoregional therapy (e.g., radiofrequency ablation, percutaneous ethanol or acetic acid injection, cryoablation, high-intensity focused ultrasound, transarterial chemoembolization, or transarterial embolization) are eligible, provided that:
The target lesion has not been previously treated, or
If treated, the lesion shows progression within or adjacent to the treated area as per RECIST v1.1.
Any clinically significant acute toxicities from prior therapy must have resolved to ≤ Grade 1 (except for alopecia) before study entry.
Diagnostic Assessment
8. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 within 7 days before randomization.
9. Child–Turcotte–Pugh (Child–Pugh) class A liver function within 7 days before randomization.
10. Adequate organ and bone marrow function, as defined by the following laboratory parameters (unless otherwise specified, obtained within 7 days before randomization):
a) Absolute neutrophil count (ANC) ≥ 1.5 × 10⁹/L (1,500/μL), without granulocyte colony-stimulating factor.
b) Lymphocyte count ≥ 0.5 × 10⁹/L (500/μL).
c) Platelet count ≥ 75 × 10⁹/L (75,000/μL), without transfusion.
d) Hemoglobin ≥ 90 g/L (9 g/dL) (transfusions allowed to meet this criterion).
e) AST, ALT, and alkaline phosphatase (ALP) ≤ 5 × upper limit of normal (ULN).
f) Total bilirubin ≤ 3 × ULN.
g) Creatinine clearance ≥ 50 mL/min (by Cockcroft–Gault formula or per institutional standard).
h) Serum albumin ≥ 28 g/L (2.8 g/dL), without albumin transfusion.
i) For patients not receiving anticoagulant therapy: international normalized ratio (INR) or activated partial thromboplastin time (aPTT) ≤ 2 × ULN.
j) Urinalysis by dipstick showing proteinuria < 2+ within 7 days before study intervention.
k) If dipstick shows ≥ 2+ proteinuria, eligibility may be met if 24-hour urine protein < 1 g.
l) Total cholesterol ≤ 400 mg/dL (10.34 mmol/L) and triglycerides ≤ 400 mg/dL (4.52 mmol/L) within 28 days before randomization (lipid-lowering therapy permitted, excluding fibrates).
Negative test result for human immunodeficiency virus (HIV) at screening.
Documented hepatitis viral status confirmed by screening for hepatitis B virus (HBV) and hepatitis C virus (HCV):
a) For participants with active HBV infection: HBV DNA < 500 IU/mL at screening, on antiviral therapy for at least 14 days prior to randomization, and willing to continue antiviral treatment during the study (per local standard of care, e.g., nucleos[t]ide analogs).
Reproductive and Sexual Health
13. Females of childbearing potential: must agree to remain abstinent (refrain from heterosexual intercourse) or use two effective methods of contraception (at least one with <1% annual failure rate) 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 is longer).
In addition, they must not donate eggs during this period.
a) A negative serum pregnancy test is required within 7 days before the start of study intervention.
Males: must agree to remain abstinent (refrain from heterosexual intercourse) or use contraception during treatment and for at least:
6 months after the last dose of bevacizumab, or
3 months after the last dose of TPST-1120/placebo (whichever is longer),
and must not donate sperm during this period.
Other Requirements
15. Willing to submit and provide a mandatory tumor tissue sample for central assessment of PD-L1 status. The specimen may be an archival tumor sample (collected within ≤3 years) or a fresh tumor biopsy if archival tissue is unavailable. The quantity and quality of the sample must be sufficient to determine PD-L1 status.
Exclusion Criteria
Exclusion Criteria
Patients are ineligible if any of the following apply:
Disease-Related
Known fibrolamellar histology, sarcomatoid hepatocellular carcinoma (HCC), or combined hepatocellular–cholangiocarcinoma.
History of a malignancy other than HCC within 5 years prior to screening, except malignancies with negligible risk of metastasis or death (e.g., 5-year overall survival >90%), such as adequately treated carcinoma in situ of the cervix, non-melanoma skin cancer, low-grade prostate cancer, ductal carcinoma in situ, or stage I endometrial cancer.
Symptomatic, untreated, or actively progressing central nervous system (CNS) metastases, or any history of leptomeningeal disease.
a) Patients with previously treated CNS lesions are eligible if all of the following are met:
i) A measurable lesion exists outside the CNS per RECIST v1.1;
ii) Contrast-enhanced brain imaging at screening (preferably MRI; CT acceptable) is obtained;
iii) Metastases are confined to the cerebellum or supratentorial regions (i.e., none in midbrain, pons, medulla, or spinal cord);
iv) All CNS lesions received definitive therapy (e.g., stereotactic radiotherapy ≥7 days before study start, or neurosurgical resection ≥28 days before study start);
v) No CNS cancer–related symptoms and no corticosteroids for CNS disease (stable antiepileptics allowed);
vi) No evidence of CNS disease progression between definitive therapy and randomization;
vii) No history of intracranial or spinal hemorrhage.
Metastatic disease involving major airways or major vessels, or a central mediastinal mass (<30 mm from the carina).
a) Portal or hepatic vein invasion is permitted.
Untreated or incompletely treated esophageal and/or gastric varices.
a) Esophagogastroduodenoscopy (EGD) is required, and all varices (small to large) must receive definitive therapy per local standard of care (e.g., band ligation) prior to enrollment.
b) If EGD and definitive variceal therapy were completed within 6 months prior to study start, a screening EGD is not required.
Grade ≥3 bleeding/hemorrhage within 8 weeks before first study intervention.
History of hemoptysis within 1 month prior to first dose (≥2.5 mL bright red blood per episode).
Evidence of a bleeding diathesis or significant coagulopathy (in the absence of anticoagulation).
Uncontrolled hypertension, defined as average systolic BP >150 mmHg and/or diastolic BP >100 mmHg based on ≥3 measurements at ≥2 time points.
a) Antihypertensive therapy to achieve control is allowed.
History of hypertensive crisis or hypertensive encephalopathy.
History of hepatic encephalopathy.
Major vascular disease within 6 months prior to study start (e.g., aortic aneurysm requiring repair, recent peripheral arterial thrombosis).
History of tracheoesophageal or abdominal fistula, gastrointestinal (GI) perforation, or intra-abdominal abscess within 6 months.
History and/or symptoms of bowel obstruction or GI obstructive syndrome, including sub-occlusion/occlusion due to underlying disease, or need for routine parenteral hydration/nutrition or tube feeding.
a) Patients with signs/symptoms of sub-occlusion/occlusion at initial diagnosis are eligible if they received definitive (surgical) treatment to relieve symptoms.
Evidence of free intraperitoneal air not explained by paracentesis or recent surgery.
Serious non-healing or dehiscent wound, active ulcer, or untreated fracture.
Clinically significant intra-abdominal inflammatory process within 6 months prior to study start (e.g., peptic ulcer disease, diverticulitis, colitis).
Uncontrolled pleural effusion, pericardial effusion, or ascites requiring repeated drainage (≥ once monthly).
a) Indwelling catheters (e.g., PleurX®) are allowed.
Core-needle biopsy or other minor surgery within 3 days before study start (excluding vascular access device placement).
Major surgery, open biopsy, or significant trauma within 28 days; abdominal surgery/intervention or significant abdominal trauma within 60 days; anticipated need for major surgery during the study; or failure to recover from effects of any such procedures.
Known active tuberculosis (TB).
a) Patients with a positive PPD or TB blood test and a negative chest X-ray/CT are eligible.
Uncontrolled tumor-related pain.
a) Patients requiring analgesics must be on a stable regimen at study entry.
b) Symptomatic lesions appropriate for palliative radiotherapy (e.g., bone metastases or lesions causing nerve compression) should be treated prior to randomization (see washouts in Exclusion #33).
c) For asymptomatic metastatic lesions that could lead to functional deficits or refractory pain if they progress (e.g., epidural metastases without current cord compression), consider locoregional therapy prior to enrollment when appropriate.
Uncontrolled or symptomatic hypercalcemia (ionized Ca >1.5 mmol/L, total Ca >12 mg/dL, or corrected Ca > ULN).
Serum potassium, calcium, or magnesium levels that cannot be corrected to > lower limit of normal (LLN) with supplementation.
Active autoimmune disease or immunodeficiency, or a history thereof (including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener’s granulomatosis, Sjögren’s syndrome, Guillain-Barré syndrome, or multiple sclerosis), except:
a) Controlled hypothyroidism or type 1 diabetes mellitus on stable therapy;
b) Patients with eczema, psoriasis, chronic lichen simplex, or vitiligo with skin-only involvement (excluding psoriatic arthritis) are eligible if all of the following apply:
i) Rash involves <10% body surface area;
ii) Disease is well-controlled at baseline and requires only low-potency topical corticosteroids (U.S. class 6 or 7 or equivalent);
iii) No acute exacerbations of the condition in the past 12 months requiring PUVA, methotrexate, retinoids, biologics, oral calcineurin inhibitors, or high-potency/oral corticosteroids.
History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT.
a) History of radiation-induced fibrosis is allowed.
Major cardiovascular disease within 3 months prior to study start (e.g., NYHA class ≥II heart disease, myocardial infarction, or cerebrovascular accident), unstable arrhythmia, or unstable angina.
Severe infection within 4 weeks prior to study start, including hospitalization for infection, bacteremia, or severe pneumonia, or any active infection that, in the investigator’s judgment, may compromise patient safety.
Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory result that would contraindicate the use of study drugs, could interfere with interpretation of results, or may place the patient at high risk for treatment complications.
QTc interval (Fridericia) >470 ms at screening.
Prior/Concomitant Therapies
31. Prior treatment with a CD137 agonist or immune checkpoint inhibitors, including anti-CTLA-4, anti-PD-1, or anti-PD-L1 antibodies.
32. Liver-directed locoregional therapy within 28 days before first study intervention (e.g., radiofrequency ablation, percutaneous ethanol or acetic acid injection, cryoablation, high-intensity focused ultrasound, transarterial chemoembolization, transarterial embolization, or Y-90 radioembolization).
33. External-beam radiotherapy within 28 days before first study intervention, with exceptions:
i) Whole-abdomen/pelvis radiotherapy within 60 days is not allowed;
ii) Palliative radiotherapy to bone within 7 days is not allowed;
iii) Stereotactic radiotherapy to CNS lesions within 7 days is not allowed.
a) Per #33, the washout for Y-90 radioembolization is 28 days.
Receipt of a live attenuated vaccine within 4 weeks prior to study start, or anticipated need for such vaccines during atezolizumab therapy or within 5 months after the last atezolizumab dose.
Treatment with fibrates (e.g., gemfibrozil, fenofibrate) within 28 days prior to study start.
Use within 7 days prior to study start of strong CYP3A4 inhibitors (e.g., atazanavir, clarithromycin, grapefruit juice, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) or strong CYP3A4 inducers (e.g., barbiturates, efavirenz, nevirapine, ritonavir, topiramate); 30 days for enzalutamide and apalutamide.
Current or recent use (≤10 days before study start) of:
a) Aspirin ≥325 mg/day, or treatment with clopidogrel, dipyridamole, ticlopidine, or cilostazol;
b) Therapeutic-dose oral or parenteral anticoagulants or thrombolytics (prophylactic anticoagulation to maintain catheter patency is allowed if, within 14 days before study start, the drug effect results in INR <1.5 × ULN and aPTT within normal range; use prophylactic doses per approved labeling).
Therapeutic oral or intravenous antibiotics for any systemic infection within 2 weeks before study start.
a) Prophylactic antibiotics (e.g., for UTI prevention or COPD exacerbation prevention) are allowed.
Systemic immunostimulants (including but not limited to interferons or interleukin-2) within 4 weeks or 5 drug half-lives before study start (whichever is longer).
Systemic immunosuppressive therapy within 2 weeks before study start (including but not limited to >10 mg/day prednisone equivalent corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, or anti–TNF-α agents), except:
a) Acute, low-dose systemic immunosuppression or a single pulse dose (e.g., 48-hour corticosteroid premedication for contrast allergy) with medical monitor approval;
b) Mineralocorticoids or inhaled corticosteroids for COPD/asthma, or low-dose corticosteroids for orthostatic hypotension or adrenal insufficiency.
Prior allogeneic stem-cell or solid-organ transplantation.
Prior/Concurrent Clinical Trial Participation
42. Receipt of an investigational therapy within 28 days prior to study start.
Other Exclusions
43. Known allergy or hypersensitivity to any study intervention or its excipients.
44. Inability to swallow intact oral dosage forms, or any condition likely to interfere with adequate oral absorption (including intractable nausea/vomiting, uncontrolled diarrhea, malabsorption, major small-bowel resection or gastric bypass, or use of a feeding tube).
45. Pregnant or breastfeeding women.
Patients are ineligible if any of the following apply:
Disease-Related
Known fibrolamellar histology, sarcomatoid hepatocellular carcinoma (HCC), or combined hepatocellular–cholangiocarcinoma.
History of a malignancy other than HCC within 5 years prior to screening, except malignancies with negligible risk of metastasis or death (e.g., 5-year overall survival >90%), such as adequately treated carcinoma in situ of the cervix, non-melanoma skin cancer, low-grade prostate cancer, ductal carcinoma in situ, or stage I endometrial cancer.
Symptomatic, untreated, or actively progressing central nervous system (CNS) metastases, or any history of leptomeningeal disease.
a) Patients with previously treated CNS lesions are eligible if all of the following are met:
i) A measurable lesion exists outside the CNS per RECIST v1.1;
ii) Contrast-enhanced brain imaging at screening (preferably MRI; CT acceptable) is obtained;
iii) Metastases are confined to the cerebellum or supratentorial regions (i.e., none in midbrain, pons, medulla, or spinal cord);
iv) All CNS lesions received definitive therapy (e.g., stereotactic radiotherapy ≥7 days before study start, or neurosurgical resection ≥28 days before study start);
v) No CNS cancer–related symptoms and no corticosteroids for CNS disease (stable antiepileptics allowed);
vi) No evidence of CNS disease progression between definitive therapy and randomization;
vii) No history of intracranial or spinal hemorrhage.
Metastatic disease involving major airways or major vessels, or a central mediastinal mass (<30 mm from the carina).
a) Portal or hepatic vein invasion is permitted.
Untreated or incompletely treated esophageal and/or gastric varices.
a) Esophagogastroduodenoscopy (EGD) is required, and all varices (small to large) must receive definitive therapy per local standard of care (e.g., band ligation) prior to enrollment.
b) If EGD and definitive variceal therapy were completed within 6 months prior to study start, a screening EGD is not required.
Grade ≥3 bleeding/hemorrhage within 8 weeks before first study intervention.
History of hemoptysis within 1 month prior to first dose (≥2.5 mL bright red blood per episode).
Evidence of a bleeding diathesis or significant coagulopathy (in the absence of anticoagulation).
Uncontrolled hypertension, defined as average systolic BP >150 mmHg and/or diastolic BP >100 mmHg based on ≥3 measurements at ≥2 time points.
a) Antihypertensive therapy to achieve control is allowed.
History of hypertensive crisis or hypertensive encephalopathy.
History of hepatic encephalopathy.
Major vascular disease within 6 months prior to study start (e.g., aortic aneurysm requiring repair, recent peripheral arterial thrombosis).
History of tracheoesophageal or abdominal fistula, gastrointestinal (GI) perforation, or intra-abdominal abscess within 6 months.
History and/or symptoms of bowel obstruction or GI obstructive syndrome, including sub-occlusion/occlusion due to underlying disease, or need for routine parenteral hydration/nutrition or tube feeding.
a) Patients with signs/symptoms of sub-occlusion/occlusion at initial diagnosis are eligible if they received definitive (surgical) treatment to relieve symptoms.
Evidence of free intraperitoneal air not explained by paracentesis or recent surgery.
Serious non-healing or dehiscent wound, active ulcer, or untreated fracture.
Clinically significant intra-abdominal inflammatory process within 6 months prior to study start (e.g., peptic ulcer disease, diverticulitis, colitis).
Uncontrolled pleural effusion, pericardial effusion, or ascites requiring repeated drainage (≥ once monthly).
a) Indwelling catheters (e.g., PleurX®) are allowed.
Core-needle biopsy or other minor surgery within 3 days before study start (excluding vascular access device placement).
Major surgery, open biopsy, or significant trauma within 28 days; abdominal surgery/intervention or significant abdominal trauma within 60 days; anticipated need for major surgery during the study; or failure to recover from effects of any such procedures.
Known active tuberculosis (TB).
a) Patients with a positive PPD or TB blood test and a negative chest X-ray/CT are eligible.
Uncontrolled tumor-related pain.
a) Patients requiring analgesics must be on a stable regimen at study entry.
b) Symptomatic lesions appropriate for palliative radiotherapy (e.g., bone metastases or lesions causing nerve compression) should be treated prior to randomization (see washouts in Exclusion #33).
c) For asymptomatic metastatic lesions that could lead to functional deficits or refractory pain if they progress (e.g., epidural metastases without current cord compression), consider locoregional therapy prior to enrollment when appropriate.
Uncontrolled or symptomatic hypercalcemia (ionized Ca >1.5 mmol/L, total Ca >12 mg/dL, or corrected Ca > ULN).
Serum potassium, calcium, or magnesium levels that cannot be corrected to > lower limit of normal (LLN) with supplementation.
Active autoimmune disease or immunodeficiency, or a history thereof (including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener’s granulomatosis, Sjögren’s syndrome, Guillain-Barré syndrome, or multiple sclerosis), except:
a) Controlled hypothyroidism or type 1 diabetes mellitus on stable therapy;
b) Patients with eczema, psoriasis, chronic lichen simplex, or vitiligo with skin-only involvement (excluding psoriatic arthritis) are eligible if all of the following apply:
i) Rash involves <10% body surface area;
ii) Disease is well-controlled at baseline and requires only low-potency topical corticosteroids (U.S. class 6 or 7 or equivalent);
iii) No acute exacerbations of the condition in the past 12 months requiring PUVA, methotrexate, retinoids, biologics, oral calcineurin inhibitors, or high-potency/oral corticosteroids.
History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT.
a) History of radiation-induced fibrosis is allowed.
Major cardiovascular disease within 3 months prior to study start (e.g., NYHA class ≥II heart disease, myocardial infarction, or cerebrovascular accident), unstable arrhythmia, or unstable angina.
Severe infection within 4 weeks prior to study start, including hospitalization for infection, bacteremia, or severe pneumonia, or any active infection that, in the investigator’s judgment, may compromise patient safety.
Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory result that would contraindicate the use of study drugs, could interfere with interpretation of results, or may place the patient at high risk for treatment complications.
QTc interval (Fridericia) >470 ms at screening.
Prior/Concomitant Therapies
31. Prior treatment with a CD137 agonist or immune checkpoint inhibitors, including anti-CTLA-4, anti-PD-1, or anti-PD-L1 antibodies.
32. Liver-directed locoregional therapy within 28 days before first study intervention (e.g., radiofrequency ablation, percutaneous ethanol or acetic acid injection, cryoablation, high-intensity focused ultrasound, transarterial chemoembolization, transarterial embolization, or Y-90 radioembolization).
33. External-beam radiotherapy within 28 days before first study intervention, with exceptions:
i) Whole-abdomen/pelvis radiotherapy within 60 days is not allowed;
ii) Palliative radiotherapy to bone within 7 days is not allowed;
iii) Stereotactic radiotherapy to CNS lesions within 7 days is not allowed.
a) Per #33, the washout for Y-90 radioembolization is 28 days.
Receipt of a live attenuated vaccine within 4 weeks prior to study start, or anticipated need for such vaccines during atezolizumab therapy or within 5 months after the last atezolizumab dose.
Treatment with fibrates (e.g., gemfibrozil, fenofibrate) within 28 days prior to study start.
Use within 7 days prior to study start of strong CYP3A4 inhibitors (e.g., atazanavir, clarithromycin, grapefruit juice, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) or strong CYP3A4 inducers (e.g., barbiturates, efavirenz, nevirapine, ritonavir, topiramate); 30 days for enzalutamide and apalutamide.
Current or recent use (≤10 days before study start) of:
a) Aspirin ≥325 mg/day, or treatment with clopidogrel, dipyridamole, ticlopidine, or cilostazol;
b) Therapeutic-dose oral or parenteral anticoagulants or thrombolytics (prophylactic anticoagulation to maintain catheter patency is allowed if, within 14 days before study start, the drug effect results in INR <1.5 × ULN and aPTT within normal range; use prophylactic doses per approved labeling).
Therapeutic oral or intravenous antibiotics for any systemic infection within 2 weeks before study start.
a) Prophylactic antibiotics (e.g., for UTI prevention or COPD exacerbation prevention) are allowed.
Systemic immunostimulants (including but not limited to interferons or interleukin-2) within 4 weeks or 5 drug half-lives before study start (whichever is longer).
Systemic immunosuppressive therapy within 2 weeks before study start (including but not limited to >10 mg/day prednisone equivalent corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, or anti–TNF-α agents), except:
a) Acute, low-dose systemic immunosuppression or a single pulse dose (e.g., 48-hour corticosteroid premedication for contrast allergy) with medical monitor approval;
b) Mineralocorticoids or inhaled corticosteroids for COPD/asthma, or low-dose corticosteroids for orthostatic hypotension or adrenal insufficiency.
Prior allogeneic stem-cell or solid-organ transplantation.
Prior/Concurrent Clinical Trial Participation
42. Receipt of an investigational therapy within 28 days prior to study start.
Other Exclusions
43. Known allergy or hypersensitivity to any study intervention or its excipients.
44. Inability to swallow intact oral dosage forms, or any condition likely to interfere with adequate oral absorption (including intractable nausea/vomiting, uncontrolled diarrhea, malabsorption, major small-bowel resection or gastric bypass, or use of a feeding tube).
45. Pregnant or breastfeeding women.
The Estimated Number of Participants
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Taiwan
40 participants
-
Global
740 participants
