A Phase II Study to Evaluate the Efficacy and Safety of Y-90, Durvalumab, Tremelimumab, and Zanzalintinib in Patients With Unresectable and Locally-Advanced Hepatocellular Carcinoma
试验速览
- 阶段
- 2 期
- 状态
- 尚未招募
- 入组人数
- 40
- 试验地点
- 1
- 主要终点
- Proportion of progression-free at 6-months
研究概览
简要总结
This phase II trial tests how well giving Y-90 radioembolization, durvalumab, tremelimumab and zanzalintinib works for the treatment of hepatocellular carcinoma that cannot be removed by surgery (unresectable) and that has spread to nearby tissue or lymph nodes (locally advanced). Y-90 radioembolization is a therapy that injects radioactive particles directly into an artery that feeds liver tumors to cut off their blood supply. Immunotherapy with monoclonal antibodies, such as durvalumab and tremelimumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Zanzalintinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving Y-90 radioembolization, durvalumab, tremelimumab and zanzalintinib may be effective for treating unresectable and locally-advanced hepatocellular carcinoma.
详细描述
PRIMARY OBJECTIVE:
I. To assess proportion of participants that are progression-free at 6 months.
SECONDARY OBJECTIVES:
I. To assess safety of study intervention. II. To estimate objective response rate (ORR) for study intervention. III. To estimate disease control rate (DCR) for study intervention. IV. To estimate time to disease progression (TTP) for study intervention. V. To estimate progression-free survival. VI. To estimate overall survival (OS) for study intervention.
EXPLORATORY OBJECTIVE:
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Participant must provide written informed consent before any study-specific procedures or interventions are performed
- •Participants aged ≥ 18 years
- •Body weight > 30 kg
- •Patients must have radiologically, or histologically or cytologically confirmed hepatocellular cancer that is not amenable to transplant or resection:
- •Barcelona Clinic Liver Cancer Stage B or C
- •Cirrhosis grade of Child-Pugh (CP) A or CP-B7 (excluding albumin-bilirubin [ALBI] grade 3)
- •Fibrolamellar and mixed hepatocellular/cholangiocarcinoma subtypes are not eligible
- •Disease must not be amenable to surgical resection, transplantation, or thermal ablation, or recurrent hepatocellular carcinoma (HCC) after a previous definitive therapy (surgery or thermoablative therapy)
- •Venous invasion (portal, hepatic, biliary) and infiltrative growth pattern are eligible
- •Eligible for Y-90 transarterial radioembolization (TARE) based on planning angiogram, with evidence of:
- •≥ 30% hepatic reserve (i.e., untreated background liver) AND
- •Estimated lung exposure < 30 Gy/ treatment (or 50 Gy cumulative total)
- •Patients with bi-lobar disease amenable to simultaneous or sequential TARE are eligible
- •Eastern Cooperative Oncology Group (ECOG) 0 - 1 at enrollment
- •Recovery to baseline or ≤ grade 1 (per Common Terminology Criteria for Adverse Events [CTCAE] version [v] 5.0) from toxicities related to any prior treatments, unless adverse events (AE[s]) are clinically non-significant and/or stable on supportive therapy
- •Hemoglobin ≥ 9 g/dL (≥ 90 g/L) (within 14 days before first dose of study treatment)
- •White blood cell count ≥ 2500/μL (within 14 days before first dose of study treatment)
- •Absolute neutrophil count (ANC) ≥ 1.5 × 10^9/L (1500/μL), without granulocyte colony-stimulating factor support within 2 weeks of screening laboratory sample collection (within 14 days before first dose of study treatment)
- •Platelet count ≥ 75 × 10^9/L (≥ 75,000/μL), without transfusion within 2 weeks of screening laboratory sample collection (within 14 days before first dose of study treatment)
- •Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤ 5 x upper limit of normal (ULN) (within 14 days before first dose of study treatment)
- •Alkaline phosphatase (ALP) ≤ 5 x ULN (within 14 days before first dose of study treatment)
- •Total bilirubin ≤ 2 mg/dL (≤ 34.2 μmol/L) or < 2 x ULN, whichever is higher (within 14 days before first dose of study treatment)
- •Serum albumin ≥ 2.8 g/dL (within 14 days before first dose of study treatment)
- •International normalized ratio (INR) ≤ 1.7 x laboratory ULN (within 14 days before first dose of study treatment)
- •Stable renal function defined as serum creatinine ≤ 1.5 x ULN or calculated creatinine clearance (CrCL) ≥ 40mL/min (≥ 0.675mL/sec) using the Cockcroft-Gault equation (within 14 days before first dose of study treatment)
- •Urine protein/creatinine ratio (UPCR) ≤ 1 mg/mg (≤ 113.2 mg/mmol), or 24-h urine protein ≤ 1 g (within 14 days before first dose of study treatment)
- •Has at least one measurable target lesion based on modified Response Evaluation Criteria in Solid Tumors (mRECIST)
- •Participants must have at least one lesion that is amendable to biopsy
- •Participant are asked to consent to tumor biopsies for biomarker analysis of the acquired tissue at the following timepoints: pre-treatment, on-treatment (i.e., after completing the initial combination cycle of durvalumab, tremelimumab and zanzalintinib), and at time of disease progression. These biopsies are optional and are not required for study participation
- •Sexually active fertile participants and their partners must agree to use medically accepted methods of contraception (e.g., barrier methods, including male condom, female condom, or diaphragm with spermicidal gel) during the course of the study and for:
- •96 days for sperm-producing participants or
- •186 days for participants of child-bearing potential (POCBP) after the last dose of zanzalintinib. Additionally, sperm-producing participants must agree not to donate sperm and POCBP must agree to not donate eggs (ova, oocyte) for the purpose of reproduction during these same periods
- •POCBP must not be pregnant at screening. POCBP participants are considered to be of childbearing potential unless one of the following criteria is met:
- •Documented permanent sterilization (hysterectomy, bilateral salpingectomy, or bilateral oophorectomy) or documented postmenopausal status (defined as 12 months of amenorrhea in a woman > 45 years-of-age in the absence of other biological or physiological causes.
- •Participants < 55 years-of-age must have a serum follicle stimulating (FSH) level > 40 mIU/mL to confirm menopause).
- •Note: Documentation may include review of medical records, medical examinations, or medical history interview by study site
排除标准
- •Another primary tumor
- •Extrahepatic metastases
- •Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery (including radiosurgery) and stable for at least 4 weeks before first dose of study treatment.
- •Note: Eligible participants must be neurologically asymptomatic and without corticosteroid treatment at the time of enrollment.
- •Note: Base of skull lesions without definitive evidence of dural or brain parenchymal involvement are allowed
- •Prior systemic therapy for HCC
- •Prior Y-90 radioembolization
- •Note: prior transarterial chemoembolization is permitted if > 6 months prior to enrollment
- •Advanced liver disease with a CP-B7 (ALBI grade 3), CP-B8, CP-B9 or CP- C, or active gastrointestinal bleeding or encephalopathy or refractory ascites
- •Radiation therapy within 4 weeks before first dose of study treatment. Systemic treatment with radionuclides within 6 weeks before first dose of study treatment. Subjects with clinically relevant ongoing complications from prior radiation therapy are not eligible
- •Prior treatment with an anti-PD-1, anti-PD-L1, or anti-CTLA4 agent, or with an agent directed to another co-inhibitory T-cell receptor (e.g., TIGIT, LAG-3, TIM-3)
- •Prior treatment with zanzalintinib, cabozantinib, or similar class of multitargeted Tyrosine Kinase Inhibitor (mTKI)
- •Receipt of any type of small molecule kinase inhibitor (including investigational kinase inhibitor) within 2 weeks before first dose of study treatment
- •Participants cannot be on other forms of anti-cancer therapy at the same time, except as described within this protocol
- •Concomitant anticoagulation with coumarin agents (e.g., warfarin), direct thrombin inhibitors (e.g., dabigatran), direct factor Xa inhibitors (e.g., rivaroxaban), or platelet inhibitors (e.g., clopidogrel). Allowed anticoagulants are the following:
- •Prophylactic use of low-dose aspirin for cardio-protection (per local applicable guidelines) and low dose low molecular weight heparins (LMWH).
- •Therapeutic doses of LMWH or anticoagulation with direct factor Xa inhibitors rivaroxaban, edoxaban, or apixaban in participants without known brain metastases who are on a stable dose of the anticoagulant for at least 1 week before first dose of study treatment without clinically significant hemorrhagic complications from the anticoagulation regimen.
- •Note: participants must have discontinued oral anticoagulants within 3 days or 5 half-lives prior to first dose of study treatment, whichever is longer
- •Any complementary medications (e.g., herbal supplements or traditional medicines) to treat their HCC under study within 2 weeks before first dose of study treatment
- •Participant has uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions:
- •Unstable of deteriorating cardiovascular disorders:
- •Congestive heart failure New York Heart Association Class 3 or 4, class 2 or higher, unstable angina pectoris, new-onset angina, serious cardiac arrhythmias (e.g., ventricular flutter, ventricular fibrillation, Torsades de pointes).
- •Uncontrolled hypertension defined as sustained blood pressure (BP) > 140 mm Hg systolic or > 90 mm Hg diastolic despite optimal antihypertensive treatment.
- •Stroke (including transient ischemic attack [TIA]), myocardial infarction (MI), or other clinically significant arterial thrombotic and/or ischemic event within 6 months before first dose of study treatment.
- •Pulmonary embolism (PE) or deep vein thrombosis (DVT) or prior clinically significant venous events within 3 months before first dose of study treatment.
- •Note: Participants with a diagnosis of DVT within 6 months are allowed if asymptomatic and stable at screening and are on a stable dose of the anticoagulant for at least 1 week before first dose of study treatment without clinically significant hemorrhagic complications from the anticoagulation regimen.
- •Note: Participants who don't require prior anticoagulation therapy may be eligible but must be discussed and approved by the Principal Investigator.
- •Prior history of myocarditis
- •Gastrointestinal (GI) disorders including those associated with a high risk of perforation or fistula formation:
- •Participant has evidence of tumor invading the GI tract,
- •Active peptic ulcer disease, inflammatory bowel disease (e.g., Crohn's disease), diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, or acute pancreatitis
- •Acute obstruction of the bowel, gastric outlet, or pancreatic or biliary duct within 6 months before first dose unless cause of obstruction is definitively managed and subject is asymptomatic
- •Abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal abscess within 6 months before first dose of study treatment.
- •Note: Complete healing of an intra-abdominal abscess must be confirmed before first dose of study treatment.
- •Known gastric or esophageal varices that are untreated or incompletely treated with bleeding or high risk for bleeding. Participants treated with adequate endoscopic therapy (according to institutional standards) without any episodes of recurrent GI bleeding requiring transfusion or hospitalization for at least 6 months prior to study entry are eligible.
- •Ascites, pleural effusion, or pericardial fluid requiring drainage in last 4 weeks
- •Clinically significant hematuria, hematemesis, or hemoptysis of > 0.5 teaspoon (2.5 ml) of red blood, or other history of significant bleeding (e.g., pulmonary hemorrhage) within 12 weeks before start of study intervention
- •Lesions invading a major blood vessel including, but not limited to, inferior vena cava, pulmonary artery, or aorta. Participants with lesions invading the hepatic portal vasculature are eligible
- •Elevated lung shunting precluding safe treatment with Y-90 within acceptable thresholds of lung exposure, defined as > 30 Gy/treatment or 50 Gy total for multiple treatments
- •Patients with future liver remnant volume < 30% after Y-90 treatment
- •Patients in whom Y-90 is deemed unsafe due to risks of extra-pulmonary non-target embolization
- •Any deposition to the GI tract (per 99mTc-MAA SPECT-CT or Cone Beam CT)
- •Hepatic artery catheterization is contraindicated (e.g., vascular abnormalities or bleeding diathesis)
- •Severe liver dysfunction, including hepatic encephalopathy, clinically evident ascites or treatment with diuretics for ascites
- •Type Vp4 Portal vein tumor thrombosis (PVTT) involvement and lack of Tc-99m MAA deposition on the PVT per Tc-99m MAA SPECT/CT
- •Participants with renal failure currently requiring dialysis of any kind are not eligible
- •Cavitating pulmonary lesion(s) or known endotracheal or endobronchial disease manifestation
- •Known allergy or hypersensitivity to any of the study drug or any of the study drug excipients
- •Other clinically significant disorders that would preclude safe study participation.
- •Active infection requiring systemic treatment.
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研究组 & 干预措施
Treatment (Y-90, tremelimumab, durvalumab, zanzalintinib)
CYCLE 1: Patients receive tremelimumab IV and durvalumab IV, over 60 minutes, on day 1. 7-14 days later patients undergo transarterial radioembolization with Y-90 in the absence of disease progression or unacceptable toxicity. 7 days to 12 weeks later patients proceed to cycle 2.
CYCLE 2-12: Patients receive durvalumab IV, over 30-60 minutes, on day 1 and zanzalintinib PO QD on days 1-28 of each cycle. Cycles repeat every 28 days for 12 cycles in the absence of disease progression or unacceptable toxicity.
Patients undergo angiogram during screening and undergo SPECT, CT scan or MRI, and blood and urine sample collection throughout the study. Patients optionally undergo tumor biopsy throughout the study.
干预措施: Magnetic Resonance Imaging (Procedure)
Treatment (Y-90, tremelimumab, durvalumab, zanzalintinib)
CYCLE 1: Patients receive tremelimumab IV and durvalumab IV, over 60 minutes, on day 1. 7-14 days later patients undergo transarterial radioembolization with Y-90 in the absence of disease progression or unacceptable toxicity. 7 days to 12 weeks later patients proceed to cycle 2.
CYCLE 2-12: Patients receive durvalumab IV, over 30-60 minutes, on day 1 and zanzalintinib PO QD on days 1-28 of each cycle. Cycles repeat every 28 days for 12 cycles in the absence of disease progression or unacceptable toxicity.
Patients undergo angiogram during screening and undergo SPECT, CT scan or MRI, and blood and urine sample collection throughout the study. Patients optionally undergo tumor biopsy throughout the study.
干预措施: Angiogram (Procedure)
Treatment (Y-90, tremelimumab, durvalumab, zanzalintinib)
CYCLE 1: Patients receive tremelimumab IV and durvalumab IV, over 60 minutes, on day 1. 7-14 days later patients undergo transarterial radioembolization with Y-90 in the absence of disease progression or unacceptable toxicity. 7 days to 12 weeks later patients proceed to cycle 2.
CYCLE 2-12: Patients receive durvalumab IV, over 30-60 minutes, on day 1 and zanzalintinib PO QD on days 1-28 of each cycle. Cycles repeat every 28 days for 12 cycles in the absence of disease progression or unacceptable toxicity.
Patients undergo angiogram during screening and undergo SPECT, CT scan or MRI, and blood and urine sample collection throughout the study. Patients optionally undergo tumor biopsy throughout the study.
干预措施: Biopsy Procedure (Procedure)
Treatment (Y-90, tremelimumab, durvalumab, zanzalintinib)
CYCLE 1: Patients receive tremelimumab IV and durvalumab IV, over 60 minutes, on day 1. 7-14 days later patients undergo transarterial radioembolization with Y-90 in the absence of disease progression or unacceptable toxicity. 7 days to 12 weeks later patients proceed to cycle 2.
CYCLE 2-12: Patients receive durvalumab IV, over 30-60 minutes, on day 1 and zanzalintinib PO QD on days 1-28 of each cycle. Cycles repeat every 28 days for 12 cycles in the absence of disease progression or unacceptable toxicity.
Patients undergo angiogram during screening and undergo SPECT, CT scan or MRI, and blood and urine sample collection throughout the study. Patients optionally undergo tumor biopsy throughout the study.
干预措施: Biospecimen Collection (Procedure)
Treatment (Y-90, tremelimumab, durvalumab, zanzalintinib)
CYCLE 1: Patients receive tremelimumab IV and durvalumab IV, over 60 minutes, on day 1. 7-14 days later patients undergo transarterial radioembolization with Y-90 in the absence of disease progression or unacceptable toxicity. 7 days to 12 weeks later patients proceed to cycle 2.
CYCLE 2-12: Patients receive durvalumab IV, over 30-60 minutes, on day 1 and zanzalintinib PO QD on days 1-28 of each cycle. Cycles repeat every 28 days for 12 cycles in the absence of disease progression or unacceptable toxicity.
Patients undergo angiogram during screening and undergo SPECT, CT scan or MRI, and blood and urine sample collection throughout the study. Patients optionally undergo tumor biopsy throughout the study.
干预措施: Computed Tomography (Procedure)
Treatment (Y-90, tremelimumab, durvalumab, zanzalintinib)
CYCLE 1: Patients receive tremelimumab IV and durvalumab IV, over 60 minutes, on day 1. 7-14 days later patients undergo transarterial radioembolization with Y-90 in the absence of disease progression or unacceptable toxicity. 7 days to 12 weeks later patients proceed to cycle 2.
CYCLE 2-12: Patients receive durvalumab IV, over 30-60 minutes, on day 1 and zanzalintinib PO QD on days 1-28 of each cycle. Cycles repeat every 28 days for 12 cycles in the absence of disease progression or unacceptable toxicity.
Patients undergo angiogram during screening and undergo SPECT, CT scan or MRI, and blood and urine sample collection throughout the study. Patients optionally undergo tumor biopsy throughout the study.
干预措施: Single Photon Emission Computed Tomography (Procedure)
Treatment (Y-90, tremelimumab, durvalumab, zanzalintinib)
CYCLE 1: Patients receive tremelimumab IV and durvalumab IV, over 60 minutes, on day 1. 7-14 days later patients undergo transarterial radioembolization with Y-90 in the absence of disease progression or unacceptable toxicity. 7 days to 12 weeks later patients proceed to cycle 2.
CYCLE 2-12: Patients receive durvalumab IV, over 30-60 minutes, on day 1 and zanzalintinib PO QD on days 1-28 of each cycle. Cycles repeat every 28 days for 12 cycles in the absence of disease progression or unacceptable toxicity.
Patients undergo angiogram during screening and undergo SPECT, CT scan or MRI, and blood and urine sample collection throughout the study. Patients optionally undergo tumor biopsy throughout the study.
干预措施: Yttrium-90 Microsphere Radioembolization (Procedure)
Treatment (Y-90, tremelimumab, durvalumab, zanzalintinib)
CYCLE 1: Patients receive tremelimumab IV and durvalumab IV, over 60 minutes, on day 1. 7-14 days later patients undergo transarterial radioembolization with Y-90 in the absence of disease progression or unacceptable toxicity. 7 days to 12 weeks later patients proceed to cycle 2.
CYCLE 2-12: Patients receive durvalumab IV, over 30-60 minutes, on day 1 and zanzalintinib PO QD on days 1-28 of each cycle. Cycles repeat every 28 days for 12 cycles in the absence of disease progression or unacceptable toxicity.
Patients undergo angiogram during screening and undergo SPECT, CT scan or MRI, and blood and urine sample collection throughout the study. Patients optionally undergo tumor biopsy throughout the study.
干预措施: Tremelimumab (Biological)
Treatment (Y-90, tremelimumab, durvalumab, zanzalintinib)
CYCLE 1: Patients receive tremelimumab IV and durvalumab IV, over 60 minutes, on day 1. 7-14 days later patients undergo transarterial radioembolization with Y-90 in the absence of disease progression or unacceptable toxicity. 7 days to 12 weeks later patients proceed to cycle 2.
CYCLE 2-12: Patients receive durvalumab IV, over 30-60 minutes, on day 1 and zanzalintinib PO QD on days 1-28 of each cycle. Cycles repeat every 28 days for 12 cycles in the absence of disease progression or unacceptable toxicity.
Patients undergo angiogram during screening and undergo SPECT, CT scan or MRI, and blood and urine sample collection throughout the study. Patients optionally undergo tumor biopsy throughout the study.
干预措施: Zanzalintinib (Drug)
Treatment (Y-90, tremelimumab, durvalumab, zanzalintinib)
CYCLE 1: Patients receive tremelimumab IV and durvalumab IV, over 60 minutes, on day 1. 7-14 days later patients undergo transarterial radioembolization with Y-90 in the absence of disease progression or unacceptable toxicity. 7 days to 12 weeks later patients proceed to cycle 2.
CYCLE 2-12: Patients receive durvalumab IV, over 30-60 minutes, on day 1 and zanzalintinib PO QD on days 1-28 of each cycle. Cycles repeat every 28 days for 12 cycles in the absence of disease progression or unacceptable toxicity.
Patients undergo angiogram during screening and undergo SPECT, CT scan or MRI, and blood and urine sample collection throughout the study. Patients optionally undergo tumor biopsy throughout the study.
干预措施: Durvalumab (Biological)
结局指标
主要结局
Proportion of progression-free at 6-months
时间窗: From first dose of study intervention, up to 6 months
Will be reported with 95% exact confidence interval.
次要结局
- Incidence of grade ≥ 3 adverse events (AEs)(From first dose of study intervention to 30 days for AEs or 100 days for serious adverse events (SAEs) from last dose of study intervention)
- Objective response rate(From first dose of study intervention to last dose of study intervention)
- Disease control rate(From first dose of study intervention to date of progression up to 12 months from last dose of study intervention)
- Time to progression (TTP)(From first dose of study intervention to date of progression up to 12 months from last dose of study intervention)
- Progression free survival(From first dose of study intervention to date of progression or death (any cause) up to 12 months from last dose of study intervention)
- Overall survival(From first dose of study intervention to date of death (any cause) up to 12 months from last dose of study intervention)
研究者
Adel Kardosh M.D., Ph.D.
Principal Investigator
OHSU Knight Cancer Institute