Durvalumab for Hepatocellular carcinoma

Inclusion criteria

• {"criterion_text":"- Male or female subjects; age ≥ 18 years (all countries except Japan) or ≥ 20 years (Japan only) at the time of screening.\n- Consent to provide a newly acquired or archival tumor tissue (< 3 years) for correlative biomarker studies.\n- Adequate organ and marrow function, as defined below. Criteria “a,” “b,” “c,” and “f” cannot be met with transfusions, infusions, or growth factor support administered within 14 days of starting the first dose. a. Hemoglobin ≥ 9 g/dL b. Absolute neutrophil count ≥ 1,000/µL c. Platelet count ≥75000/µL d. Total bilirubin (TBL) ≤ 2.0 × ULN (Upper Limit of Normal) e. AST and ALT ≤ 5 × ULN f. Albumin ≥ 2.8 g/dL g. International Normalized Ratio ≤ 1.6 h. Calculated creatinine clearance ≥ 50 mL/minute as determined by Cockcroft-Gault (using actual body weight) or 24-hour urine creatinine clearance i. Part 4 only: Proteinuria < 2+. For patients with proteinuria ≥ 2+, further assessment of 24-hour proteinuria should be < 1 gram.\n- Females of childbearing potential who are sexually active with a non-sterilized male partner must use a highly effective method of contraception (per Table 4.1.2-1 of protocol) from the time of screening, and must agree to continue using such precautions for 90 days (durvalumab and tremelimumab monotherapy) or 180 days (durvalumab combined with tremelimumab) after the final dose of investigational product(s). Male partners of a female subject must use male condom plus spermicide (or male condom in countries where spermicides are not approved or available) throughout these periods. Cessation of contraception after this point should be discussed with a responsible physician. Not engaging in sexual activity for the total duration of the study and the drug washout period is an acceptable practice; however, occasional abstinence, the rhythm method, and the withdrawal method are not acceptable methods of contraception. Female subjects should refrain from breastfeeding throughout these periods. a. Females of childbearing potential are defined as those who are not surgically sterile (ie, have not undergone bilateral tubal ligation, bilateral oophorectomy, or complete hysterectomy) or those who are not postmenopausal (defined as 12 months with no menses without an alternative medical cause). The following age-specific requirements apply to the definition of postmenopausal: i. Females < 50 years of age would be considered postmenopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle stimulating hormone levels in the postmenopausal range for the institution. ii. Females ≥ 50 years of age will be considered postmenopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced oophorectomy with last menses > 1 year ago, had chemotherapy-induced menopause with >1 year interval since last menses, or underwent surgical sterilization (bilateral oophorectomy or hysterectomy). b. Highly effective methods of contraception are described in Table 4.1.2-1. A highly effective method of contraception is defined as one that results in a low failure rate (ie, less than 1% per year) when used consistently and correctly. Note that some contraception methods are not considered highly effective (eg, male or female condom with or without spermicide; female cap, diaphragm, or sponge with or without spermicide; non-copper containing intrauterine device; progestogen-only oral hormonal contraceptive pills where inhibition of ovulation is not the primary mode of action [excluding Cerazette ® /desogestrel which is considered highly effective]; and triphasic combined oral contraceptive pills); not all of these methods are approved or available in Japan (see Table 4.1.2-1).\n- Non-sterilized male subjects who are sexually active with a female partner of childbearing potential must use a highly effective method of contraception (see Table 4.1.2-1 of protocol) from Day 1 through 90 days (durvalumab and tremelimumab monotherapy) or 180 days (durvalumab combined with tremelimumab) after receipt of the final dose of investigational product(s). Not engaging in sexual activity for the total duration of the study and the drug washout period is an acceptable practice; however, occasional abstinence, the rhythm method, and the withdrawal method are not acceptable methods of contraception. Male subjects should refrain from sperm donation throughout these periods. Female partners of a male subject must use a highly effective method of contraception throughout these periods.\n- Body weight >30kg.\n- Must have a life expectancy of at least 12 weeks.\n- Written informed consent and any locally required authorization, Health Insurance and Portability and Accountability Act in the US, European Union Data Privacy Directive in the European Union obtained from the subject/legal representative prior to performing any protocol-related procedures, including screening evaluations.\n- Confirmed HCC based on histopathological findings from tumor tissues. Advanced HCC with diagnosis confirmed pathologically or with noninvasive methods (as described below). a. Noninvasive methods: focal lesion > 1 cm with arterial hypervascularity and venous or delayed phase washout on a 4 phase multi-detector computed tomography (CT) or dynamic contrast enhanced magnetic resonance imaging (MRI)\n- Immunotherapy-naive and have either progressed on, are intolerant to, or refused treatment with sorafenib or another approved VEGFR TKI. Part 4 only: Must not have received prior systemic therapy for HCC.\n- Child-Pugh Score class A.\n- ECOG performance status of 0 or 1.\n- Patients with HBV infection [as characterized by positive hepatitis B surface antigen (HBsAg) and/or hepatitis B core antibodies (anti-HBcAb) with detectable HBV DNA (≥10 IU/ml)] must be treated with antiviral therapy, as per institutional practice, to ensure adequate viral suppression (HBV DNA ≤ 2000 IU/mL) prior to enrollment. Patients must remain on antiviral therapy for the study duration and for 6 months after the last dose of study medication. Patients who test positive for antiHBc with undetectable HBV DNA (<10 IU/ml) do not require anti-viral therapy prior to enrollment. These subjects will be tested at every cycle to monitor HBV DNA levels and initiate antiviral therapy if HBV DNA is detected (≥10 IU/ml). HBV DNA detectable subjects must initiate and remain on antiviral therapy for the study duration and for 6 months after the last dose of study medication.\n- Patients with HCV infection must have confirmed diagnosis of HCV characterized by the presence of detectable HCV RNA or anti-HCV antibody upon enrollment (management of this disease is per local institutional practice).\n- At least 1 lesion, not previously irradiated, that can be accurately measured at baseline as ≥10 mm in the longest diameter (except lymph nodes which must have a short axis ≥15 mm) with computed tomography (CT) or magnetic resonance imaging (MRI) and that is suitable for accurate repeated measurements as per RECIST 1.1 guidelines. Subjects in Part 1A, Part 1B, or Part 2A must consent to pretreatment biopsies of tumor. Subjects in Part 2B and Part 3 must provide a newly acquired (fresh or acquired within 3 months, preferred) or archival (< 3 years) tumor sample. For subjects in Part 4, newly acquired (fresh or acquired within 3 months) tumor samples will be required."}

Exclusion criteria

• {"criterion_text":"- History of hepatic encephalopathy within past 12 months or requirement for medications to prevent or control encephalopathy (eg, no lactulose, rifaximin, etc if used for purposes of hepatic encephalopathy).\n- Active infection including tuberculosis (TB) (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice), or human immunodeficiency virus (positive human HIV 1/2 antibodies).\n- Patients co-infected with HBV and HCV, or co-infected with HBV and hepatitis D virus (HDV). HBV positive [presence of hepatitis B surface antigen (HBsAg) and/or hepatitis B core antibodies (anti-HBcAb) with detectable HBV DNA (≥10IU/ml)]; HCV positive (presence of anti-HCV antibodies); HDV positive (presence of anti-HDV antibodies).\n- Concurrent enrollment in another clinical study, unless it is an observational (noninterventional) clinical study or the follow-up period of an interventional study.\n- Receipt of any conventional or investigational anticancer therapy not otherwise specified above within 28 days prior to the first dose of durvalumab or tremelimumab.\n- Any concurrent chemotherapy, immunotherapy, or biologic or hormonal therapy for cancer treatment with the exception of subjects on adjuvant endocrine therapy for ≥ 5 years for a history of breast cancer. Concurrent use of hormones for noncancer-related conditions (eg, insulin for diabetes and hormone replacement therapy) is acceptable. In addition, local treatment (eg, by local surgery or radiotherapy) of isolated lesions for palliative intent is acceptable with prior consultation and in agreement with the medical monitor.\n- Any toxicity from prior therapy which has not completely resolved to baseline at the time of consent. Subjects with NCI CTCAE v4.03 Grade 1 or 2 toxicities that are deemed stable or irreversible can be enrolled on a case-by-case basis with prior consultation and agreement with the medical monitor.\n- Current or prior use of immunosuppressive medication within 14 days prior to the first dose of IP. The following are exceptions to this criterion: - Intranasal, inhaled, topical, or local steroid injections (eg, intra-articular injection). - Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or equivalent. - Steroids as premedication for hypersensitivity reactions (eg, CT scan premedication).\n- History of primary immunodeficiency or solid organ transplantation.\n- Receipt of live, attenuated vaccine within 30 days prior to the first dose of investigational products (Note: Subjects, if enrolled, should not receive live vaccine during the study and 30 days after the last dose of investigational product[s]). Vaccination with a killed vaccine is permitted at any time with consultation with the medical monitor.\n- Female patients who are pregnant or breastfeeding, or male or female patients of reproductive potential who are not willing to employ effective birth control from screening to 90 days after the last dose of durvalumab (Durvalumab) monotherapy or 180 days after the last dose of durvalumab plus tremelimumab or bevacizumab combination therapy. Not engaging in sexual activity, as per the patient’s preferred and usual lifestyle, for the total duration of the treatment and washout periods is an acceptable practice.\n- GI Bleeding (eg, esophageal varices or ulcer bleeding) within 12 months. (Note: For patients with a history of GI bleeding for more than 12 months or assessed as high risk for esophageal variceal by the Investigator, adequate endoscopic therapy according to institutional standards is required).\n- Major surgery (as defined by the investigator) within 28 days prior to first dose of IP or still recovering from prior surgery. Local procedures (eg, core needle biopsy, and prostate biopsy) are allowed if completed at least 3 days prior to the administration of the first dose of study treatment.\n- History of leptomeningeal carcinomatosis\n- Other invasive malignancy within 2 years except for noninvasive malignancies such as cervical carcinoma in situ, in situ prostate cancer, nonmelanomatous carcinoma of the skin, lobular or ductal carcinoma in situ of the breast that has been surgically cured.\n- Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension (defined as systolic blood pressure ≥ 150 mmHg and/or diastolic blood pressure ≥ 90 mmHg, with or without antihypertensive medication), unstable angina pectoris, cardiac arrhythmia, vena cava thrombosis, active peptic ulcer disease or gastritis, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs from IP, or compromise the ability of the subject to give written informed consent.\n- Any condition that, in the opinion of the investigator or sponsor, would interfere with evaluation of the investigational products or interpretation of subject safety or study results.\n- Subjects who are involuntarily incarcerated or are unable to willingly provide consent or are unable to comply with the protocol procedures.\n- History of, or current, brain metastases or spinal cord compression. Patients with suspected brain metastases at screening should have an MRI (preferred) or CT, each preferably with IV contrast of the brain prior to study entry.\n- Additional Exclusion Criteria Specific to Part 4 Only: Clinically significant (eg, active) cardiovascular disease, including: - Myocardial infarction or unstable angina within ≤6 months of randomization - New York Heart Association Grade≥ 2 congestive heart failure - Poorly controlled cardiac arrhythmia despite medication (patient with rate controlled atrial fibrillation are eligible), or any clinically significant abnormal finding on resting ECG - Peripheral vascular disease Grade ≥3 (eg, symptomatic and interfering with activities of daily living requiring repair or revision) - Previous cerebrovascular accident, transient ischemic attack, or sub-arachnoids hemorrhage within 6 months prior to randomization.\n- Additional Exclusion Criteria Specific to Part 4 Only: Known hereditary predisposition to bleeding or thrombosis; History of arterioembolic event including a stroke or myocardial infarction.\n- Additional Exclusion Criteria Specific to Part 4 Only: Non-healing wound, active ulcer, or bone fracture. Patients with granulating incisions healing by secondary intention with no evidence of facial dehiscence or infection are eligible but require wound examinations every 3 weeks.\n- Clinically meaningful ascites defined as ascites requiring non-pharmacologic intervention (eg, paracentesis) to maintain symptomatic control, within 6 months prior to the first scheduled dose. Subjects on stable doses of diuretics for ascites for ≥ 2 months are eligible.\n- Main portal vein thrombosis (Vp4) as documented on imaging. (VP4 is defined as portal vein thrombosis in the main trunk of the portal vein or a portal vein branch contralateral to the primarily involved lobe (or both)).\n- Prior exposure to immunotherapy, including, but not limited to, other anti-CTLA-4, anti-PD-1, or anti-PD-L1 mAbs.\n- Known allergy or hypersensitivity to study drug formulations.\n- Requires ongoing therapeutic anti-coagulation or anti-platelet therapy; the subject must be off either therapy for at least 7 days prior to the first dose of investigational product. Lowdose aspirin for cardiac prophylaxis/protection is permitted per local institutional standards.\n- Active or prior documented autoimmune or inflammatory disorders including inflammatory bowel disease (eg, colitis, Crohn’s disease), diverticulitis, celiac disease, systemic lupus erythematosus; Wegener syndrome (granulomatosis with polyangitis); myasthenia gravis; Graves’ disease; rheumatoid arthritis, hypophysitis, uveitis, etc. The following are exceptions to this criterion: a) Subjects with vitiligo or alopecia. b) Subjects with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement. c) Subjects with psoriasis or eczema not requiring systemic treatment.\n- Irritable bowel syndrome or other serious gastrointestinal chronic conditions associated with diarrhea within the past 3 years prior to the start of treatment."}

Primary endpoints

• {"endpoint_text":"- Number (percentage) of subjects reporting adverse events and number (percentage) of subjects reporting serious adverse events.\n- Number (percentage) of subjects discontinuing investigational product(s) due to toxicity.\n- Changes from baseline in laboratory parameters (including liver and viral laboratory tests), electrocardiograms and vital signs.","definition_or_measurement_approach":"First: reported adverse events and serious adverse events summarized as counts and percentages. Second: discontinuations due to toxicity summarized as counts and percentages. Third: laboratory parameters (including liver and viral tests), ECGs and vital signs compared as changes from baseline (laboratory values, ECG findings, vital sign measurements)."}

Secondary endpoints

• {"endpoint_text":"- Objective response rate (ORR), disease control rate (DCR), time to response (TTR), duration of response (DoR), time to progression (TTP), progression-free survival (PFS) based on investigator assessments and Blinded Independent Central Review (BICR) according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, and overall survival (OS).\n- AEs, SAEs, discontinuation of investigational product(s) due to toxicity, and changes from baseline in laboratory parameters (including liver and viral laboratory tests), ECG, and vital signs in 3 distinct HCC populations: uninfected, HBV+, and HCV+.\n- PD-L1 expression within the tumor microenvironment.","definition_or_measurement_approach":"First: tumor response endpoints (ORR, DCR, TTR, DoR, TTP, PFS, OS) assessed per RECIST v1.1 by investigator assessment and Blinded Independent Central Review (BICR). Second: safety endpoints summarized by HCC population (uninfected, HBV+, HCV+) using AE/SAE counts, discontinuations, and changes from baseline in labs/ECG/vitals. Third: PD-L1 expression measured in tumor microenvironment (biomarker assays on tumor tissue)."}

Italy

Earliest CTIS Part Ii Submission Date

17-09-2024

Latest Decision Or Authorization Date

16-10-2024

Processing Time Days

29

Number Of Sites

1

Number Of Participants

2

Primary sponsor

Full Name

AstraZeneca AB

Organisation Type

Pharmaceutical company

Country Of Registered Address

Sweden

Contract research organisations

Name

Perceptive Eclinical Limited

Responsibilities

sponsorDuties codes: [3]

Name

Perceptive Informatics Inc.

Responsibilities

sponsorDuties codes: [3]

Name

Parexel International (IRL) Limited

Responsibilities

sponsorDuties codes: [1, 12, 2]

Name

Almac Clinical Services Limited

Responsibilities

sponsorDuties codes: [14, 15]; IMP disposal

Name

Almac Pharmaceutical Services Pte Ltd

Responsibilities

sponsorDuties codes: [14]

Name

Fisher Clinical Services GmbH

Responsibilities

sponsorDuties codes: [14, 15]; IMP distribution

Third parties

• {"country":"United Kingdom","full_name":"Perceptive Eclinical Limited","duties_or_roles":"sponsorDuties codes: [3]","organisation_type":"Pharmaceutical company"}
• {"country":"Germany","full_name":"Fisher Clinical Services GmbH","duties_or_roles":"sponsorDuties codes: [14, 15]; value for code 15: IMP distribution","organisation_type":"Pharmaceutical company"}
• {"country":"Singapore","full_name":"Almac Pharmaceutical Services Pte Ltd","duties_or_roles":"sponsorDuties codes: [14]","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Perceptive Informatics Inc.","duties_or_roles":"sponsorDuties codes: [3]","organisation_type":"Pharmaceutical company"}
• {"country":"United Kingdom (Northern Ireland)","full_name":"Almac Clinical Services Limited","duties_or_roles":"sponsorDuties codes: [14, 15]; value for code 15: IMP disposal","organisation_type":"Pharmaceutical company"}
• {"country":"Ireland","full_name":"Parexel International (IRL) Limited","duties_or_roles":"sponsorDuties codes: [1, 12, 2]","organisation_type":"Pharmaceutical company"}