INTESTIFIX for Hepatocellular carcinoma|Non-resectable hepatocellular carcinoma

Inclusion criteria

• {"criterion_text":"- Subjects must be ≥ 18 years at the time of screening.\n- For patients with active HBV: HBV DNA < 500 IU/ml obtained within 28 days prior to initiation of study treatment and anti-HBV treatment per local standard of care for a minimum of 14 days prior to study entry and willingness to continue treatment for the length of the study\n- For patients with active HCV infection (as characterized by the presence of detectable HCV RNA): must be managed per local institutional practice for the length of the study.\n- Adequate organ and marrow function measured within 72 hours prior to randomization as follows: a. Hemoglobin ≥ 8 g/dL b. Absolute neutrophil count ≥ 1.0 x 109/L c. Platelet count ≥ 50 x 109/L d. Total bilirubin ≤ 3.0 x the upper limit of normal (ULN) e. Alanine aminotransferase (ALT) and aspartate aminotransferase ≤ 5 x ULN f. International normalized ratio ≤ 1.6. g. Calculated creatinine clearance ≥ 30 mL/min as determined by Cockroft-Gault\n- Use of reliable contraception for women of childbearing potential and men.\n- Negative pregnancy test for women of childbearing potential\n- Ability of subject to understand character and individual consequences of clinical trial and to comply with the study protocol and dosing regimen.\n- Written informed consent (must be available before enrolment in the clinical trial)\n- Subject willing to undergo tumor biopsy. This requires a tumor lesion accessible for a biopsy.\n- Confirmed HCC (either by imaging in a cirrhotic liver [liver lesions that show typical features of HCC on IV contrast-enhanced CT or MRI scans, i.e., hypervascularity in the arterial phase with washout in the portal or the late venous phase] or histopathologically from biopsy specimen or surgery).\n- Disease not amenable to resection, liver transplantation or loco-regionary therapy, such as curative ablation, trans-arterial chemoembolization (TACE) or trans-arterial radio-embolization (TARE).\n- Eligible for therapy with Atezolizumab / Bevacizumab according to standard of care.\n- Measurable disease per RECIST 1.1.\n- Preserved liver function with a Child-Pugh score A or B (maximally 7 points).\n- Performance status ECOG 0-1.\n- Available CT scan of thorax and MRI or CT scan of abdomen with contrast agent not older than 30 days before start of treatment (A/B C1d1).\n- Documented virology status of hepatitis, as confirmed by screening HBV and HCV serology test"}

Exclusion criteria

• {"criterion_text":"- Use of immunosuppressive medication within 6 months prior to the first dose of Atezolizumab / Bevacizumab. The following are exceptions to this criterion: a. Intranasal, inhaled, topical steroids or local steroid injections (e.g. intra-articular injection). b. Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or equivalent c. Steroids as premedication for hypersensitivity reactions or as an anti-emetic.\n- Usage of systemic antibiotic therapy within 2 weeks prior to the first dose of Atezolizumab/Bevacizumab (C1d1).\n- Usage of probiotic products/supplements within 1 week prior to the first dose of Atezolizumab/Bevacizumab (C1d1).\n- Known fibrolamellar HCC, sarcomatoid HCC, infiltrative-type HCC, or mixed chol-angiocarcinoma and HCC.\n- History of another primary malignancy. Exceptions include: a. malignancy treated with curative intent or has low potential risk for recurrence with no known active disease ≥ 5 years before the first dose of study intervention; b. malignancy which occurred < 5 years before the first study intervention, is not active, and not expected to recur or be clinically relevant in the next 2 years.\n- Receipt of live attenuated vaccine within 30 days prior to the first dose of study intervention.\n- Pregnancy or lactation.\n- History of hypersensitivity to the investigational medicinal product or to any drug with similar chemical structure or to any excipient present in the pharmaceutical form of the investigational medicinal product.\n- Participation in other interventional clinical trials or observation period of competing clinical trials, respectively.\n- Held in an institution by legal or official order.\n- Legally incapacitated.\n- Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease, diverticulitis, systemic lupus erythematosus, sarcoidosis, granulomatosis with polyangiitis, Graves’ disease, rheumatoid arthritis, hypophysitis, uveitis, autoimmune pneumonitis, autoimmune myocarditis, etc.). The following are exceptions to this criterion: a. Subjects with vitiligo or alopecia. b. Subjects with hypothyroidism stable on hormone replacement. c. Any chronic skin condition that does not require systemic therapy. d. Subjects with coeliac disease controlled by diet alone. e. Subjects without active disease in the last 5 years may be included but only after consultation with the study clinical lead.\n- Known hypersensitivity to any component of the vancomycin, atezolizumab or bevacizumab formulation.\n- Prior exposure to immune-mediated therapy including, but not limited to, other anti-CTLA-4, anti-PD-1, anti-PD-L1, and anti-VEGF antibodies.\n- Known to have tested positive for human immunodeficiency virus (HIV) infection.\n- Co-infection of HBV and HCV. Subjects with a history of HCV infection but who are negative for HCV RNA by PCR will be considered non-infected with HCV.\n- Evidence by investigator assessment of varices at risk of bleeding on upper endoscopy undertaken within 12 months of randomization.\n- Refractory nausea and vomiting, chronic gastrointestinal disease, inability to swallow a formulated product, or previous significant bowel resection that would preclude adequate absorption, distribution, metabolism or excretion of investigational product.\n- Uncontrolled arterial hypertension defined by a systolic pressure > 150 mm Hg or diastolic pressure > 90 mm Hg or other hypertensive cardiovascular complications despite standard medical treatment.\n- Any history of nephrotic or nephritic syndrome."}

Primary endpoints

• {"endpoint_text":"- The primary immunological patient variable is the count of tumor-infiltrating CD8+ T lymphocytes in the tumor biopsy after two cycles of A/B (d38). CD8+T lymphocyte density will be quantitatively assessed after manual delineation of tumor area in the biopsy (count of CD8+ cells per square millimeter tumor area). Tumor areas with crush artifacts or necrosis will be excluded from analysis.","definition_or_measurement_approach":"CD8+ T lymphocyte density will be quantitatively assessed after manual delineation of tumor area in the biopsy (count of CD8+ cells per square millimeter tumor area). Tumor areas with crush artifacts or necrosis will be excluded from analysis."}
• {"endpoint_text":"- Incidence and severity of AEs and SAEs from treatment start until 42 days after the fourth cycle of A/B (d105). The occurrence of AEs and SAEs is assessed for each patient, including incidence, severity, timing, seriousness, relatedness to study treatment, action taken with study medication and outcome. Detailed information is provided in section 8.","definition_or_measurement_approach":"Occurrence assessed for each patient including incidence, severity, timing, seriousness, relatedness to study treatment, action taken with study medication and outcome; assessment window: from treatment start until 42 days after the fourth cycle of A/B (d105)."}

Germany

Earliest CTIS Part Ii Submission Date

16-01-2024

Latest Decision Or Authorization Date

22-01-2026

Processing Time Days

737

Number Of Sites

9

Number Of Participants

48

Primary sponsor

Full Name

Universitaetsklinikum Heidelberg AöR

Organisation Type

Hospital/Clinic/Other health care facility

Country Of Registered Address

Germany