Advanced Hepatocellular Carcinoma
Conditions
Keywords
MTL-CEBPA, Atezolizumab, Bevacizumab
Brief summary
This is a single-center, phase 1, open label, dose-escalation study of MTL-CEBPA co-administered with atezolizumab and bevacizumab to assess the PK, PD, and potential toxicities of the drug combination in advanced HCC patients, and to determine the MTD, OBD or RP2D. The sample size employed is a minimally modified standard 3+3 cohort model commonly used in Phase I oncology studies. Once determined, the MTD/OBD/RP2D will be administered to an Expansion Cohort (Phase Ib) of 10 additional patients with advanced HCC.
Detailed description
Objectives and Study Endpoints Study Objectives 1. Primary Objectives * To determine the safety and tolerability of combination treatment MTL-CEBPA + atezolizumab + bevacizumab and determine the maximum tolerated dose (MTD) or optimum biologic dose (OBD), dose-limiting toxicities (DLTs), and recommended phase 2 dose (RP2D) for patients with advanced HCC. * To determine the anti-tumor response using RECIST v1.1. of combination treatment MTL-CEBPA + atezolizumab + bevacizumab. 2. Secondary Objectives * To assess the pharmacodynamics (PD) of combination treatment MTL-CEBPA + atezolizumab + bevacizumab notably on the effects on TIME (tumor immune microenvironment). * To assess the pharmacokinetics (PK) of combination treatment MTL-CEBPA + atezolizumab + bevacizumab. * To evaluate anti-tumour response using HCC modified RECIST (HCC mRECIST) and immune-modified RECIST (imRECIST) for combination treatment MTL-CEBPA + atezolizumab + bevacizumab in patients with advanced HCC. Study Endpoints 1. Primary Endpoint * Dose escalation part of the study (Phase 1a): the primary endpoint will be dose limiting toxicity (DLT) as defined in Section 4.4.2. * Dose expansion part of the study (Phase 1b): the primary endpoint will be objective response rate (ORR) using RECIST v1.1 for a response duration of at least 6 weeks. 2. Secondary Endpoints In phase 1a and 1b, the secondary endpoints are: * The frequency of adverse events graded according to toxicity criteria (CTCAE v5.0) and categorized by body system and diagnosis. * PK parameters defined by the maximum plasma concentration (Cmax), time to maximum plasma concentration (Tmax), area under the plasma concentration curve (AUC) and the half-life of MTL-CEBPA after intravenous administration. * Evaluation of changes in surrogate biomarkers, notably changes in levels of MDSCs In phase 1b, additional secondary endpoints include: * Progression free survival (PFS) defined as time from first dose of study drug to until progression or relapse, or death from any cause, whichever occurred first * Overall survival (OS) defined as time from first dose of study drug until death from any cause. 3. Exploratory Endpoints In phase 1a and 1b, exploratory endpoints are: * Objective response rate (ORR) using HCC mRECIST and imRECIST. * Changes from baseline of protein expression levels in blood and tumour tissue (including CEBPα and P21) as well as mRNA expression levels in blood (including CEBPA mRNA) will be evaluated. * Changes in Tumour Mutational Burden (TMB) and PD-L1 status (biopsy samples) will both be assessed.
Interventions
DRUGMTL-CEBPA
The starting dose will be at dose level 1. For cycle 1 only, there will be a lead-in period whereby patients will receive one dose of MTL-CEBPA, 7 days prior to cycle 1 day 1. MTL-CEBPA is then administered on Day 1 and 8 of each cycle, atezolizumab is administered on Day 1 of each cycle and bevacizumab is administered on Day 1 of each cycle. One cycle of treatment consists of 21 days.
DRUGAtezolizumab
The starting dose will be at dose level 1. For cycle 1 only, there will be a lead-in period whereby patients will receive one dose of MTL-CEBPA, 7 days prior to cycle 1 day 1. MTL-CEBPA is then administered on Day 1 and 8 of each cycle, atezolizumab is administered on Day 1 of each cycle and bevacizumab is administered on Day 1 of each cycle. One cycle of treatment consists of 21 days.
DRUGBevacizumab
The starting dose will be at dose level 1. For cycle 1 only, there will be a lead-in period whereby patients will receive one dose of MTL-CEBPA, 7 days prior to cycle 1 day 1. MTL-CEBPA is then administered on Day 1 and 8 of each cycle, atezolizumab is administered on Day 1 of each cycle and bevacizumab is administered on Day 1 of each cycle. One cycle of treatment consists of 21 days.
Sponsors
National University Hospital, Singapore
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
21 Years to 99 Years
Healthy volunteers
No
Inclusion criteria
* Subjects must meet ALL of the following inclusion criteria to participate in this study: * Signed informed consent. * Age ≥ 21 years * Life expectancy \>3 months * Eastern Cooperative Oncology Group (ECOG) performance status (ECOG PS) score of 0 or 1 * Histologically confirmed metastatic and/or unresectable HCC with cirrhosis resulting from hepatitis B, hepatitis C, alcohol-related liver disease or any other aetiology OR Histologically confirmed metastatic and/or unresectable HCC with or without cirrhosis * Child-Pugh class A * Disease that is not amenable to curative surgical and/or locoregional therapies, or progressive disease after surgical and /or locoregional therapies * No prior systemic therapy (including systemic investigational agents) for HCC * At least one measurable (per RECIST v1.1) untreated lesion * Patients who received prior 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 the target lesion(s) have not been previously treated with local therapy or the target lesion(s) within the field of local therapy have subsequently progressed in accordance with RECIST version 1.1. * Acceptable laboratory parameters, as demonstrated by: 1. Platelets ≥ 75 x 109/L 2. Serum albumin ≥ 28 g/L 3. ALT and AST ≤ 5 x ULN 4. Bilirubin ≤ 3 x ULN 5. Absolute neutrophil count ≥ 1.5 x 109/L 6. Haemoglobin ≥ 9.0 g/dL. Patients may be transfused to meet this criterion. 7. INR \< 1.7 (for patients not receiving therapeutic anticoagulation) 8. Serum creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 50 mL/min (calculated using the Cockcroft-Gault formula) 9. Urine dipstick for proteinuria \< 2+. Patients discovered to have ≥ 2+ proteinuria on dipstick urinalysis at baseline should undergo a 24-hour urine collection and must demonstrate \< 2 g of protein in 24 hours. * For patients with active hepatitis B virus (HBV): HBV DNA \< 500 IU/mL obtained within 28 days prior to initiation of study treatment, and on anti-HBV treatment (per local standard of care; e.g., entecavir) prior to study entry and willingness to continue treatment for the length of the study * By signing the consent form patients will confirm they agree to undergo all mandated biopsies, if this can be performed safely. Waiver of biopsy may be granted on a case-to-case basis after discussion with the PI. * Willingness and ability to comply with all protocol requirements including scheduled visits, treatment plans, laboratory tests and other study procedures * Women of childbearing potential (WOCBP) must have a negative pregnancy test at study entry. Subjects not considered WOCBP are those without menses for ≥ 12 consecutive months, and those who have undergone hysterectomy and/or bilateral salpingo-oophorectomy. WOCBP must be willing to use acceptable methods of birth control (i.e., a hormonal contraceptive, intra-uterine device, diaphragm with spermicide, or condom with spermicide, or abstinence) for the duration of the study and 6 months after the last dose of treatment. * Male participants with partners of child bearing potential are required to use barrier contraception in addition to having their partner use another method of contraception during the study and for 6 months after the last dose of treatment. Male participants will also be advised to abstain from sexual intercourse with pregnant or lactating women, or to use condoms. * Patients must undergo an esophagogastroduodenoscopy (EGD), and all size of varices (small to large) must be assessed and treated per local standard of care prior to enrolment. Patients who have undergone an EGD within 6 months of prior to initiation of study treatment do not need to repeat the procedure.
Exclusion criteria
* Patients should not enter the study if ANY of the following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Evaluable for Objective Response | 5 years | Only those patients who have measurable disease present at baseline, have received at least one cycle of therapy, and have had their disease re-evaluated will be considered evaluable for response (using RECIST v1.1) |
| Evaluable Non-Target Disease Response | 5 years | Patients who have lesions present at baseline that are evaluable but do not meet the definitions of measurable disease, have received at least one cycle of therapy, and have had their disease re-evaluated will be considered evaluable for non-target lesion assessment. The response assessment is based on the presence, absence, or unequivocal progression of the lesions. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Measurable Disease | 5 years | Measurable lesions are defined as those that can be accurately measured in at least one dimension (longest diameter to be recorded) as ≥ 20 mm by chest x-ray, as ≥ 10 mm with CT scan, or ≥ 10 mm with calipers by clinical exam. All tumor measurements must be recorded in millimeters. |
| Evaluation of Best Overall Response | 5 years | The best overall response is the best response recorded from the start of the treatment until disease progression/recurrence or non-protocol therapy (taking as reference for progressive disease the smallest measurements recorded since the treatment started). The patient's best response assignment will depend on the achievement of both measurement and confirmation criteria. |
Countries
Singapore
Outcome results
None listed