Status and phase
Conditions
Treatments
About
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.
Full description
Objectives and Study Endpoints
Study Objectives
Primary Objectives
Secondary Objectives
Study Endpoints
Primary Endpoint
Secondary Endpoints
In phase 1a and 1b, the secondary endpoints are:
In phase 1b, additional secondary endpoints include:
Exploratory Endpoints
In phase 1a and 1b, exploratory endpoints are:
Enrollment
Sex
Ages
Volunteers
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:
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 exclusion criteria are fulfilled:
Child-Pugh class B or C
Patients who have been treated with loco-regional therapy within the last 28 days prior to study treatment initiation
Major surgery within the last 28 days prior to study treatment initiation
Any systemic therapy or investigational agent in the advanced setting within 28 days prior to initiation of study treatment
Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies or treatment with systemic immunostimulatory agents (including, but not limited to, interferon and interleukin 2 [IL-2]) within 4 weeks or 5 half-lives of the drug (whichever is longer) prior to initiation of study treatment.
Grade > 1 prior treatment-related toxicity (excluding alopecia) at the time of screening
Use of filgrastim or peg-filgrastim 14 days prior to study entry
Patients with clinically significant cancer ascites
Any episode of bleeding from oesophageal varices or other uncontrolled bleeding within the last 6 months prior to study treatment initiation
Patients administered with serum albumin within the last 7 days prior to the first study drug administration
Known infection with human immunodeficiency virus (HIV)
Known active tuberculosis (TB)
Leptomeningeal metastasis
Symptomatic brain metastases. Asymptomatic patients with treated brain metastases are eligible, provided that all of the following criteria are met:
Treatment with strong CYP3A4 inducers within 14 days prior to initiation of study treatment, including rifampin (and its analogues) or St. John's wort.
Treatment with systemic immunosuppressive medication (including, but not limited to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-TNF-α agents) within 2 weeks prior to initiation of study treatment, or anticipation of need for systemic immunosuppressive medication during study treatment, with the following exceptions:
Patients who received acute, low-dose (≤10 mg prednisolone or equivalent per day), systemic immunosuppressant medication or a one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of corticosteroids for a contrast allergy, premedication to prevent infusion reaction) are eligible for the study after PI approval has been obtained. Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids for chronic obstructive pulmonary disease (COPD) or asthma, or low-dose corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible for the study.
Inadequately controlled arterial hypertension (defined as systolic blood pressure (BP) ≥150 mmHg and/or diastolic blood pressure ≥100 mmHg. Anti-hypertensive therapy to achieve these parameters is allowed.
Prior history of hypertensive crisis or hypertensive encephalopathy
Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to initiation of study treatment
History of significant hemoptysis (≥2.5 mL of bright red blood per episode) within 1 month prior to initiation of study treatment
Evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic anticoagulation)
Patients on anticoagulation for therapeutic purposes and is unable to discontinue anti-coagulation (see section 4.12.3 for prohibited anti-coagulant drugs)
Patients on warfarin (for therapeutic or prophylactic purpose)
History of abdominal or tracheoesophageal fistula, gastrointestinal (GI) perforation, bowel obstruction or intra-abdominal abscess within 6 months prior to initiation of study treatment.
Clinical signs or symptoms of GI obstruction including sub-occlusive disease related to the underlying disease or requirement for routine parenteral hydration, parenteral nutrition, or tube feeding prior to initiation of study treatment. Patients with signs/symptoms of sub-/occlusive syndrome/intestinal obstruction at time of initial diagnosis may be enrolled if they had received definitive (surgical) treatment for symptom resolution.
Serious, non-healing or dehiscing wound, active ulcer, or untreated bone fracture.
Radiotherapy within 28 days prior to initiation of study treatment, except palliative radiotherapy to bone lesions within 7 days prior to initiation of study treatment.
Local therapy to liver (e.g., radiofrequency ablation, percutaneous ethanol or acetic acid injection, cryoablation, high-intensity focused ultrasound, transarterial chemoembolization, transarterial embolization, etc.) within 28 days prior to initiation of study treatment or non-recovery from side effects of any such procedure.
Active or history of autoimmune disease or immune deficiency, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease antiphospholipid antibody syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, or multiple sclerosis, with the following exceptions:
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 computed tomography (CT) scan. History of radiation pneumonitis in the radiation field (fibrosis) is permitted.
History of congenital long QT syndrome or corrected QT interval > and = 500 ms (calculated with use of the Fridericia method) at screening.
Signs and symptoms of heart failure characterised as greater than the New York Heart Association (NYHA) Class I or other clinically significant cardiac abnormalities (including history of myocardial infarction) including stable abnormalities.
Patients with history of stem cell / solid organ transplantation.
Severe infection within 4 weeks prior to initiation of study treatment, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia.
Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study treatment. Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection or chronic obstructive pulmonary disease exacerbation) are eligible for the study.
Pregnant or lactating women
Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study treatment, or anticipation of need for such a vaccine during atezolizumab treatment or within 5 months after the last dose of atezolizumab.
Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC.
Any other condition (e.g., known or suspected poor compliance, etc.) that, in the judgment of the investigator, may affect the participant's ability to follow the protocol specific procedures.
Known hypersensitivity to Chinese hamster ovary cell products or the active substance (MTL-CEBPA, atezolizumab or bevacizumab).
History of malignancy other than HCC within 5 years prior to screening, with the exception of adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ, or Stage I uterine cancer.
Untreated or incompletely treated esophageal and/or gastric varices with bleeding or high risk for bleeding.
A prior bleeding event due to esophageal and/or gastric varices within 6 months prior to initiation of study treatment.
Primary purpose
Allocation
Interventional model
Masking
33 participants in 1 patient group
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Central trial contact
Cheng Ean Chee
Data sourced from clinicaltrials.gov
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