TERTIO : Evaluation of the interest to combine a CD4 Th1-inducer cancer vaccine derived from telomerase and atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma: a proof of concept randomized phase II study
- Trial ID
- 2022-500643-20-00
- Protocol
- 2022/680
- Sponsor
- CHUR Of Besançon
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to assess the **efficacy** of a therapeutic strategy combining UCPVax, a CD4 Th1-inducer cancer vaccine derived from telomerase, with atezolizumab and bevacizumab in patients with unresectable hepatocellular carcinoma. This will be evaluated by measuring the objective response rate at 6 months according to RECIST v1.1 criteria. The clinical relevance of this objective lies in its potential to improve treatment outcomes for patients with advanced liver cancer, a condition with limited therapeutic options.
Secondary objectives include:
- Investigating the impact of UCPVax and atezolizumab plus bevacizumab on overall survival and progression-free survival.
- Evaluating disease control and objective response rates according to RECIST v1.1 and imRECIST.
- Assessing the impact of combined immunotherapy on patients' health-related quality of life (QoL).
- Evaluating the tolerance of UCPVax in association with anti-PD-L1 and anti-angiogenic agents.
- Analyzing tumor genotyping for TERT promoter mutations, telomerase, and PD-L1 expression, and studying the correlation of these biomarkers with treatment efficacy.
- Evaluating telomerase-specific T cell responses before and after treatment in peripheral blood mononuclear cells.
- Investigating how the immune contexture defined on baseline biopsies impacts the efficacy of UCPVax/atezolizumab plus bevacizumab, including the infiltration of lesions by tumor-infiltrating lymphocytes (TIL) and HCC genomic profiling.
- Characterizing the predictive value of soluble biomarkers, such as soluble PD-L1, angiogenic and stroma-related biomarkers, and nutritional status, including inflammatory biomarkers and assessment of sarcopenia.
Participants
The clinical trial involves participants diagnosed with **hepatocellular carcinoma** that is locally advanced, metastatic, or unresectable. The study population includes both male and female subjects aged 18 years and older. Participants are required to have a measurable disease as defined by RECIST v1.1 guidelines and must not have received prior systemic anti-cancer treatment. The trial includes individuals who have previously undergone chemoembolization, radioembolization, and/or radiotherapy, provided they have recovered from any treatment-related toxicity to a level of ≤ grade 1, except for Grade 2 alopecia. Participants must have a performance status of less than 2 and be classified as Child–Pugh Class A. The trial also considers lifestyle factors such as the use of effective contraceptive measures for females of childbearing potential and the documentation of virology status for hepatitis B and C. The sponsor has not provided information regarding the total number of participants in the study.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy of a combination therapy involving **UCPVax**, **atezolizumab**, and **bevacizumab** in patients with unresectable hepatocellular carcinoma. This is a randomized, double-blind, controlled phase II study. The primary objective is to assess the objective response rate at six months, evaluated by RECIST criteria v1.1. Secondary endpoints include overall survival, progression-free survival, disease control rate, health-related quality of life, and the ability of the treatment to promote antigen-specific T lymphocyte activity.
The trial is expected to last until September 2027, with recruitment starting in September 2022. Participants will be involved for a maximum treatment period of 24 months. The study includes several key visits: an initial screening visit to confirm eligibility, regular follow-up visits every eight weeks to monitor health-related quality of life and disease progression, and an end-of-study visit to evaluate the overall outcomes and any adverse events. The inclusion criteria require participants to have a histologically confirmed diagnosis of locally advanced, metastatic, or unresectable hepatocellular carcinoma, be at least 18 years old, and have a performance status of less than 2, among other conditions.
Participants may be terminated early from the study if they experience unacceptable toxicity, withdraw consent, or if the investigator deems it in the participant's best interest. The trial will be conducted in compliance with ethical standards and regulatory requirements, ensuring the safety and well-being of all participants throughout the study duration.
Treatment
The clinical trial involves the administration of **MVASI**, a **bevacizumab**-based medication, which is provided as a 25 mg/mL concentrate for solution for infusion. This pharmaceutical form is intended for **intravenous** administration. The maximum daily dose is 15 mg/kg, with a total maximum dose of 520 mg/kg over a treatment period of up to 24 months. The active substance, bevacizumab, is a protein of non-human origin, and the product is manufactured by Amgen Technology (Ireland) UC. Participant compliance with the dosing schedule will be monitored throughout the trial.
**Tecentriq**, containing the active substance **atezolizumab**, is another investigational product used in this study. It is available as a 1,200 mg concentrate for solution for infusion, also administered intravenously. The maximum daily dose is 1,200 mg, with a total maximum dose of 41,600 mg over a 24-month period. Atezolizumab is a protein of non-human origin, produced by Roche Registration GmbH. The administration schedule and participant adherence will be closely monitored to ensure compliance with the study protocol.
The trial also includes the administration of **UCPVax**, which contains the active substance **UCP4**. This product is formulated as a 1 mg/2 mL emulsion for injection and is administered via **subcutaneous injection**. The maximum daily dose is 0.5 mg, with a total maximum dose of 6 mg over a 12-month period. UCP4 is a protein of non-human origin, and the product is developed by CHUBPROD. The dosing schedule and participant compliance will be rigorously monitored to maintain adherence to the study requirements.
No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified in this trial. The study focuses on evaluating the efficacy of the combination of UCPVax, atezolizumab, and bevacizumab in patients with unresectable hepatocellular carcinoma. The trial aims to assess the objective response rate at 6 months, following the RECIST v1.1 criteria.
Efficacy
The efficacy of the treatment strategy combining UCPVax, atezolizumab, and bevacizumab in patients with unresectable hepatocellular carcinoma will be assessed primarily through the **objective response rate (ORR)** at 6 months. This primary endpoint will be evaluated using the RECIST criteria version 1.1, which defines ORR as the sum of complete response (CR) and partial response (PR) rates. Secondary endpoints include overall survival (OS), progression-free survival (PFS), and disease control rate (DCR) at 6 months, also evaluated by RECIST criteria v1.1 and imRECIST. Health-related quality of life will be measured using the EORTC-QLQ-C30 every 8 weeks, and toxicities will be graded according to NCI-CTCAE criteria version 5.
Additional assessments will include the ability of UCPVax and atezolizumab plus bevacizumab to promote antigen-specific T lymphocyte activity in peripheral blood, measured by ELISPOT assays for IFN-γ production before and after treatment. The study will also characterize the ability of the TH1-inducing vaccine (UCPVax) to promote epitope spreading in patients treated with atezolizumab and bevacizumab, with antigen-specific CD8 T cells recognizing glypican and NY-ESO1 peptides being assessed. Biomarkers correlated with the efficacy of the combined immunotherapy will also be evaluated. The trial is estimated to conclude by September 2027, with recruitment having started in September 2022.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Signed informed consent
- Females must be using highly effective contraceptive measures and have a negative pregnancy test prior to the start of dosing if of childbearing potential, or must have evidence of non-childbearing potential
- Documented virology status of hepatitis, as confirmed by screening HBV and HCV tests: - For patients with active HBV: HBV DNA <500 IU/ml during screening, initiation of anti-HBV treatment at least 14 days prior to randomization and willingness to continue anti-HBV treatment during the study (per local standard of care; e.g., entecavir) - Patients with HCV, either with resolved infection (as evidenced by detectable antibody) or chronic infection (as evidence by detectable HCV RNA), are eligible
- Performance of an esophagogastroduodenoscopy and assessment and treatment of varices of all sizes per local standard of care prior to randomization
- Patient affiliated to or beneficiary of French social security system
- Ability to comply with the study protocol, in the Investigator’s judgment
- Histologically confirmed hepatocellular carcinoma
- Locally advanced, metastatic, or unresectable disease
- Patient who had not previously received systemic anti-cancer treatment
- Age ≥ 18 years
- Measurable disease defined according to RECIST v1.1 guidelines
- Patients who have received previous chemoembolization, radioembolization and/or radiotherapy should have recovered from any treatment related toxicity, to a level of ≤ grade 1 (according to National Cancer Institute [NCI] common terminology criteria for adverse events, version 5 (CTCAE v5) with the exception of Grade 2 alopecia
- Performance status < 2
- Child–Pugh Class A status
- Signed informed consent 2. Histologically confirmed hepatocellular carcinoma 3. Locally advanced, metastatic, or unresectable disease 4. Patient who had not previously received systemic anti-cancer treatment 5. Age ≥ 18 years 6. Measurable disease defined according to RECIST v1.1 guidelines (Appendix 1; Note: Previously irradiated lesions can be considered as measurable disease only if disease progression has been unequivocally documented at that site since radiation.) 7. Patients who have received previous chemoembolization, radioembolization and/or radiotherapy should have recovered from any treatment related toxicity, to a level of ≤ grade 1 (according to National Cancer Institute [NCI] common terminology criteria for adverse events, version 5 (CTCAE v5; Appendix 2) with the exception of Grade 2 alopecia 8. Performance status < 2 (Appendix 3) 9. Child–Pugh Class A status (Appendix 4) 10. Females must be using highly effective contraceptive measures (see Section V-5-1), and have a negative pregnancy test prior to the start of dosing if of childbearing potential, or must have evidence of non-childbearing potential by fulfilling one of the following criteria at screening: •Post-menopausal is defined as aged more than 50 years and amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatments. •Women under the age of 50 years would be considered postmenopausal if they have been amenorrhoeic for 12 months or more following cessation of exogenous hormonal treatments and with luteinizing hormone and follicle stimulating hormone levels in the post-menopausal range for the institution. •Women with documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation. Male patients with a female partner of childbearing potential should be willing to use barrier contraception during the study and for 5 months following discontinuation of study drug. Patients should refrain from donating sperm from the start of dosing until 5 months after discontinuing study treatment. 11. Documented virology status of hepatitis, as confirmed by screening HBV and HCV tests: - For patients with active HBV: HBV DNA <500 IU/ml during screening, initiation of anti-HBV treatment at least 14 days prior to randomization and willingness to continue anti-HBV treatment during the study (per local standard of care; e.g., entecavir) - Patients with HCV, either with resolved infection (as evidenced by detectable antibody) or chronic infection (as evidence by detectable HCV RNA), are eligible 12. Performance of an esophagogastroduodenoscopy and assessment and treatment of varices of all sizes per local standard of care prior to randomization 13. Patient affiliated to or beneficiary of French social security system 14. Ability to comply with the study protocol, in the Investigator’s judgment.
Exclusion Criteria
- Patients previously exposed to anti-tumor immunotherapy as anti-PD-1, anti-PD-L1, or anti-CTLA4 agent or any immune therapy
- Diagnosis of additional malignancy within 3 years prior to the inclusion with the exception of curatively treated basal cell carcinoma of the skin and/or curatively resected in situ cervical or breast cancer
- Patient with any medical or psychiatric condition or disease, which would make the patient inappropriate for entry into this study
- Current participation in a study of an investigational agent or in the period of exclusion
- Patient under guardianship, curatorship or under the protection of justice
- Know fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC
- Uncontrolled pleural effusion, pericardial effusion, ascites or symptomatic fistula
- Uncontrolled tumor-related pain: exposing patients to risk of exposure to corticoids or iterative hospitalizations. Symptomatic lesions amenable to palliative radiotherapy should be treated prior to inclusion. Patients should be recovered from the effects of radiation. There is no required minimum recovery period
- Known active central nervous system metastases and/or carcinomatous meningitis. Subject with previously treated brain metastases and with radiological and clinical stability are allowed
- History of encephalopathy
- Prior bleeding event due to untreated or incompletely treated esophageal and/or gastric varices within 6 months prior to randomization
- Inadequate organ functions: known cardiac failure of unstable coronaropathy, respiratory failure, or uncontrolled infection or another life-risk condition
- HIV positive (HIV 1/2 antibodies patients), or a known history of active Tuberculosis bacillus
- Any immunosuppressive therapy (i.e. corticosteroids >10mg of hydrocortisone or equivalent dose) within 14 days before the planned start of study therapy
- Active autoimmune disease that has required a systemic treatment in past 2 years (i.e. corticosteroids or immunosuppressive drugs).
- Prior allogeneic bone marrow transplantation or prior solid organ transplantation
- History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
- Known hypersensitivity or allergy to Chinese hamster ovary cell products or any component of atezolizumab or bevacizumab formulation
- History of idiopathic or secondary pulmonary fibrosis (History of radiation pneumonitis in the radiation field fibrosis is permitted), or evidence of active pneumonitis requiring a systemic treatment with 28 days before the planned start of study therapy
- Major surgical procedure other than for diagnosis within 4 weeks prior to initiation of study treatment, or anticipation of need for a major surgical procedure during the course of the study
- 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
- Patients under chronic treatment with systemic corticoids or other immunosuppressive drugs (prednisone or prednisolone ≤ 10 mg/day is allowed) for a period of at least 4 weeks and whose treatment was not stopped 1 week prior to the start of the study treatment
- Patient with intra-alveolar hemorrhage, pulmonary fibrosis, or uncontrolled asthma, or chronic obstructive disease (COPD), defined as at least one hospitalization within 4 months prior to enrollment or as at least 3 exacerbations during the last year prior to enrollment
- Patients requiring oxygen therapy
- Patients with LEVF<40%
- Hospitalization for cardiovascular or pulmonary disease within 4 weeks prior to enrollment
- Receipt of a live, attenuated vaccine within 4 weeks prior to inclusion or anticipation that such a live, attenuated vaccine will be required during the study Note: Patients must agree not to receive live, attenuated influenza vaccine (e.g.,FluMist®) within 28 days prior to randomization, during treatment or within 5 months following the last dose of atezolizumab
- Current or recent (within 10 days prior of Day 1 of Cycle 1) use of aspirine (>325 mg/day) or current or recent treatment with dipyramidole, ticlopidine, clopidogrel, and cilostazol.
- Current or recent (within 10 days prior to Day 1 of Cycle 1) use of full-dose oral or parenteral anticoagulants or thrombolytic agents for therapeutic (as opposed to prophylactic) purpose - Prophylactic anticoagulation for the patency of venous access devices is allowed provided the activity of the agent results in an INR <1.5 x ULN and aPTT is within normal limits (according to institutional standards) within 14 days prior to Day 1 of Cycle 1. - Prophylactic use of low-molecular-weight heparin (LMWH) (i.e., enoxaparin 40 mg/day) is allowed. However, the use of direct oral anticoagulant therapies such as dabigatran (Pradaxa®) and rivaroxaban (Xarelto®) is not recommended due to bleeding risk.
- Chronic daily treatment with a non-steroidal anti-inflammatory drug (NSAID).
- Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 3 days prior to Day 1 of Cycle 1.
- Major surgical procedure within 4 weeks prior to Day 1 of Cycle 1 or anticipation of need for a major surgical procedure during the study.
- Inadequate hematology function: Lymphocyte count at baseline <800/mm3; neutrophil count <1000/mm3, platelets <75000/mm3 (without transfusion), Hemoglobin <9g/dL (patients may be transfused to meet this criterion).
- Inadequate hepatic function: bilirubin 3 fold ULN, AST/ALT 5 fold ULN, International normalized thromboplastin time ratio >2
- Inadequate renal function: MDRD CrCl <30ml/min, Urine dipstick for proteinuria ≥2+ (within 7 days prior to Day 1 of Cycle1) - Patients discovered to have ≥2+ proteinuria on dipstick urinalysis at baseline should undergo a 24-hour urine collection and must demonstrate <1g of protein in 24 hours.
- Others inadequate laboratory values: serum albumin<28 g/L; troponin > ULN; BNP > ULN.
- Active alcohol or drug abuse
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Recruiting | 01 Sept 2022 | 104 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
MVASI 25 mg/mL concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS | 15 | 24 | PRD5803005 |
Tecentriq 1,200 mg concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS | 1200 | 24 | PRD5434939 |
UCPVax 1mg/2ml | Test | EMULSION FOR INJECTION | SUBCUTANEOUS INJECTION | 0.5 | 12 | PRD5563328 |