TERTIO : Evaluation de l’intérêt de combiner un vaccin inducteur de CD4-Th1 dérivé de la télomérase avec un traitement par atezolizumab et bevacizumab chez des patients avec un carcinome hépatocellulaire non résécable : une étude de phase II randomisée preuve du concept

Overview

Sponsor-declared trial summary

Key facts

Sponsor

CHUR Of Besançon, Centre Hospitalier Regional Universitaire

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Digestive System Diseases [C06]

Trial duration

27 Sep 2022 → ongoing

Decision date (initial)

2022-08-01

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

CHU de Besançon

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy, Therapy

to assess the efficacy of a strategy combining UCPVax and atezolizumab plus bevacizumab combination in patients with unresectable hepatocellular carcinoma by evaluation, according to RECIST v1.1, of the objective response rate at 6 months.

Secondary objectives 10

1. To investigate the impact of UCPVax and atezolizumab plus bevacizumab on the overall survival
2. To investigate the impact of UCPVax and atezolizumab plus bevacizumab on the progression-free survival
3. To investigate the impact of UCPVax and atezolizumab plus bevacizumab on the disease control and objective response rates, according to RECIST v1.1 and imRECIST
4. To assess the impact of combined immunotherapy on patient’s health related quality of life (QoL)
5. To evaluate the tolerance of UCPVax in association with anti-PD-L1 plus anti-angiogenic
6. To analyze the tumor genotyping for TERT promoter mutations, telomerase and PD-L1 expression, and to study the correlation of these biomarkers with treatment efficacy
7. To evaluate telomerase-specific T cell responses before and after treatment in peripheral blood mononuclear cells
8. To investigate how the immune contexture defined on baseline biopsies impact UCPVax/atezolizumab plus bevacizumab efficacy. Infiltration of lesions by tumor infiltrating lymphocytes (TIL) and HCC genomic profiling will be investigated in case of tumor surgery or in optional biopsies at progression.
9. To characterize the predictive value of soluble biomarkers (soluble PD-L1 as well as angiogenic and stroma related biomarkers) and nutritional status (inflammatory biomarkers and assessment of sarcopenia)
10. 1. To investigate the impact of UCPVax and atezolizumab plus bevacizumab on the overall survival 2. To investigate the impact of UCPVax and atezolizumab plus bevacizumab on the progression-free survival 3. To investigate the impact of UCPVax and atezolizumab plus bevacizumab on the disease control and objective response rates, according to RECIST v1.1 and imRECIST (Appendix 1) 4. To assess the impact of combined immunotherapy on patient’s health related quality of life (QoL) 5. To evaluate the tolerance of UCPVax in association with anti-PD-L1 plus anti-angiogenic 6. To analyze the tumor genotyping for TERT promoter mutations, telomerase and PD-L1 expression, and to study the correlation of these biomarkers with treatment efficacy 7. To evaluate telomerase-specific T cell responses before and after treatment in peripheral blood mononuclear cells 8. To investigate how the immune contexture defined on baseline biopsies impact UCPVax/atezolizumab plus bevacizumab efficacy. Infiltration of lesions by tumor infiltrating lymphocytes (TIL) and HCC genomic profiling will be investigated in case of tumor surgery or in optional biopsies at progression. 9. To characterize the predictive value of soluble biomarkers (soluble PD-L1 as well as angiogenic and stroma related biomarkers) and nutritional status (inflammatory biomarkers and assessment of sarcopenia)

Conditions and MedDRA coding

Patients with locally advanced, metastatic or unresectable hepatocellular carcinoma

Study design 1 period

Regulatory references

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 15

1. Signed informed consent
2. 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
3. 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
4. Performance of an esophagogastroduodenoscopy and assessment and treatment of varices of all sizes per local standard of care prior to randomization
5. Patient affiliated to or beneficiary of French social security system
6. Ability to comply with the study protocol, in the Investigator’s judgment
7. Histologically confirmed hepatocellular carcinoma
8. Locally advanced, metastatic, or unresectable disease
9. Patient who had not previously received systemic anti-cancer treatment
10. Age ≥ 18 years
11. Measurable disease defined according to RECIST v1.1 guidelines
12. 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
13. Performance status < 2
14. Child–Pugh Class A status
15. 1. 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 38

1. Patients previously exposed to anti-tumor immunotherapy as anti-PD-1, anti-PD-L1, or anti-CTLA4 agent or any immune therapy
2. 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
3. Patient with any medical or psychiatric condition or disease, which would make the patient inappropriate for entry into this study
4. Current participation in a study of an investigational agent or in the period of exclusion
5. Patient under guardianship, curatorship or under the protection of justice
6. Know fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC
7. Uncontrolled pleural effusion, pericardial effusion, ascites or symptomatic fistula
8. 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
9. Known active central nervous system metastases and/or carcinomatous meningitis. Subject with previously treated brain metastases and with radiological and clinical stability are allowed
10. History of encephalopathy
11. Prior bleeding event due to untreated or incompletely treated esophageal and/or gastric varices within 6 months prior to randomization
12. Inadequate organ functions: known cardiac failure of unstable coronaropathy, respiratory failure, or uncontrolled infection or another life-risk condition
13. HIV positive (HIV 1/2 antibodies patients), or a known history of active Tuberculosis bacillus
14. Any immunosuppressive therapy (i.e. corticosteroids >10mg of hydrocortisone or equivalent dose) within 14 days before the planned start of study therapy
15. Active autoimmune disease that has required a systemic treatment in past 2 years (i.e. corticosteroids or immunosuppressive drugs).
16. Prior allogeneic bone marrow transplantation or prior solid organ transplantation
17. History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
18. Known hypersensitivity or allergy to Chinese hamster ovary cell products or any component of atezolizumab or bevacizumab formulation
19. 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
20. 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
21. 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
22. 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
23. 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
24. 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
25. Patients requiring oxygen therapy
26. Patients with LEVF<40%
27. Hospitalization for cardiovascular or pulmonary disease within 4 weeks prior to enrollment
28. 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
29. 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.
30. 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.
31. Chronic daily treatment with a non-steroidal anti-inflammatory drug (NSAID).
32. Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 3 days prior to Day 1 of Cycle 1.
33. 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.
34. 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).
35. Inadequate hepatic function: bilirubin 3 fold ULN, AST/ALT 5 fold ULN, International normalized thromboplastin time ratio >2
36. 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.
37. Others inadequate laboratory values: serum albumin<28 g/L; troponin > ULN; BNP > ULN.
38. Active alcohol or drug abuse

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The primary endpoint is the objective response rate (ORR) at 6 months, evaluated by RECIST criteria v1.1. ORR is defined as the addition of complete response (CR) and partial response (PR) rates, evaluated by RECIST criteria v1.1

Secondary endpoints 8

1. Overall survival (OS): defined as the delay from the date of randomization to death from any cause. Alive patient will be censored at last date known to be alive.
2. Progression-free survival (PFS): defined as the delay from the date of randomization to the disease progression or death from any cause whichever occurs first. Alive patient without progression will be censored at last radiological evaluation available showing no progression
3. Disease control rate (DCR) at 6 months: defined as the addition of complete response (CR), partial response (PR), and stable disease (SD) rates, evaluated by RECIST criteria v1.1 and imRECIST
4. Health related quality of life: EORTC-QLQ-C30 every 8 weeks
5. Toxicities graded according to NCI-CTCAE criteria version 5
6. To show the ability of UCPvax and atezolizumab plus bevacizumab to promote activity of antigen specific T lymphocytes in the peripheral blood. For this purpose, ELISPOT assays will be performed to measure IFN-γ production of telomerase-specific T cell responses before and after treatment
7. To characterize the ability of TH1-inducing vaccine (UCPvax) to promote an epitope spreading in HCC patients treated with atezolizumab and bevacizumab. Antigen specific CD8 T cells recognizing glypican, NY-ESO1 peptides were assessed in patients exposed or not to TERT-derived TH1-inducing vaccine
8. Biomarkers correlated with combined immunotherapy efficacy

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

CHUR Of Besançon

Sponsor organisation

CHUR Of Besançon

Address

3 Boulevard Alexander Fleming, Cs 81816 Cs 81816

City

Besancon Cedex

Postcode

25030

Country

France

Scientific contact point

Organisation

CHUR Of Besançon

Contact name

Manager project

Public contact point

Organisation

CHUR Of Besançon

Contact name

Manager project

Centre Hospitalier Regional Universitaire

Sponsor organisation

Centre Hospitalier Regional Universitaire

Address

2 Place Saint Jacques, Cs 51804 Cs 51804

City

Besancon Cedex

Postcode

25030

Country

France

Scientific contact point

Organisation

Centre Hospitalier Regional Universitaire

Contact name

Chargé de projet

Public contact point

Organisation

Centre Hospitalier Regional Universitaire

Contact name

Chef de projet

Locations

1 EU/EEA country · 15 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 19 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

7 submissions — initial application plus substantial / non-substantial modifications