Hepatocellular Carcinoma
Conditions
Brief summary
The trial is designed as a single-arm, open-label, phase I study investigating an off-the-shelf, multi-peptide-base HCC vaccine plus Montanide, combined with Durvalumab in patients with very early, early and intermediate stage of HCC. The investigational agents will be applied without concomitant anti-tumour therapy with the intention to reduce risk of recurrence/progression in patients who have received all indicated standard treatments.
Detailed description
The proposed phase I HepaVac-201 will investigate safety, tolerability and immunogenicity of the same investigational IMA-970A agent, formulated in Montanide combined with an anti-PD-L1 (i.e.Durvalumab). Compared to the previous HepaVac-101 clinical trial, two major differences are introduced. The adjuvant Montanide (oil and water mix) will replace the CV8102 (TLR agonist) which was used in the HepaVac-101 trial. The anti-PD-L1 Durvalumab is introduced in the protocol. Indeed, several reports have shown that, inhibitory receptors are induced after vaccination. Blocking these inhibitory pathways lead to amplification of the T cell-mediated immune response. In particular, IFNγ production by antitumour-specific T cells could also upregulate PD-L1 on tumour cells, as a resistance mechanism to adaptive immunity, thereby promoting PD-L1-PD-1 blockade after vaccination. Several early phases clinical trials have been performed to validate this hypothesis. The aim is to verify whether these two changes in the HepaVac-201 protocol will improve the immunogenicity of the vaccine keeping the same safety profile as in the HepaVac-101 protocol. The phase I clinical trial HepaVac-201 will be conducted at the Istituto Nazionale Tumori, IRCCS Fondazione G. Pascale, Naples, Italy. Dr. Luigi Buonaguro will be the coordinator of the trial. Dr. Francesco Izzo and Dr. Paolo A. Ascierto are the lead Investigators. The trial is designed as a single-arm, open-label, phase I study investigating an off-the-shelf, multi-peptide-base HCC vaccine plus Montanide, combined with Durvalumab in patients with very early, early and intermediate stage of HCC. The investigational agents will be applied without concomitant anti-tumour therapy with the intention to reduce risk of recurrence/progression in patients who have received all indicated standard treatment.
Interventions
BIOLOGICALPeptide-based hepatocellular carcinoma vaccine IMA970A
IMA970A is a lyophilized multi-peptide vaccine consisting of 17 individual peptides (active pharmaceutical ingredients) and 2 excipients (Poloxamer 338 and Mannitol). All peptides have been chemically manufactured by well established solid phase peptide synthesis procedures. All peptides are composed of linear, unmodified L- amino acid chains with chain length in the range of 9 to 21 amino acids.
COMBINATION_PRODUCTDurvalumab
anti-PD-L1
OTHERMontanide (Adjuvant)
Montanide ISA™ 51 is a water-in-oil (W/O) emulsion composed of a mineral oil and a surfactant from the mannide monooleate family with immune stimulatory effect .
Sponsors
National Cancer Institute, Naples
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Open-label
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. Written informed consent and any locally required authorization (e.g., Health Insurance Portability and Accountability Act in the US, European Union \[EU\] Data Privacy Directive in the EU) obtained from the patient/legal representative prior to performing any protocol-related procedures, including screening evaluations. 2. Age \> 18 years at time of study entry. 3. HLA type: HLA-A\*02 and/or HLA-A\*24 positive. 4. Very early, early and intermediate stage (Barcelona Clinic Liver Cancer (BCLC) stage 0, A, B disease) hepatocellular carcinoma (HCC) diagnosed by biopsy or resected tissue (patho-histological diagnosis) or imaging findings (non-invasive criteria) following any standard treatment (e.g. hepatic resection, Radiofrequency Ablation / Percutaneous Ethanol injection (RFA/PEI), Transarterial chemoembolization (TACE) and SIRT) and without any evidence of active disease that warrant further treatment. 5. Minimum life expectancy of 1 year. 6. Patho-histological diagnosis of HCC based on biopsy is required for all nodules occurring in non-cirrhotic livers, and for those cases with inconclusive or atypical imaging appearance in cirrhotic livers. 7. Non-invasive criteria can only be applied to cirrhotic patients and need to be based on imaging techniques obtained by 4-phase multidetector CT scan or dynamic contrast enhanced MRI and on the identification of the typical hallmark of HCC (hypervascular in the arterial phase with washout in the portal venous or delayed phase). One imaging technique is sufficient for nodules beyond 1 cm (\> 1 cm) in diameter. 8. Patients for whom no standard anti-tumour therapy is indicated for the next 3 months thereafter any standard anti-tumour therapies applied for the treatment of BCLC stage 0, A and B HCC (e.g. RFA/PEI, TACE, and SIRT) are allowed to be applied in combination with the study treatment. Patients for whom treatment for advanced disease (e.g. sorafenib) is indicated will be withdrawn from study treatment. 9. Eastern Cooperative Oncology Group (ECOG) performance status 0/1 with the specific characteristics indicated in the
Exclusion criteria
. 10. Child-Pugh A5-6 and B7 disease or no liver function impairment. 11. Body weight \>30 kg. 12. Adequate normal organ and marrow function as defined below: 1. Haemoglobin ≥9.0 g/dL 2. Absolute neutrophil count (ANC) ≥1.0 × 109 /L 3. Platelet count ≥75 × 109 /L 4. Serum bilirubin ≤1.5 x institutional upper limit of normal (ULN). This will not apply to patients with confirmed Gilbert's syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of haemolysis or hepatic pathology), who will be allowed only in consultation with their physician. 5. AST (SGOT)/ALT (SGPT) ≤5 x institutional upper limit of normal 6. Measured creatinine clearance (CL) \>40 mL/min or Calculated creatinine CL\>40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance: Males: Creatinine CL (mL/min) = Weight (kg) x (140 - Age) 72 x serum creatinine (mg/dL) Females: Creatinine CL (mL/min) = Weight (kg) x (140 - Age) x 0.85 72 x serum creatinine (mg/dL) 13. Willingness and ability to comply with the study protocol for the duration of the study. 14. Female patient of child-bearing potential: * Female patients of childbearing potential who are not totally sexually abstinent (i.e., refraining from heterosexual intercourse during the entire period of risk associated with study interventions) and intend to be sexually active with a non sterilised male partner must use at least 1 highly effective method of contraception (Appendix 4). They should have been stable on their chosen method of birth control for a minimum of 3 months before entering the study and continue to use it throughout the total duration of the drug treatment and the drug washout period (90 days after the last dose of study treatment). Non sterilised male partners of a female patient of childbearing potential must use male condom plus spermicide throughout this period. Cessation of birth control after this point should be discussed with a responsible physician. Periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of birth control. Female patients should also refrain from breastfeeding throughout this period. Male patients with a female partner of childbearing potential: * Non-sterilised male patients who are not abstinent and intend to be sexually active with a female partner of childbearing potential must use a male condom plus spermicide from the time of screening throughout the total duration of the drug treatment and the drug washout period (90 days after the last dose of study treatment). Periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of contraception. Male patients should refrain from sperm donation throughout this period. Vasectomised males are considered fertile and should still use a male condom plus spermicide as indicated above during the clinical study. * Even if the female partner is pregnant, male participants should still use a condom plus spermicide (where approved), as indicated above during the clinical study, if there is a concern about damaging the developing foetus from drug in ejaculate. * Female partners (of childbearing potential) of male patients must also use a highly effective method of contraception throughout this period (Appendix 4).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability) | 55 months (approximately 4.5 years) | Safety assessments will consist of continuous monitoring and reporting of adverse events (AEs) including serious adverse events (SAEs), regular monitoring of vital signs, ECOG performance status and regular conduct of physical examinations and laboratory assessments (haematology, clinical \[bio\]chemistry including C reactive protein (CRP) and glomerular filtration rate (GFR), coagulation test, assessment of viral infection, thyroid function test (TFT), urinalysis), electrocardiogram (ECG) and pregnancy tests (if applicable). Possible cross-reactivity with live attenuated vaccination or flu vaccine will be assessed. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Additional immunological parameters in blood (e.g. regulatory T-cells, myeloid derived suppressor cells) | 55 months (approximately 4.5 years) | The number of events and the frequency of several MDSC and Treg populations will be presented. |
| Infiltrating T-lymphocytes, immune cells and potential other (bio)markers in tumour tissue (depending on availability of tissue) | 55 months (approximately 4.5 years) | The number of events and the frequency of infiltrating T-lymphocytes (TILs), other immune cells and potential other (bio)markers will be presented. |
| DFS | 55 months (approximately 4.5 years) | Disease-free survival |
| PFS | 55 months (approximately 4.5 years) | progression-free survival |
| OS | Patients will be followed for overall survival every 2 months for up to 2 years after having completed the interventional part of the study at EOS. | Overall survival |
Other
| Measure | Time frame | Description |
|---|---|---|
| Additional immunological parameters | 55 months (approximately 4.5 years) | e.g. regulatory T-cells, myeloid-derived suppressor cells |
| Infiltrating T-lymphocytes in tissue | 55 months (approximately 4.5 years) | Infiltrating T-lymphocytes in tissue (depending on availability of tissue) |
| Serum/plasma biomarkers | 55 months (approximately 4.5 years) | Analysis of other immune cell populations that may influence T-cell responses such as regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSC) (cellular biomarkers) will be performed using PBMCs from pre- and post-vaccination time points. |
| Assessment of the potential impact of the standard therapy on the natural immune response to peptides contained in IMA970A | 55 months (approximately 4.5 years) | The assessment of the natural immune response to peptides contained in IMA970A will be performed before start of standard anti-tumor therapy and thereafter (S 2) to assess whether the selected standard therapy has an influence on a potentially pre-existing (natural) immune response. Thus, available blood samples are used to reach this study endpoint and can therefore be justified, even if some patients turn out not to be eligible for study participation during S 2 procedures. Standardized sample collection, PBMC isolation and storage and standardized immunomonitoring assays will be used for this analysis. |
| Immunogenicity | 55 months (approximately 4.5 years) | The assessment of T-cell response in peripheral blood will be performed for all patients using standardized immune-monitoring assays. Peripheral blood mononuclear cells (PBMCs) of patients will be analysed for the occurrence of T-cell responses to peptides contained in IMA970A vaccine before application of standard therapy, such as before and after vaccination. The induction of immune responses by IMA970A vaccine will be subsequently analysed. |
Countries
Italy
Outcome results
None listed