Clinical Trials /

IMA970A Plus CV8102 in Very Early, Early and Intermediate Stage Hepatocellular Carcinoma Patients

NCT03203005

Description:

This study is being carried out in order to evaluate a new cancer vaccine called IMA970A combined with CV8102, a new adjuvant for the treatment of liver cancer (hepatocellular carcinoma). It will be investigated whether IMA970A and CV8102 is safe and can trigger an immune response against the tumor, which may prevent the tumor (cancer) from recurring or spreading or may even lead to tumor shrinkage following the standard treatments the patients have previously received.

Related Conditions:
  • Hepatocellular Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: IMA970A Plus CV8102 in Very Early, Early and Intermediate Stage Hepatocellular Carcinoma Patients
  • Official Title: A Phase I/II Trial of IMA970A Plus CV8102 Following a Single Pre-vaccination Infusion of Cyclophosphamide in Patients With Very Early, Early and Intermediate Stage of Hepatocellular Carcinoma After Any Standard Treatments

Clinical Trial IDs

  • ORG STUDY ID: HepaVac-101
  • NCT ID: NCT03203005

Conditions

  • Hepatocellular Carcinoma

Interventions

DrugSynonymsArms
IMA970A plus CV8102 and CyclophosphamideCyclophosphamide Injection 1 gIMA970A plus CV8102 and Cyclophosphamide

Purpose

This study is being carried out in order to evaluate a new cancer vaccine called IMA970A combined with CV8102, a new adjuvant for the treatment of liver cancer (hepatocellular carcinoma). It will be investigated whether IMA970A and CV8102 is safe and can trigger an immune response against the tumor, which may prevent the tumor (cancer) from recurring or spreading or may even lead to tumor shrinkage following the standard treatments the patients have previously received.

Detailed Description

      The trial is designed as a single-arm, open-label, multi-center, first-in-man phase I/II
      study investigating an off-the-shelf, multi-peptide-based HCC vaccine (IMA970A) plus CV8102
      adjuvant (RNAdjuvant®) following a single pre-vaccination infusion of low-dose
      cyclophosphamide (CY) acting as an immunomodulator, in patients with very early, early and
      intermediate stage HCC.

      The study treatment is applied without any concomitant anti-tumor therapy, with the intention
      to reduce the risk of tumor recurrence/progression in patients who have received all
      indicated standard treatments.

      Overall, it is planned to treat about 40 patients with IMA970A (off-the-shelf vaccine) plus
      CV8102 (adjuvant) plus a single low-dose of pre-vaccination CY acting as an immunomodulator
      in the HepaVac-101 study.

      Patients are requested to sign the 1st informed consent (IC 1) for screening 1 procedures
      (blood drawings for Human Leukocyte Antigen (HLA) typing and for cellular immunomonitoring,
      capture of demographics and staging of disease [routinely performed, older images may be used
      if requirements are met]), which takes up to 4 weeks. Thereafter, patients receive indicated
      standard treatment followed by recovery, which lasts for at least 4 weeks and up to 12 weeks.
      The main-phase with full safety surveillance starts with the patient's signature of the 2nd
      informed consent (IC 2) and lasts until the end of the EoV (End-of-Visit, Visit 10) Visit
      (4-6 weeks after last vaccination). For each patient this main-phase lasts up to approx. 6.5
      months consisting of up to 4 weeks screening 2, about 4.5 months vaccination period and about
      4 weeks follow up (until EOV Visit [Visit 10]).
    

Trial Arms

NameTypeDescriptionInterventions
IMA970A plus CV8102 and CyclophosphamideExperimentalInvestigational treatment with IMA970A, CV8102, Cyclophosphamide
  • IMA970A plus CV8102 and Cyclophosphamide

Eligibility Criteria

        Inclusion Criteria:

          1. Aged at least 18 years

          2. HLA type: HLA-A*02 and/or HLA-A*24 positive (Screening 1)

          3. 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
             (pathohistological 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

               1. Pathohistological 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

               2. Non-invasive criteria can only be applied to cirrhotic patients and need to be
                  based on imaging techniques obtained by 4-phase multi-detector 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.

          4. Patients for whom no standard anti-tumor therapy is indicated for the next 3 months
             (until after visit 7); thereafter any standard anti-tumor 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.

          5. Eastern Cooperative Oncology Group (ECOG) performance status 0

          6. Child-Pugh A5-6 and B7 disease

          7. Able to understand the nature of the study and give written informed consent

          8. Willingness and ability to comply with the study protocol for the duration of the
             study

          9. Female patients who are post-menopausal (no menstrual period for a minimum of 1 year
             without any alternative medical cause), or surgically sterile (bilateral
             salpingectomy, bilateral oophorectomy, or hysterectomy) or practice a highly effective
             method of birth control from signing of IC 2 by the patient to visit 10/EoV or last
             study visit

               1. Combined (estrogen and progestogen containing) hormonal contraception associated
                  with inhibition of ovulation applied intravaginal or transdermal for a minimum of
                  1 full cycle (based on the patient's usual menstrual cycle period) before first
                  study drug application

               2. Progestogen-only hormonal contraception associated with inhibition of ovulation
                  applied via injection or implant for a minimum of 1 full cycle (based on the
                  patient's usual menstrual cycle period) before first study drug application

               3. Total abstinence from sexual intercourse is acceptable, if it was established
                  prior to the trial and if this is the preferred and usual lifestyle of the
                  patient.

               4. Intrauterine device (IUD) and intrauterine hormone-releasing system (IUS).

         10. Male patients willing to use contraception (condoms with spermicidal jellies or cream)
             or have undergone bilateral orchiectomy and his non-pregnant WOCBP (women of
             childbearing potential partner) willing to use contraception (a highly effective
             method of birth control, see criteria above) from signing of IC 2 by the patient to
             visit 10/EOV or last study visit, however, at least 100 days after application of CY
             at Visit C

        Exclusion Criteria:

          1. Any prior systemic anti-tumor treatment (including drug or treatment regimen, approved
             or experimental) within 2 weeks before signing of the IC 1 by the patient

          2. Concurrent participation in a clinical trial

          3. Liver transplanted patients; patients who are on the liver transplantation waiting
             list are allowed to be enrolled

          4. Previous or concurrent cancer that is no HCC except cervical carcinoma in situ,
             treated basal cell carcinoma, superficial bladder tumors [Ta, Tis & T1] or any cancer
             curatively treated > 3 years prior to signing of IC 2 by the patient

          5. Patients with a history or evidence of systemic autoimmune disease, e.g. rheumatoid
             arthritis, multiple sclerosis, systemic lupus erythematodes (SLE), scleroderma,
             Sjögren's syndrome, Wegener's granulomatosis, Guillain-Barre syndrome

          6. Need for concomitant treatment with immunosuppressive drugs or other immune-modifying
             drugs. The use of inhaled and nasally applied steroids, as well as topical steroids
             outside the vaccination area are permitted

          7. Any medically diagnosed or suspected condition of immunodeficiency or medical history
             thereof

          8. Known HIV infection

          9. Any other known infection with a biological agent that can cause a severe disease and
             poses a severe danger to lab personnel working on patients' blood or tissue. Examples
             are: rabies, Mycobacterium leprae, Plasmodium falciparum, Coccidiodes immitis

         10. Acute and active infections requiring oral or intravenous antibiotics, antiviral or
             antifungal therapy within 30 days prior to signing of the IC 2 by the patient
             (exception: Hepatitis B Virus (HBV) and/or Hepatitis C Virus (HCV) infections;
             direct-acting antivirals may be applied as medically indicated.)

         11. Patients undergoing renal dialysis or with relevant chronic renal failure

         12. Abnormal laboratory values as specified below:

               1. Hematology: Hemoglobin (< 8.5 g/dl), platelets (< 75,000/µl), leukocytes (<
                  2,500/µl), neutrophils (< 1,000/µl), lymphocytes (< 500/µl)

               2. Liver function: serum bilirubin (≥ 3 x ULN), Alanine aminotransferase (ALAT) or
                  Aspartate aminotransferase (ASAT) (≥ 5 x ULN)

               3. Renal function: serum creatinine (≥ 1.5 x ULN)

         13. Patients with seizure disorder requiring medication (such as steroids or
             anti-epileptics drugs)

         14. Encephalopathy

         15. Clinically relevant ascites with the only exception of patients that remain free from
             symptomatic ascites under low-dose diuretics (Spironolactone >100 mg daily and
             Furosemide >40 mg daily).

         16. Hypersensitivity to the study drugs (CY, IMA970A, or CV8102) including excipients and
             to CT/MRI contrast agent

         17. Known type I allergy to beta-lactam antibiotics

         18. Evidence of current alcohol or drug abuse

         19. Patient dependent on the sponsor or an investigator (e.g. employee, relative)

         20. Serious intercurrent illness, which according to the investigator, poses an undue risk
             to the patient when participating in the trial, including, but not limited to, any of
             the following:

               1. Clinically significant cardiovascular disease (e.g., uncontrolled hypertension;
                  clinically significant cardiac arrhythmia, clinically significant
                  QT-prolongation),

               2. New York Heart Association class III-IV congestive heart failure,

               3. Symptomatic peripheral vascular disease,

               4. Severe pulmonary dysfunction,

               5. Psychiatric illness or known social situation that would preclude study
                  compliance.

               6. Systemic inflammatory condition

         21. Less than 6 months since any of the following:

               1. Myocardial infarction,

               2. Severe or unstable angina pectoris,

               3. Coronary or peripheral artery bypass graft,

               4. Cerebrovascular event incl. transient ischemic attack,

               5. Pulmonary embolism / deep vein thrombosis (DVT)

         22. Patients with contra-indications for treatment with cyclophosphamide (acute
             infections, bone-marrow aplasia, urinary tract infection, acute urothelial toxicity
             from cytotoxic chemotherapy or radiation therapy, urinary outflow obstruction)

         23. Pregnancy or breastfeeding

         24. Any condition which in the judgment of the investigator would place the patient at
             undue risk or interfere with the results of the study
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability)
Time Frame:Through study completion, up to two years
Safety Issue:
Description: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 (hematology, 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). Additionally, an Independent Data Safety Monitoring Board (DSMB) will be implemented to evaluate safety data independently and at defined intervals.

Secondary Outcome Measures

Measure:Additional immunological parameters in blood (e.g. regulatory T-cells, myeloid-derived suppressor cells)
Time Frame:Up to two years
Safety Issue:
Description: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
Measure:Infiltrating T-lymphocytes, immune cells and potential other (bio)markers in tumor tissue
Time Frame:Up to two years
Safety Issue:
Description:Analysis of paraffin-embedded tumor tissues (also potentially in liquid-nitrogen frozen tissue, if available) will be performed to characterize both the tumor cells and the tumor-infiltrating components by immunohistochemistry (IHC) and potentially other analysis techniques. Classical hematoxylin-eosin (HE) staining will be first performed to assess the cellular and stroma composition of the tumor tissue. Markers such as Cytokeratin 8, Cytokeratin 18 and HepPar-1, will be assessed to distinguish tumor cells from other cellular components. The tumor infiltrating cells will be characterized to assess leukocyte subpopulations such as myeloid (monocyte-macrophages, granulocytes) and lymphoid (T, B, NK) cells.
Measure:Assessment of the potential impact of the standard therapy on the natural imune response to peptides contained in IMA970A
Time Frame:Up to two years
Safety Issue:
Description:The assessment of the natural immune response to peptides contained in IMA970A will be performed before start of standard anti-tumor therapy and thereafter to assess whether the selected standard therapy has an influence on a potentially pre-existing (natural) immune response.
Measure:Time to progression (TTP)
Time Frame:Up to two years
Safety Issue:
Description:The time-related secondary efficacy endpoint for the trial is time-to-progression, with time being measured from baseline CT/MRI scan (at Visit B) to documented tumor progression.
Measure:Overall survival (OS)
Time Frame:Patients will be followed for overall survival every 2 months for up to 3 years after having completed the interventional part of the study at EOV/Visit 10
Safety Issue:
Description:Patients will be followed for overall survival

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute, Naples

Last Updated

October 19, 2017