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

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.

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 \[Visit 10\]).

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 or no liver function impairment
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 CY application
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. History of other malignancies within the last 3 years except for adequately treated except cervical carcinoma in situ, basal cell carcinoma and 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