Trial Title:
A Phase I Trial of IMA970A Plus Montanide in Combination with Durvalumab (anti-PD-L1)
NCT ID:
NCT06218511
Condition:
Hepatocellular Carcinoma
Conditions: Official terms:
Carcinoma
Carcinoma, Hepatocellular
Durvalumab
Monatide (IMS 3015)
Study type:
Interventional
Study phase:
Phase 1
Overall status:
Recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Intervention model description:
Open-label
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Biological
Intervention name:
Peptide-based hepatocellular carcinoma vaccine IMA970A
Description:
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.
Arm group label:
Single arm
Intervention type:
Combination Product
Intervention name:
Durvalumab
Description:
anti-PD-L1
Arm group label:
Single arm
Intervention type:
Other
Intervention name:
Montanide (Adjuvant)
Description:
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 .
Arm group label:
Single arm
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.
Criteria for eligibility:
Criteria:
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).
Exclusion Criteria:
Patients should not enter the study if any of the following exclusion criteria are
fulfilled:
1. Any prior systemic anti-tumour treatment (including drug or treatment regimen,
approved or experimental) within 2 weeks before study treatment administration.
2. Major surgical procedure (as defined by the Investigator) within 28 days prior to
the first dose of IP. Note: Local surgery of isolated lesions for palliative intent
is acceptable
3. Liver transplanted patients; patients who are on the liver transplantation waiting
list are not allowed to be enrolled.
4. Concurrent enrolment in another clinical study, unless it is an observational (non
interventional) clinical study or during the follow-up period of an interventional
study.
5. Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with the
exception of alopecia, vitiligo, and the laboratory values defined in the inclusion
criteria
1. Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis
after consultation with the Study Physician.
2. Patients with irreversible toxicity not reasonably expected to be exacerbated
by treatment with durvalumab may be included only after consultation with the
Study Physician.
6. History of allogenic organ transplantation.
7. History or evidence of systemic autoimmune disease, e.g. rheumatoid arthritis,
multiple sclerosis, systemic lupus erythematosus (SLE), scleroderma, Sjögren's
syndrome, Wegener's granulomatosis, Guillain-Barre syndrome.
8. 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.
9. Uncontrolled intercurrent illness, including but not limited to, ongoing or active
infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable
angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic
gastrointestinal conditions associated with diarrhoea, or psychiatric illness/social
situations that would limit compliance with study requirement, substantially
increase risk of incurring AEs or compromise the ability of the patient to give
written informed consent.
10. History of other malignancies within the last 3 years except for adequately treated
except cervical carcinoma in situ, basal cell carcinoma and superficial bladder
tumours [Ta, Tis & T1] or any cancer curatively treated > 3 years prior to signing
of informed consent by the patient.
11. History of leptomeningeal carcinomatosis.
12. Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥470 ms
calculated from 3 ECGs (within 15 minutes at 5 minutes apart). Regardless of whether
this criterion stays or not, all patients should have a baseline ECG.
13. Any medically diagnosed or suspected condition of immunodeficiency or medical
history thereof
14. Known to have tested positive for human immunodeficiency virus (HIV) (positive HIV
1/2 antibodies) or active tuberculosis infection (clinical evaluation that may
include clinical history, physical examination and radiographic findings, or
tuberculosis testing in line with local practice).
15. 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, Coccidioides
immitis.
16. Acute and active infections requiring oral or intravenous antibiotics, antiviral or
antifungal therapy within 30 days prior to enrolment (exception: Hepatitis B Virus
(HBV) and/or Hepatitis C Virus (HCV) infections; direct-acting antivirals may be
applied as medically indicated).
17. Receipt of live attenuated vaccine within 30 days prior to the first dose of IP.
Note:
Patients, if enrolled, should not receive live vaccine whilst receiving IP and up to
30 days after the last dose of IP.
18. Female patients who are pregnant or breastfeeding or male or female patients of
reproductive potential who are not willing to employ effective birth control from
screening to 6 months after receiving the last dose of treatment combination or 3
months after receiving the last dose of durvalumab monotherapy.
19. Known allergy or hypersensitivity to any of the study drugs or any of the study drug
excipients.
20. Prior randomisation or treatment in a previous durvalumab clinical study regardless
of treatment arm assignment.
21. Patients who have received prior anti-PD-1, anti PD-L1 or anti CTLA-4:
1. Must not have experienced a toxicity that led to permanent discontinuation of
prior immunotherapy.
2. All AEs while receiving prior immunotherapy must have completely resolved or
resolved to baseline prior to screening for this study.
3. Must not have experienced a ≥Grade 3 immune related AE or an immune related
neurologic or ocular AE of any grade while receiving prior immunotherapy. NOTE:
Patients with endocrine AE of ≤Grade 2 are permitted to be enrolled if they are
stably maintained on appropriate replacement therapy and are asymptomatic.
4. Current or prior use of immunosuppressive medication within 14 days before the
first dose of durvalumab. The following are exceptions to this criterion:
- Intranasal, inhaled, topical steroids, or local steroid injections (e.g.,
intra articular injection
- Systemic corticosteroids at physiologic doses not to exceed <<10 mg/day>>
of prednisone or its equivalent
- Steroids as premedication for hypersensitivity reactions (e.g., CT scan
premedication)
22. Patients undergoing renal dialysis or with relevant chronic renal failure.
23. Abnormal laboratory values as specified below:
1. Haematology: Haemoglobin (< 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)
24. Patients with seizure disorder requiring medication (such as steroids or anti
epileptics drugs).
25. Encephalopathy.
26. 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).
27. Hypersensitivity to the study drugs (IMA970A, Montanide or Durvalumab) including
excipients and to CT/MRI contrast agent.
28. Evidence of current alcohol or drug abuse.
29. 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
30. 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)
31. Any condition which in the judgment of the investigator would place the patient at
undue risk or interfere with the results of the study.
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Luigi Buonaguro
Address:
City:
Napoli
Zip:
80131
Country:
Italy
Status:
Recruiting
Contact:
Last name:
Luigi Buonaguro
Phone:
0817770587
Email:
l.buonaguro@istitutotumori.na.it
Contact backup:
Last name:
Paolo Antonio Ascierto
Contact backup:
Last name:
Francesco Izzo
Start date:
November 22, 2022
Completion date:
November 2026
Lead sponsor:
Agency:
National Cancer Institute, Naples
Agency class:
Other
Source:
National Cancer Institute, Naples
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06218511
