Hepatocellular Carcinoma
Conditions
Brief summary
The PRIME-HCC trial will assess the effects of combination treatment with nivolumab (OPDIVO) and ipilimumab (YERVOY) pre-operatively in hepatocellular carcinoma patients for whom liver resection is planned. The trial will be conducted at a small number of National Health Service hospitals in the UK. Participants will receive two doses of nivolumab and a single dose of ipilimumab in the weeks before their planned surgery.
Detailed description
This is a single-arm, open-label study to be conducted in 32 patients at a small number of UK hospitals. The study is in 2 parts: Part 1 will confirm, in a small number of patients, that the treatment regimen is safe and doesn't result in unacceptable delay to liver resection. Part 2 will expand the number of patients studied, and provide the opportunity to assess survival over about 2 years after liver resection. The decision to proceed to Part 2 will be taken with advice from an independent, expert committee. Patients with early-stage HCC will first undergo screening procedures during a 28-day time window between giving consent and starting drug treatment. Screening procedures will include: * Medical interview and physical exam * ECG * Tumour biopsy * Tumour imaging by MRI * Tumour imaging by CT * Blood and urine samples * Stool sample (optional) Patients meeting the protocol-specified criteria will be enrolled and on Day 1 will have the following: * Medical interview, and physical exam (if required) * Blood and urine samples * Intravenous dose of ipilimumab ('YERVOY') 1 milligram per kilogram body weight * Intravenous dose of nivolumab ('OPDIVO') 3 milligrams per kilogram body weight On Day 22 the participants will have the following: * Medical interview, and physical exam (if required) * Blood and urine samples * Intravenous dose of nivolumab ('OPDIVO') 3 milligrams per kilogram body weight On Day 43 the participants will have the following: * Medical interview, and physical exam (if required) * ECG * Tumour imaging by MRI * Blood and urine samples * Stool sample (optional) Patients who remain eligible for liver resection will likely undergo surgery within a few days of the Day 43 visit. On Day 127 the participants will have the following: * Medical interview, and physical exam (if required) * Tumour imaging by MRI * Blood and urine samples Every 4 months thereafter until 2 years later, or until starting another anti-cancer treatment, participants will have tumour imaging by MRI.
Interventions
BIOLOGICALIpilimumab
Ipilimumab is a monoclonal antibody given as an immunotherapy
BIOLOGICALNivolumab
Nivolumab is a monoclonal antibody given as an immunotherapy
Sponsors
Imperial College London
Bristol-Myers Squibb
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Written informed consent for the trial. 2. Aged ≥18 years 3. Confirmed diagnosis of HCC 4. Willing to provide tissue from an excisional biopsy of a tumour lesion 5. Have measurable disease by Computed Tomography (CT)-scan or Magnetic Resonance Imaging (MRI) defined by RECIST 1.1 criteria 6. Ineligible for liver transplantation 7. Medically fit to undergo surgery as determined by the treating medical and surgical oncology team 8. ECOG performance status 0 or 1 9. Adequate organ function 10. Overall Child-Pugh class A 11. Female patient of childbearing potential should have a negative serum pregnancy test within 24 h of her first dose of IMP 12. Women of childbearing potential must be willing to use a highly effective method of contraception for the course of the study through 5 months after the last dose of Investigational Medicinal Product (IMP). Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the patient. 13. Sexually active males must agree to use an adequate method of contraception starting with the first dose of IMP through 7 months after the last dose of study therapy. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the patient.
Exclusion criteria
1. Extrahepatic metastasis 2. Prior systemic anticancer treatment for HCC, including an anti-PD-1, anti-PD-L1 or anti-CTLA-4 antibody 3. Prior orthotopic liver transplantation 4. Any major surgery within the 3 weeks prior to enrolment 5. Hepatic encephalopathy 6. Ascites that is refractory to diuretic therapy 7. Is currently receiving anti-cancer therapy (chemotherapy, radiation therapy, immunotherapy or biologic therapy) or has participated or is participating in a study of an IMP or used an investigational device within 4 weeks of the first dose of IMP 8. Diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy 9. Known history of active Bacillus Tuberculosis (TB) 10. History of known hypersensitivity to any monoclonal antibody or any of their excipients 11. Known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy, or in situ cervical cancer 12. Active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment 13. Known history of, or any evidence of active, non-infectious pneumonitis 14. Active infection requiring systemic therapy, with exceptions relating to Hepatitis B and C virus infection 15. History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the patient's participation for the full duration of the trial, or is not in the best interest of the patient to participate, in the opinion of the treating Principal Investigator (PI) 16. Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial 17. Pregnant or breastfeeding 18. Known history of Human Immunodeficiency Virus (HIV; HIV 1/2 antibodies) 19. Received a live vaccine within 30 days of first dose of IMP administration. Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Delay to Surgery | Up to Day 89 | Number of patients with an unplanned delay to surgery to Day 89 or later |
| Frequency of Treatment-related Adverse Events [Safety and Tolerability] | Up to Day 127 | Safety and tolerability of the nivolumab and ipilimumab combination based on NCI CTCAE v5.0 criteria from the day of first nivolumab and ipilimumab administration to 126 days later. Treatment-related adverse events (TRAE) are defined as any unfavorable medical occurrence, symptom, or abnormal laboratory finding in a participant that is deemed to be either definitely, probably, or possibly caused by the trial treatment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate | Up to Day 43 | Objective response rate (complete or partial response) on pre-resection imaging 42 days after the day of first nivolumab and ipilimumab administration using Response Evaluation Criteria in Solid Tumours (RECIST) criteria v1.1. The criteria classifies response based on the assessment of target and non-target lesions on scans as: Complete Response (CR): requires all of: * disappearance of all target and non-target lesions * pathological lymph nodes must have reduced to \<10 mm in short axis * no new lesions Partial Response (PR): requires all of: * at least 30% decrease in sum of diameters (SOD) of target lesions compared to baseline sum diameters * non-progressive disease of non-target lesions * no new lesions Progressive Disease (PD): either one of: * any new lesions * at least 20% relative and 5 mm absolute increase of SOD of target lesions compared to smallest SOD ever recorded for the patient Stable Disease (SD): not meeting criteria for PD or PR. |
| Pathologic Response Rate | Up to Day 88 or up to liver resection, whichever came first | Pathologic response rate (≥70%) on hematoxylin and eosin evaluation of the resected specimen. |
Countries
United Kingdom
Contacts
PRINCIPAL_INVESTIGATORDavid J Pinato
Imperial College London
Baseline characteristics
| Characteristic | — |
|---|---|
| Aetiology Alcohol | 8 Participants |
| Aetiology Cryptogenic | 9 Participants |
| Aetiology Hemochromatosis | 1 Participants |
| Aetiology Hepatitis B Virus (HBV) | 4 Participants |
| Aetiology Hepatitis C Virus (HCV) | 8 Participants |
| Aetiology Metabolic dysfunction-Associated Steatotic Liver Disease | 3 Participants |
| Age, Continuous | 68 years |
| Barcelona Clinic Liver Cancer (BCLC) stage Stage A | 23 Participants |
| Barcelona Clinic Liver Cancer (BCLC) stage Stage B | 10 Participants |
| Child-Pugh score Class A: Score 5 | 28 Participants |
| Child-Pugh score Class A: Score 6 | 5 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance status (PS) score Score 0 | 25 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance status (PS) score Score 1 | 8 Participants |
| Race/Ethnicity, Customized Asian | 7 Participants |
| Race/Ethnicity, Customized Black | 3 Participants |
| Race/Ethnicity, Customized Other Ethnic Group | 1 Participants |
| Race/Ethnicity, Customized White | 22 Participants |
| Region of Enrollment United Kingdom | 33 participants |
| Sex: Female, Male Female | 8 Participants |
| Sex: Female, Male Male | 25 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 4 / 33 |
| other Total, other adverse events | 28 / 33 |
| serious Total, serious adverse events | 3 / 33 |
Outcome results
None listed