Hepatocellular CarcinomaPhase 1NCT03203304
Stereotactic Body Radiotherapy (SBRT) Followed by Immunotherapy in Liver Cancer
A Phase 1 study testing Nivolumab and Ipilimumab in people with Hepatocellular Carcinoma, run by University of Chicago at 3 sites in United States.
Trial summary
External beam photon stereotactic body radiotherapy (SBRT) using a linear accelerator to a total dose of 40 Gy in 5 fractions delivered once daily with at least 48 hours between each fraction. SBRT treatment will be completed within a 21-day window. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Hepatocellular Carcinoma
- What is being tested?
- Nivolumab and Ipilimumab
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 14 participants
- Where
- 3 sitesUnited States
- Study dates
- 25 Aug 2017to 13 Mar 2019
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Be willing and able to provide written informed consent for the trial.
- Be ≥ 18 years of age on day of signing informed consent.
- Have ECOG performance status 0-1.
- Pretreatment CT chest /abdomen /pelvis within 28 days of protocol enrollment.
- Pathologic diagnosis of hepatocellular carcinoma (including fibrolamellar variants and biphenotypic tumors with an HCC component).
- Child Pugh Class A (score = 5 or 6)cirrhosis (assessed within 14 days of SBRT)
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- Deemed ineligible for curative intent therapy with surgical resection or liver transplantation.
- Patients with diffuse/multifocal liver involvement are eligible.
- Patients with extrahepatic disease are eligible.
- Prior systemic therapies for HCC are allowed but not required.
- Must have at least one intrahepatic lesion amenable to SBRT.
- Prior transarterial chemoembolization (TACE) or radiofrequency ablation (RFA) allowed, however, patient must have separate intrahepatic lesion amenable to SBRT and biopsy.
- Intrahepatic lesion amenable to pre and post SBRT biopsies, unless the investigator determines that the tumor biopsies would be unsafe.
- Have measurable disease based on RECIST 1.1.
- Demonstrate adequate organ function as defined in Table 1. All screening labs should be performed within 14 days of treatment initiation.
- Table 1 - Adequate Organ Function Laboratory Values System Laboratory Value Hematological Platelets ≥ 40,000 / mcL Hepatic Serum total bilirubin ≤ 3 mg/dL AST (SGOT) and ALT (SGPT) ≤ 5 X ULN
- Negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication for female subjects of childbearing age.
- Subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 150 days after the last dose of study therapy (for women of child-bearing potential) or 210 days after the last dose of study therapy (for men who have partners of child-bearing potential).
- Have a life expectancy of greater than 6 months (in the opinion of the treating physician).
Who cannot join
- Prior external beam radiation therapy to the liver (defined as > 1 Gy).
- Prior yttrium-90 radioembolization treatment.
- Patients with HBV viral load > 100 IU/mL (antiviral therapy per local practice is required).
- Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment.
- Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy at a dose of >10 mg prednisone daily or equivalent at time of first dose of trial treatment.
- Has a known history of active TB (Bacillus Tuberculosis).
Show all 17Show fewer
- Hypersensitivity to nivolumab or ipilimumab or any of its excipients.
- Has had prior anticancer therapy within 4 weeks of study Day 1 or has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier.
- Has a known additional malignancy that is progressing or requires active treatment.
- Has 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 (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. Patients with allografts (including liver transplants) are not eligible for this protocol.
- Has known history of, or any evidence of active, non-infectious pneumonitis.
- Has an active infection requiring systemic therapy.
- Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
- Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
- Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 120 days after the last dose of trial treatment.
- Has received a live vaccine within 30 days of planned start of study therapy.
- 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.
Trial locations and contacts
3 sites in 1 country.
United States3 sites
Roswell Park Cancer Institute
Buffalo, New York, 14263
University of Chicago
Chicago, Illinois, 60637
Medical College of Wisconsin
Milwaukee, Wisconsin, 53226
About this study
Official title: Phase I Study of Stereotactic Body Radiotherapy (SBRT) Followed by Nivolumab or Ipilimumab With Nivolumab in Unresectable Hepatocellular Carcinoma
External beam photon stereotactic body radiotherapy (SBRT) using a linear accelerator to a total dose of 40 Gy in 5 fractions delivered once daily with at least 48 hours between each fraction. SBRT treatment will be completed within a 21-day window. Starting within 14 days after completion of SBRT, intravenous nivolumab 240 mg will be given every 2 weeks as monotherapy or in combination with ipilimumab 1 mg/kg IV every 6 weeks.
Read the detailed description
1.1 Primary Objective \& Hypothesis Determine the safety and tolerability of SBRT followed by nivolumab or ipilimumab with nivolumab for hepatocellular carcinoma by establishing the rates of toxicity that occur within 6 months from start of SBRT. Hypothesis: SBRT followed by nivolumab or nivolumab and ipilimumab will have similar toxicity to historical controls of SBRT or nivolumab monotherapy.
1.2 Secondary Objectives and Hypotheses Estimate the investigator determined best overall response rate. Hypothesis: Combining radiation and nivolumab or nivolumab and ipilimumab will improve the best overall response rate compared to historical controls with SBRT or nivolumab alone.
Estimate the rates of long-term adverse events (after 6 months) from the end of SBRT. Hypothesis: Long-term toxicity from SBRT with nivolumab or nivolumab and ipilimumab will be comparable to that observed with nivolumab monotherapy.
Summarize the distant disease control, progression-free survival, and overall survival. Hypothesis: Disease control and survival will be comparable to (or better than) that observed with nivolumab monotherapy.
Summarize the local control of the SBRT treated lesion. Hypothesis: Combining SBRT and nivolumab or nivolumab and ipilimumab will have similar (or better) local control rates as observed in SBRT only series.
1.3 Exploratory Objectives Explore changes in inflammatory biomarkers (including, but not limited to CD8/Treg ratio, total CD4 counts, total lymphocyte count) in pretreatment and on-treatment serially collected peripheral blood samples. Hypothesis: Changes in inflammatory biomarkers after radiation therapy may correlate with a more favorable response to immunotherapy.
Explore changes in the tumor microenvironment induced by radiation on pre and post treatment biopsies. Hypothesis: Changes in the tumor microenvironment after radiation therapy will be observed that may correlate with a more favorable response to immunotherapy.
- Conditions
- Hepatocellular Carcinoma
- Being tested
- Nivolumab, Ipilimumab
- Keywords
- hepatocellular carcinoma, nivolumab, ipilimumab, stereotactic body radiotherapy, SBRT
- Medical subject headings
- Carcinoma, Hepatocellular
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
NivolumabDrug
Also called Opdivo
240mg every two weeks by IV infusion
IpilimumabDrug
Also called Yervoy
1mg/kg every six weeks by IV infusion
| Study group | Role | What they receive |
|---|---|---|
| Nivolumab | Experimental | Patients will be randomly placed in either of the two arms. All patients will undergo CT simulation and stereotactic body radiotherapy (SBRT). SBRT treatment will be completed within a 21-day window.
After the final fraction of SBRT, patients will receive treatment with nivolumab 240 mg will be initiated within 14 days. Patients will receive nivolumab infusions once every 2 weeks. Patients will be restaged after every 4 doses of nivolumab (every 8 weeks). Treatment beyond progression is allowed as per irRC evaluation. Receives: Drug: Nivolumab |
| Nivolumab and ipilimumab | Experimental | Patients will be randomly placed in either of the two arms. All patients will undergo CT simulation and stereotactic body radiotherapy (SBRT). SBRT treatment will be completed within a 21-day window.
After the final fraction of SBRT, treatment with nivolumab and ipilimumab will be initiated within 14 days. Patients will be restaged after every 4 doses of nivolumab (every 8 weeks). Treatment beyond progression will be allowed as per irRC evaluation. Patients will receive nivolumab infusions once every 2 weeks and ipilimumab infusions once every 6 weeks. Receives: Drug: Nivolumab; Drug: Ipilimumab |
What is being measured
The primary outcome is the main question the study is designed to answer.
Number of participants with adverse events
To determine the safety and tolerability of SBRT followed by nivolumab or ipilimumab with nivolumab for hepatocellular carcinoma by establishing the rates of toxicity that occur within 6 months from start of SBRT by analyzing the number of patients with adverse events.
Measured: 3 years
Secondary outcomes (6)
Overall response rate
Estimate the investigator determined best overall response rate.
Measured: 3 years
Number of long-term adverse events
Estimate the rates of long-term adverse events (after 6 months) from the end of SBRT.
Measured: from date of randomization until the date of last documented adverse event or date of death from any cause, whichever comes first, up to 100 months
Time to progression free survival
Measured: from date of randomization until the date of first documented progression or date of death from any cause, whichever comes first, up to 100 months
Time of overall survival
Measured: from date of randomization until the date of death from any cause, whichever comes first, up to 100 months
Rate of disease control
Measured: from date of randomization until the date of death from any cause, whichever comes first, up to 100 months
Rate of local control of the SBRT treated lesion
Measured: from date of randomization until the date of death from any cause, whichever comes first, up to 100 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted29 Jun 2017
- Study start25 Aug 2017
- Primary completion13 Mar 2019
- Study completion13 Mar 2019
Why it stopped: Study stopped due to poor accrual.
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Hepatocellular CarcinomaStudies of the same condition, open and under way.
- More trials run by University of ChicagoThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 14 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Chicago
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Chih-Yi Liao, MD, Principal investigator, University of Chicago
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03203304
- Sponsor's protocol ID
- IRB17-0578
- Status last verified
- Jun 2021
- First submitted
- 26 Jun 2017
- Last updated
- 10 Jun 2021
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 10 Jun 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase I Study of Stereotactic Body Radiotherapy (SBRT) Followed by Nivolumab or Ipilimumab With Nivolumab in Unresectable Hepatocellular Carcinoma
- ClinicalTrials.gov ID
- NCT03203304
- Acronym / sponsor ID
- IRB17-0578
- Conditions
- Hepatocellular Carcinoma
- Keywords
- hepatocellular carcinoma, nivolumab, ipilimumab, stereotactic body radiotherapy, SBRT
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Study stopped due to poor accrual.
- Enrolment
- 14 participants (actual)
- Lead sponsor
- University of ChicagoUniversity, hospital or other
- Study start
- 25 Aug 2017 (actual)
- Primary completion
- 13 Mar 2019 (actual)
- Study completion
- 13 Mar 2019 (actual)
- First posted
- 29 Jun 2017 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
External beam photon stereotactic body radiotherapy (SBRT) using a linear accelerator to a total dose of 40 Gy in 5 fractions delivered once daily with at least 48 hours between each fraction. SBRT treatment will be completed within a 21-day window. Starting within 14 days after completion of SBRT, intravenous nivolumab 240 mg will be given every 2 weeks as monotherapy or in combination with ipilimumab 1 mg/kg IV every 6 weeks.
Detailed description
1.1 Primary Objective \& Hypothesis Determine the safety and tolerability of SBRT followed by nivolumab or ipilimumab with nivolumab for hepatocellular carcinoma by establishing the rates of toxicity that occur within 6 months from start of SBRT. Hypothesis: SBRT followed by nivolumab or nivolumab and ipilimumab will have similar toxicity to historical controls of SBRT or nivolumab monotherapy.
1.2 Secondary Objectives and Hypotheses Estimate the investigator determined best overall response rate. Hypothesis: Combining radiation and nivolumab or nivolumab and ipilimumab will improve the best overall response rate compared to historical controls with SBRT or nivolumab alone.
Estimate the rates of long-term adverse events (after 6 months) from the end of SBRT. Hypothesis: Long-term toxicity from SBRT with nivolumab or nivolumab and ipilimumab will be comparable to that observed with nivolumab monotherapy.
Summarize the distant disease control, progression-free survival, and overall survival. Hypothesis: Disease control and survival will be comparable to (or better than) that observed with nivolumab monotherapy.
Summarize the local control of the SBRT treated lesion. Hypothesis: Combining SBRT and nivolumab or nivolumab and ipilimumab will have similar (or better) local control rates as observed in SBRT only series.
1.3 Exploratory Objectives Explore changes in inflammatory biomarkers (including, but not limited to CD8/Treg ratio, total CD4 counts, total lymphocyte count) in pretreatment and on-treatment serially collected peripheral blood samples. Hypothesis: Changes in inflammatory biomarkers after radiation therapy may correlate with a more favorable response to immunotherapy.
Explore changes in the tumor microenvironment induced by radiation on pre and post treatment biopsies. Hypothesis: Changes in the tumor microenvironment after radiation therapy will be observed that may correlate with a more favorable response to immunotherapy.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Nivolumab | Experimental | Drug: NivolumabPatients will be randomly placed in either of the two arms. All patients will undergo CT simulation and stereotactic body radiotherapy (SBRT). SBRT treatment will be completed within a 21-day window. After the final fraction of SBRT, patients will receive treatment with nivolumab 240 mg will be initiated within 14 days. Patients will receive nivolumab infusions once every 2 weeks. Patients will be restaged after every 4 doses of nivolumab (every 8 weeks). Treatment beyond progression is allowed as per irRC evaluation. |
| Nivolumab and ipilimumab | Experimental | Drug: Nivolumab, Drug: IpilimumabPatients will be randomly placed in either of the two arms. All patients will undergo CT simulation and stereotactic body radiotherapy (SBRT). SBRT treatment will be completed within a 21-day window. After the final fraction of SBRT, treatment with nivolumab and ipilimumab will be initiated within 14 days. Patients will be restaged after every 4 doses of nivolumab (every 8 weeks). Treatment beyond progression will be allowed as per irRC evaluation. Patients will receive nivolumab infusions once every 2 weeks and ipilimumab infusions once every 6 weeks. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (19 listed)
- Be willing and able to provide written informed consent for the trial.
- Be ≥ 18 years of age on day of signing informed consent.
- Have ECOG performance status 0-1.
- Pretreatment CT chest /abdomen /pelvis within 28 days of protocol enrollment.
- Pathologic diagnosis of hepatocellular carcinoma (including fibrolamellar variants and biphenotypic tumors with an HCC component).
Key exclusion criteria (17 listed)
- Prior external beam radiation therapy to the liver (defined as > 1 Gy).
- Prior yttrium-90 radioembolization treatment.
- Patients with HBV viral load > 100 IU/mL (antiviral therapy per local practice is required).
- Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment.
- Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy at a dose of >10 mg prednisone daily or equivalent at time of first dose of trial treatment.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| NivolumabAlso: Opdivo240mg every two weeks by IV infusion | Drug | Nivolumab, Nivolumab and ipilimumab |
| IpilimumabAlso: Yervoy1mg/kg every six weeks by IV infusion | Drug | Nivolumab and ipilimumab |
Primary outcome
Number of participants with adverse events
Time frame: 3 years
To determine the safety and tolerability of SBRT followed by nivolumab or ipilimumab with nivolumab for hepatocellular carcinoma by establishing the rates of toxicity that occur within 6 months from start of SBRT by analyzing the number of patients with adverse events.
6 secondary outcomes
Overall response rate
Time frame: 3 years
Number of long-term adverse events
Time frame: from date of randomization until the date of last documented adverse event or date of death from any cause, whichever comes first, up to 100 months
Time to progression free survival
Time frame: from date of randomization until the date of first documented progression or date of death from any cause, whichever comes first, up to 100 months
Time of overall survival
Time frame: from date of randomization until the date of death from any cause, whichever comes first, up to 100 months
Rate of disease control
Time frame: from date of randomization until the date of death from any cause, whichever comes first, up to 100 months
Rate of local control of the SBRT treated lesion
Time frame: from date of randomization until the date of death from any cause, whichever comes first, up to 100 months
Results and safety
The study was stopped early (reason given: Study stopped due to poor accrual.). Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 10 Jun 2021.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Chih-Yi Liao, MD principal investigator
University of Chicago
3 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Nivolumab and Ipilimumab in people with Hepatocellular Carcinoma, run by University of Chicago at 3 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 19 inclusion and 17 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 10 Jun 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 3 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was stopped early (reason given: Study stopped due to poor accrual.). Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Number of participants with adverse events (time frame: 3 years). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 10 Jun 2021.