Hepatocellular CarcinomaPhase 1NCT01618253
Radiation Therapy With Sorafenib for TACE-Resistant Hepatocellular Carcinoma
A Phase 1 study testing Sorafenib and Conventional fractionation (2 Gy per day) external beam radiation therapy in people with Hepatocellular Carcinoma and Hepatocellular Cancer, run by Medical College of Wisconsin at 1 site in United States.
Trial summary
To determine the maximum tolerated radiation dose with concurrent sorafenib for unresectable hepatocellular carcinoma that has not responded to transarterial chemoembolization. Read more about this study
- Who is it for?
- Ages 18 to 80 years
- Conditions the study is for
- Hepatocellular Carcinoma, Hepatocellular Cancer, Hepatoma
- What is being tested?
- Sorafenib and Conventional fractionation (2 Gy per day) external beam radiation therapy
- Type of treatment
- Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 0 participants
- Where
- 1 siteUnited States
- Study dates
- Jun 2012to Jun 2016
- 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 to 80 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Radiographic or histologic diagnosis of hepatocellular carcinoma (HCC).
- Maximum of 3 HCC lesions within the liver.
- No evidence of lymphadenopathy or metastatic disease per either CT or PET.
- Prior transarterial chemo-embolization (TACE) at least 28 days prior to initiation of protocol therapy.
- Evidence of either progressive disease or stable disease following TACE.
- Child Pugh Class A (score 5-6) or B (score 7).
Show all 11Show fewer
- Eastern Cooperative Oncology Group (ECOG) Performance Status ≤1 (or Karnofsky ≥70%).
- Normal organ and marrow function (platelets >60,000/mc; hemoglobin ≥8.5 g/dL; international normalized ratio (INR) ≤2.3; albumin ≥2.8 g/dL; total bilirubin ≤3 mg/dL; aspartate aminotransferase (AST) / alanine aminotransferase (ALT) <5x upper limit of normal; creatinine ≤1.5x upper limit of normal).
- Negative human immunodeficiency virus serology.
- Negative pregnancy test for women of child bearing age.
- Ability to understand and willingness to sign a written informed consent document.
Who cannot join
- Less than 800 cc of normal liver.
- Child Pugh Class B (score 8-9) or C (score 10-15).
- Acute/active hepatitis B infection.
- Prior systemic chemotherapy or abdominal radiation therapy.
- Portal venous (main, primary right, or primary left trunks) or inferior vena cava thrombosis.
- Prior malignancy within 5 years of enrollment except for non-melanoma skin cancer.
Show all 11Show fewer
- Prior history of myocardial infarction, cerebrovascular accident, or esophageal variceal bleed in the last 6 months.
- Pre-existing heart failure with either a clinical classification of New York Heart Association Class III or IV or cardiac ejection fraction of <45%.
- Systolic blood pressure > 160 mmHg or diastolic pressure > 100 mmHg despite optimal medical management.
- Pulmonary hemorrhage or other serious bleeding event (grade 2+) within 4 weeks initiation of protocol therapy.
- Prior history of scleroderma or active systemic lupus erythematosus.
Trial locations and contacts
1 site in 1 country.
United States1 site
Froedtert Memorial Lutheran Hospital
Milwaukee, Wisconsin, 53226
About this study
Official title: Phase I Study of Radiation Therapy With Concurrent Sorafenib for Hepatocellular Carcinoma Not Responding to Transarterial Chemoembolization
To determine the maximum tolerated radiation dose with concurrent sorafenib for unresectable hepatocellular carcinoma that has not responded to transarterial chemoembolization.
Read the detailed description
In patients with unresectable hepatocellular carcinoma (HCC), transarterial chemoembolization (TACE) is first line therapy. Non-responders to TACE (i.e. stable or progressive disease) represent a poor prognosis population with limited options. Sorafenib is indicated for first line salvage therapy, however it only improves survival 2-3 months and just has a 2-3% response rate. Thus, sorafenib is merely a cytostatic agent that delays progression and does not cytoreduce disease.
Radiation therapy (RT) is a non-invasive treatment that can cytoreduce HCC with minimal morbidity using modern techniques. A meta-analysis and multiple retrospective series suggest TACE + RT improve survival when compared to TACE alone. Higher RT doses are similarly associated with increased survival due to improved local control. Paradoxically, some series suggest that RT can induce vascular endothelial growth factor (VEGF) expression which may stimulate HCC.
Pre-clinical data suggest that combining RT with concurrent sorafenib (a VEGF inhibitor) improves tumor control. However, clinical data is limited to case reports and safety has not been well characterized. Prior to determining if this combination can improve control of HCC in this poor prognosis population, the optimal radiation dose with concurrent sorafenib must be determined by a phase I dose escalation trial.
- Being tested
- Sorafenib, Conventional fractionation (2 Gy per day) external beam radiation therapy
- Keywords
- Transarterial Chemoembolization, TACE, Sorafenib Tosylate, Sorafenib, Nexavar, External Beam Radiation Therapy, Radiation Therapy, Radiotherapy, Radiation
- Medical subject headings
- Carcinoma, Hepatocellular, Liver Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
SorafenibDrug
Also called Sorafenib Tosylate, Nexavar
Sorafenib 400 mg PO bid will be started two weeks prior to initiation of radiation therapy (RT) and continue until the end of protocol specified radiation dose.
Conventional fractionation (2 Gy per day) external beam radiation therapyRadiation
Also called External Beam Radiation Therapy, Radiation Therapy, Radiotherapy
Patients will be stratified by the maximum diameter of HCC in any plane (≤10 cm or >10 cm) based on post-TACE, contrast enhanced MRI or CT. If only 1 lesion is present, the maximum diameter of that lesion in any plane determines stratification. If >1 but ≤3 lesions are present, the sum of the maximum diameter in any plane of all the lesions determines stratification.
The MTD will be determined utilizing a standard 3 + 3 dose escalation scheme (4 Gy increase per bin). For lesions ≤10 cm, the starting RT dose bin will be 42 Gy and escalate to a pre-determined maximum of 62 Gy if no DLT's are experienced. For lesions >10 cm, the starting RT dose bin will be 40 Gy and escalate to a pre-determined maximum of 52 Gy if no DLT's are experienced.
| Study group | Role | What they receive |
|---|---|---|
| Radiation therapy with concurrent sorafenib | Experimental | Not described Receives: Drug: Sorafenib; Radiation: Conventional fractionation (2 Gy per day) external beam radiation therapy |
What is being measured
The primary outcome is the main question the study is designed to answer.
Maximum Tolerated Dose
Maximum tolerated dose (MTD) will be determined by dose limiting toxicity (DLT) that is observed in either the acute (during treatment) or subacute (up to 3 months after treatment) setting. Acute DLT will be defined by grade 3-5 hepatic, gastrointestinal, dermatologic, hematologic, or pulmonary toxicity per Common Toxicity Criteria for Adverse Effects (CTCAE), v4.0. Subacute DLT will be defined by radiation induced liver disease (RILD) or grade 3-5 gastrointestinal, hematologic, or pulmonary toxicity per CTCAE, v4.0.
Measured: From date of enrollment until 3 months after completion of treatment.
Secondary outcomes (5)
Radiographic Response
Evaluated by either contrast enhanced MRI (preferred) or CT.
Measured: 1 & 3 months post-treatment.
Patterns of Failure
Classified as local (in-field), regional (intrahepatic out-of-field), or distant (extrahepatic, which includes porta hepatic lymph nodes).
Measured: From date of enrollment until the date of first documented progression, last known folow-up, or date of death from any cause, whichever came first, assessed up to 10 years.
Progression Free Survival
From date of enrollment until first local, regional, or distant failure following RT, last follow-up, or death from any cause.
Measured: From date of enrollment until the date of first documented progression, last known folow-up, or date of death from any cause, whichever came first, assessed up to 10 years.
Overall Survival
From date of enrollment until last follow-up or death.
Measured: From date of enrollment until the date of last known folow-up or date of death from any cause, whichever came first, assessed up to 10 years.
Health Related Quality of Life
FACT-Hep survey will be utilized to establish pre-treatment baseline and then compared to post-treatment evaluations at months 1, 2, and 3.
Measured: 1, 2, & 3 months post-treatment.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted13 Jun 2012 (estimated)
- Study startJun 2012
- Primary completionJun 2015 (estimated)
- Study completionJun 2016 (estimated)
Why it stopped: Closed due to poor accrual.
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Hepatocellular CarcinomaStudies of the same condition, open and under way.
- More trials run by Medical College of WisconsinThe 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
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 0 participants (actual)
Sponsor and investigators
- Lead sponsor
- Medical College of Wisconsin
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Beth A. Erickson-Wittmann, M.D., Principal investigator, Medical College of Wisconsin
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01618253
- Sponsor's protocol ID
- PRO00017344
- Status last verified
- Sep 2013
- First submitted
- 4 Jun 2012
- Last updated
- 5 Sep 2013
- Results posted
- No
- Data monitoring committee
- Yes
Publications
Chung YL, Jian JJ, Cheng SH, Tsai SY, Chuang VP, Soong T, Lin YM, Horng CF. Sublethal irradiation induces vascular endothelial growth factor and promotes growth of hepatoma cells: implications for radiotherapy of hepatocellular carcinoma. Clin Cancer Res. 2006 May 1;12(9):2706-15. doi: 10.1158/1078-0432.CCR-05-2721.
PubMed 16675562Plastaras JP, Kim SH, Liu YY, Dicker DT, Dorsey JF, McDonough J, Cerniglia G, Rajendran RR, Gupta A, Rustgi AK, Diehl JA, Smith CD, Flaherty KT, El-Deiry WS. Cell cycle dependent and schedule-dependent antitumor effects of sorafenib combined with radiation. Cancer Res. 2007 Oct 1;67(19):9443-54. doi: 10.1158/0008-5472.CAN-07-1473.
PubMed 17909054Ren ZG, Zhao JD, Gu K, Chen Z, Lin JH, Xu ZY, Hu WG, Zhou ZH, Liu LM, Jiang GL. Three-dimensional conformal radiation therapy and intensity-modulated radiation therapy combined with transcatheter arterial chemoembolization for locally advanced hepatocellular carcinoma: an irradiation dose escalation study. Int J Radiat Oncol Biol Phys. 2011 Feb 1;79(2):496-502. doi: 10.1016/j.ijrobp.2009.10.070. Epub 2010 Apr 24.
PubMed 20421145
Study at a glance
From the registry record, last updated by the sponsor on 5 Sep 2013. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase I Study of Radiation Therapy With Concurrent Sorafenib for Hepatocellular Carcinoma Not Responding to Transarterial Chemoembolization
- ClinicalTrials.gov ID
- NCT01618253
- Acronym / sponsor ID
- PRO00017344
- Keywords
- Transarterial Chemoembolization, TACE, Sorafenib Tosylate, Sorafenib, Nexavar, External Beam Radiation Therapy, Radiation Therapy, Radiotherapy
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- WithdrawnReason stopped: Closed due to poor accrual.
- Enrolment
- 0 participants (actual)
- Lead sponsor
- Medical College of WisconsinUniversity, hospital or other
- Study start
- Jun 2012
- Primary completion
- Jun 2015 (estimated)
- Study completion
- Jun 2016 (estimated)
- First posted
- 13 Jun 2012 (estimated)
- 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.
To determine the maximum tolerated radiation dose with concurrent sorafenib for unresectable hepatocellular carcinoma that has not responded to transarterial chemoembolization.
Detailed description
In patients with unresectable hepatocellular carcinoma (HCC), transarterial chemoembolization (TACE) is first line therapy. Non-responders to TACE (i.e. stable or progressive disease) represent a poor prognosis population with limited options. Sorafenib is indicated for first line salvage therapy, however it only improves survival 2-3 months and just has a 2-3% response rate. Thus, sorafenib is merely a cytostatic agent that delays progression and does not cytoreduce disease.
Radiation therapy (RT) is a non-invasive treatment that can cytoreduce HCC with minimal morbidity using modern techniques. A meta-analysis and multiple retrospective series suggest TACE + RT improve survival when compared to TACE alone. Higher RT doses are similarly associated with increased survival due to improved local control. Paradoxically, some series suggest that RT can induce vascular endothelial growth factor (VEGF) expression which may stimulate HCC.
Pre-clinical data suggest that combining RT with concurrent sorafenib (a VEGF inhibitor) improves tumor control. However, clinical data is limited to case reports and safety has not been well characterized. Prior to determining if this combination can improve control of HCC in this poor prognosis population, the optimal radiation dose with concurrent sorafenib must be determined by a phase I dose escalation trial.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Radiation therapy with concurrent sorafenib | Experimental | Drug: Sorafenib, Radiation: Conventional fractionation (2 Gy per day) external beam radiation therapy |
Who may qualify
- Ages
- 18 to 80 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (11 listed)
- Radiographic or histologic diagnosis of hepatocellular carcinoma (HCC).
- Maximum of 3 HCC lesions within the liver.
- No evidence of lymphadenopathy or metastatic disease per either CT or PET.
- Prior transarterial chemo-embolization (TACE) at least 28 days prior to initiation of protocol therapy.
- Evidence of either progressive disease or stable disease following TACE.
Key exclusion criteria (11 listed)
- Less than 800 cc of normal liver.
- Child Pugh Class B (score 8-9) or C (score 10-15).
- Acute/active hepatitis B infection.
- Prior systemic chemotherapy or abdominal radiation therapy.
- Portal venous (main, primary right, or primary left trunks) or inferior vena cava thrombosis.
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 |
|---|---|---|
| SorafenibAlso: Sorafenib Tosylate, NexavarSorafenib 400 mg PO bid will be started two weeks prior to initiation of radiation therapy (RT) and continue until the end of protocol specified radiation dose. | Drug | Radiation therapy with concurrent sorafenib |
| Conventional fractionation (2 Gy per day) external beam radiation therapyAlso: External Beam Radiation Therapy, Radiation Therapy, RadiotherapyPatients will be stratified by the maximum diameter of HCC in any plane (≤10 cm or >10 cm) based on post-TACE, contrast enhanced MRI or CT. If only 1 lesion is present, the maximum diameter of that lesion in any plane determines stratification. If >1 but ≤3 lesions are present, the sum of the maximum diameter in any plane of all the lesions determines stratification. The MTD will be determined utilizing a standard 3 + 3 dose escalation scheme (4 Gy increase per bin). For lesions ≤10 cm, the starting RT dose bin will be 42 Gy and escalate to a pre-determined maximum of 62 Gy if no DLT's are experienced. For lesions >10 cm, the starting RT dose bin will be 40 Gy and escalate to a pre-determined maximum of 52 Gy if no DLT's are experienced. | Radiation | Radiation therapy with concurrent sorafenib |
Primary outcome
Maximum Tolerated Dose
Time frame: From date of enrollment until 3 months after completion of treatment.
Maximum tolerated dose (MTD) will be determined by dose limiting toxicity (DLT) that is observed in either the acute (during treatment) or subacute (up to 3 months after treatment) setting. Acute DLT will be defined by grade 3-5 hepatic, gastrointestinal, dermatologic, hematologic, or pulmonary toxicity per Common Toxicity Criteria for Adverse Effects (CTCAE), v4.0. Subacute DLT will be defined by radiation induced liver disease (RILD) or grade 3-5 gastrointestinal, hematologic, or pulmonary toxicity per CTCAE, v4.0.
5 secondary outcomes
Radiographic Response
Time frame: 1 & 3 months post-treatment.
Patterns of Failure
Time frame: From date of enrollment until the date of first documented progression, last known folow-up, or date of death from any cause, whichever came first, assessed up to 10 years.
Progression Free Survival
Time frame: From date of enrollment until the date of first documented progression, last known folow-up, or date of death from any cause, whichever came first, assessed up to 10 years.
Overall Survival
Time frame: From date of enrollment until the date of last known folow-up or date of death from any cause, whichever came first, assessed up to 10 years.
Health Related Quality of Life
Time frame: 1, 2, & 3 months post-treatment.
Results and safety
The study was withdrawn before enrolling participants, so there are no results.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 5 Sep 2013.
- Background: PubMed 16675562Chung YL, Jian JJ, Cheng SH, Tsai SY, Chuang VP, Soong T, Lin YM, Horng CF. Sublethal irradiation induces vascular endothelial growth factor and promotes growth of hepatoma cells: implications for radiotherapy of hepatocellular carcinoma. Clin Cancer Res. 2006 May 1;12(9):2706-15. doi: 10.1158/1078-0432.CCR-05-2721.
- Background: PubMed 17909054Plastaras JP, Kim SH, Liu YY, Dicker DT, Dorsey JF, McDonough J, Cerniglia G, Rajendran RR, Gupta A, Rustgi AK, Diehl JA, Smith CD, Flaherty KT, El-Deiry WS. Cell cycle dependent and schedule-dependent antitumor effects of sorafenib combined with radiation. Cancer Res. 2007 Oct 1;67(19):9443-54. doi: 10.1158/0008-5472.CAN-07-1473.
- Background: PubMed 20421145Ren ZG, Zhao JD, Gu K, Chen Z, Lin JH, Xu ZY, Hu WG, Zhou ZH, Liu LM, Jiang GL. Three-dimensional conformal radiation therapy and intensity-modulated radiation therapy combined with transcatheter arterial chemoembolization for locally advanced hepatocellular carcinoma: an irradiation dose escalation study. Int J Radiat Oncol Biol Phys. 2011 Feb 1;79(2):496-502. doi: 10.1016/j.ijrobp.2009.10.070. Epub 2010 Apr 24.
Related trials for Hepatocellular Carcinoma
RecruitingObservational study
Real-world Evaluation of the HistoSonics Edison System for Treatment of Liver Tumors Across Multidisciplinary Users (BOOMBOX: Master Study)
Liver Neoplasms, Primary Liver Cancer
Recruiting
The Vanguard Study: Testing a New Way to Screen for Cancer
Bladder Carcinoma, Breast Carcinoma
Active, not recruitingPhase 1
Prospective Exploratory Study of FAPi PET/CT With Histopathology Validation in Patients With Various Cancers
Bladder Carcinoma, Cervical Carcinoma
RecruitingObservational study
A Study to Evaluate Patient-Reported Satisfaction, Effectiveness, and Safety of Atezolizumab in Participants Treated in Routine Clinical Practice
Lung Cancer, Hepatocellular Carcinoma
RecruitingPhase 2
At-Home Cancer Directed Therapy Versus in Clinic for the Treatment of Patients With Advanced Cancer
Advanced Anal Carcinoma, Advanced Biliary Tract Carcinoma
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.
Beth A. Erickson-Wittmann, M.D. principal investigator
Medical College of Wisconsin
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Sorafenib and Conventional fractionation (2 Gy per day) external beam radiation therapy in people with Hepatocellular Carcinoma and Hepatocellular Cancer, run by Medical College of Wisconsin at 1 site 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 11 inclusion and 11 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: withdrawn, as of the sponsor's last update on 5 Sep 2013. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site 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 withdrawn before enrolling participants, so there are no results.
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?
Maximum Tolerated Dose (time frame: From date of enrollment until 3 months after completion of treatment.). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01618253, which also lists 3 linked publications.
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 5 Sep 2013.