Trial name or title

Sorafenib tosylate with or without stereotactic body radiation therapy in treating patients with liver cancer

Methods

Phase III trial

Participants

People with hepatocellular carcinoma unsuitable for resection, radiofrequency ablation, or transarterial chemoembolisation (TACE)

Interventions

Experimental: Arm 1 (sorafenib tosylate): Sorafenib tosylate given orally twice a day on days 1 to 28. Treatment repeats every 28 days for up to 5 years in the absence of disease progression or unacceptable toxicity.

Experimental: Arm 2 (stereotactic body radiotherapy and sorafenib tosylate): stereotactic body radiotherapy administered every 24 to 72 hours for a total of 5 fractions over 5 to 15 days. Within 1 to 5 days post‐stereotactic body radiotherapy, treatment with sorafenib tosylate commences, given orally twice a day on days 1 to 28. Treatment repeats every 28 days for up to 5 years in the absence of disease progression or unacceptable toxicity.

Outcomes

Primary outcome measures:

• Overall survival

Secondary outcome measures:

• Time to progression

• Progression‐free survival

Health‐related quality of life assessments measured by FACT‐Hep

Starting date

April 2013

Contact information

Christopher M Iannuzzi; [email protected]

Notes

Inclusion criteria:

• Patients must have a diagnosis of hepatocellular carcinoma by at least 1 of the following criteria within 360 days prior to study entry: pathologically (histologically or cytologically) proven diagnosis of hepatocellular carcinoma (biopsies are recommended, and are to be submitted for research evaluation if patients consent); at least 1 solid liver lesion or vascular tumor thrombosis (involving portal vein, inferior vena cava, and/or hepatic vein) > 1 cm with arterial enhancement and delayed washout on multiphasic computed tomography or MRI in the setting of cirrhosis or chronic hepatitis B or C without cirrhosis. For patients whose current disease is vascular only: enhancing vascular thrombosis (involving portal vein, inferior vena cava, and/or hepatic vein) demonstrating early arterial enhancement and delayed washout on multiphasic computed tomography (CT) or MRI in a patient with known hepatocellular carcinoma (diagnosed previously < 720 days) using the above criteria.

• Measurable hepatic disease or presence of vascular tumour thrombosis (involving portal vein, inferior vena cava, and/or hepatic vein), or both, which may not be measurable as per RECIST on liver CT or MRI, within 28 days of registration.

• Appropriate for protocol entry based upon the following minimum diagnostic workup: history/physical examination including examination for encephalopathy, ascites, weight, height, and blood pressure within 14 days prior to study entry; assessment by radiation oncologist and medical oncologist or hepatologist who specialises in treatment of hepatocellular carcinoma within 28 days prior to study entry; pre‐randomisation scan (required for all patients): CT scan chest/abdomen/pelvis with multiphasic liver CT scan or multiphasic liver MRI scan within 28 days prior to study entry. MRI of abdomen with contrast and pelvis is permitted.

• Zubrod performance status 0 to 2 within 28 days prior to study entry.

• Absolute neutrophil count >= 1500 cells/mm³.

• Platelets >= 70,000 cells/mm³.

• Haemoglobin >= 8.0 g/dL (note: the use of transfusion or other intervention to achieve haemoglobin >= 8.0 g/dL is acceptable).

• Total bilirubin < 2 mg/dL.

• International normalised ratio < 1.7.

• Albumin >= 28 g/L.

• Aspartate aminotransferase and alanine aminotransferase < 6 times upper limit of normal.

• Serum creatinine =< 1.5 x upper limit of normal or creatinine clearance >= 60 mL/min.

• Barcelona Clinic Liver Cancer stage: intermediate (B) or advanced (C) within 14 days prior to study entry.

• Child‐Pugh score A within 14 days prior to study entry.

• Women of childbearing potential and male participants must agree to practice adequate contraception while on study and for at least 6 months following the last dose of radiation therapy and for at least 28 days following the last dose of sorafenib (whichever is later).

• Unsuitable for resection or transplant or radiofrequency ablation.

• Unsuitable for or refractory to TACE or drug‐eluting beads for any of the following reasons:

  • Technical contraindications: arteriovenous fistula, including surgical portosystemic shunt or spontaneous portosystemic shunt.

  • Severe reduction in portal vein flow due to tumour portal vein, inferior vena cava, or atrial invasion or bland portal vein occlusion.

  • Medical contraindications including congestive heart failure, angina, severe peripheral vascular disease.

  • Presence of extrahepatic disease.

  • No response post‐TACE (or drug‐eluting beads) or progressive hepatocellular carcinoma despite TACE; prior TACE or drug‐eluting beads is allowed but must be > 28 days from study entry.

  • Serious toxicity following prior TACE (or drug‐eluting beads); prior TACE or drug‐eluting beads must be > 28 days from study entry.

  • Other medical comorbidities making TACE (or drug‐eluting beads) unsafe or risky, or both (e.g. combination of relative contraindications including age > 80 years, tumour > 10 cm, > 50% replacement of the liver by hepatocellular carcinoma, extensive multinodular bilobar hepatocellular carcinoma, biliary drainage).

• People treated with prior surgery are eligible for this study if they otherwise meet eligibility criteria.

• Person must be able to provide study‐specific informed consent prior to study entry.

Exclusion criteria:

• Prior invasive malignancy (except non‐melanomatous skin cancer) unless disease‐free for a minimum of 2 years (note that carcinoma in situ of the breast, oral cavity, or cervix are all permissible).

• Prior sorafenib use > 60 days. Note that prior chemotherapy for hepatocellular carcinoma or a different cancer is permitted.

• Prior radiotherapy to the region of the liver that would result in overlap of radiation therapy fields.

• Prior selective internal radiotherapy/hepatic arterial yttrium therapy, at any time.

• Severe, active comorbidity, defined as follows.

  • Unstable angina or congestive heart failure, or both requiring hospitalisation within the 6 months prior to registration.

  • Transmural myocardial infarction within the 6 months prior to study entry.

  • Unstable ventricular arrhythmia within the 6 months prior to study entry.

  • Acute bacterial or fungal infection requiring intravenous antibiotics within 28 days prior to study entry.

  • Hepatic insufficiency resulting in clinical jaundice, encephalopathy, and/or variceal bleed within 60 days prior to study entry.

  • Bleeding due to any cause requiring transfusion within 60 days prior to study entry.

• Thrombolytic therapy within 28 days prior to study entry. Subcutaneous heparin is permitted.

• Known bleeding or clotting disorder.

• Uncontrolled psychotic disorder.

• Pregnancy or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception; this exclusion is necessary because the treatment involved in this study may be significantly teratogenic.

• Any 1 hepatocellular carcinoma > 15 cm.

• Total maximal sum of hepatocellular carcinomas or a single conglomerate hepatocellular carcinoma > 20 cm.

• More than 5 discrete intrahepatic parenchymal foci of hepatocellular carcinoma.

• Direct tumour extension into the stomach, duodenum, small bowel, or large bowel.

• Measureable common or main branch biliary duct involvement with hepatocellular carcinoma.

• Extrahepatic metastases or malignant nodes (that enhance with typical features of hepatocellular carcinoma) > 3.0 cm, in sum of maximal diameters (e.g. presence of one 3.4‐centimetre metastatic lymph node or two 2‐centimetre lung lesions); note that benign non‐enhancing periportal lymphadenopathy is not unusual in the presence of hepatitis and is permitted, even if the sum of enlarged nodes is > 2.0 cm.

• Use of regular phenytoin, carbamazepine, Hypericum perforatum (also known as St. John's wort), or rifampin.

• Use of combination antiretroviral therapy for HIV, as these agents may modulate cytochrome P450 isozymes.

• Prior liver transplant.

Trial name or title

Transarterial chemoembolisation plus radiotherapy or sorafenib in hepatocellular carcinoma with major vascular invasion (START)

Methods

Randomised phase II trial

Participants

People with hepatocellular carcinoma invading major intrahepatic vessels

Country: Korea

Interventions

transarterial chemoembolisation (TACE) + external beam radiotherapy versus sorafenib

Outcomes

Primary endpoint

• progression‐free survival

Secondary endpoints

• Response rate [ Time Frame: at 3 months after randomisation ] [ Designated as safety issue: No ]

• Time to failure of treatment

• Progression‐free survival

• Treatment‐related adverse events

• Overall survival

Starting date

July 2013

Contact information

Young‐Suk Lim, Associate Professor, Asan Medical Center

Notes

Estimated enrolment: 90

Inclusion criteria:

• Age > 19 years.

• Child‐Pugh class A liver function.

• Performance status: ECOG score 0 or 1.

• Hepatocellular carcinoma confirmed by dynamic computed tomography (CT) or MRI, or by biopsy.

• Hepatocellular carcinoma invasion of first or second branch portal vein or hepatic vein or inferior vena cava.

• Reserved unilateral portal blood flow at least partially.

• Hepatocellular carcinoma size larger than 1 cm and less than 50% of total liver volume.

• No extrahepatic metastasis.

• Adequate haematopoietic function:

  • haemoglobin ≥ 8.5 g/dL;

  • absolute neutrophil count ≥ 750/mm³;

  • platelet count ≥ 30,000/mm³.

• Creatinine < 1.5 mg/dL.

• No plan for pregnancy or breastfeeding. Active contraception.

• Willing to give informed consent.

Trial name or title

Comparison between radiofrequency ablation and hypofractionated proton beam radiation for recurrent/residual hepatocellular carcinoma

Methods

Phase III trial

Participants

People with recurrent/residual hepatocellular carcinoma

Interventions

Experimental: Arm A (radiofrequency ablation)

Experimental: Arm B (proton beam radiotherapy)

Outcomes

Primary outcome measures:

• Local progression‐free survival

Secondary outcome measures:

• Disease‐free survival

Other outcome measures:

• Overall survival

Starting date

October 2013

Contact information

Joong Won Park, PhD; [email protected]

Notes

Estimated enrolment: 144

Inclusion criteria:

• hepatocellular carcinoma diagnosed as (i) the presence of risk factors including hepatitis B or C virus and liver cirrhosis, a serum alpha‐fetoprotein level greater than 200 IU/mL and a radiologically compatible feature with hepatocellular carcinoma in 1 or more computed tomography (CT)/MRI/angiograms, or (ii) the presence of risk factors including hepatitis B or C virus and liver cirrhosis, a serum alpha‐fetoprotein level less than 200 IU/mL, and a radiologically compatible feature with hepatocellular carcinoma in 2 or more computed tomography (CT)/MRI/angiograms, or (iii) histological confirmation.

• hepatocellular carcinoma patients who had recurrent or residual tumour after other treatments.

• No evidence of extrahepatic metastasis.

• The largest diameter of tumour should be less than 3 cm, and the number of tumours ≤ 2.

• No previous treatment to target tumours by other forms of radiotherapy.

• Liver function of Child‐Pugh class A or B7 (Child‐Pugh score of ≤ 7).

• Age ≥ 18 years.

• Performance status of 0 to 2 on the ECOG score.

• White blood cell count ≥ 2000/mm³; haemoglobin level ≥ 7.5 g/dL; platelet count ≥ 50,000/mm³; and adequate hepatic function (total bilirubin ≤ 3.0 mg/dL; aspartate aminotransferase and alanine aminotransferase < 5.0× upper limit of normal; no ascites).

• No serious comorbidities other than liver cirrhosis.

• Written informed consent.

Exclusion criteria:

• Evidence of extrahepatic metastasis.

• Age < 18 years.

• Liver function of Child‐Pugh class B8‐9 and C (Child‐Pugh score of > 7) or uncontrolled cases of active chronic hepatitis B.

• Previous history of other forms of radiotherapy adjacent to target tumours.

• Poor performance status of 3 to 4 on the ECOG score.

• Pregnant or breastfeeding status.

• Previous history of uncontrolled other malignancies within 2 years.

Trial name or title

A trial on stereotactic body radiotherapy after incomplete transarterial chemoembolisation (TACE) versus exclusive TACE for treatment of inoperable hepatocellular carcinoma

Methods

Phase III trial

Participants

People with inoperable hepatocellular carcinoma

Interventions

Experimental: Stereotactic body radiation therapy

Active comparator: transarterial chemoembolisation (TACE)

Outcomes

Primary outcome measures:

• Local control

Secondary outcome measures:

• Progression free‐survival

• Overall survival

• Toxicity (incidence of acute and late complications)

Starting date

November 2014

Contact information

Marta Scorsetti, MD, PhD; [email protected]

Notes

Estimated enrolment: 80

Inclusion criteria:

• Age > 18 years.

• Karnofsky index > 70%.

• Child‐Turcotte‐Pugh A or B liver score.

• An initial diagnosis of primary hepatocellular carcinoma or recurrence.

• A technically unresectable lesion or medically contraindicated surgery or a case in which surgery was declined.

• Hepatocellular carcinoma (single nodule ≤ 5 cm or max 3 nodules ≤ 3 cm) diagnosed by histology or non‐invasive EASL criteria.

• Baseline computed tomography (CT) or MRI and bone scan without evidence of radiologically definable major vascular invasion or extrahepatic disease.

• Haemoglobin > 10.5.0 g/%, white blood cell count > 3000 cells/mm³, platelets > 50,000 cells/mm³, bilirubin < 2 mg/dL, aspartate and alanine aminotransferase levels < 5 times upper normal limit, and prothrombin time‐international normalised ratio ≤ 2.

• Serum creatinine < 1.7 mg/dL.

• Previously incomplete transcatheter arterial embolisation or TACE with radiologically defined residual disease.

• Informed consent.

Exclusion criteria:

• Extrahepatic disease and refractory ascites.

• Previous abdominal radiation therapy.

• Haemorrhage/bleeding event = grade 3 within 4 weeks of enrolment in the study.

• Pregnant or breastfeeding women.

• People with uncontrolled infections or HIV seropositive patients.

• Mental conditions rendering the person incapable of understanding the nature, scope, and consequences of the study.

Trial name or title

Proton radiotherapy versus radiofrequency ablation for patients with medium or large hepatocellular carcinoma

Methods

Phase III trial

Participants

People with medium (> 3, ≤ 5 cm) or large (> 5, ≤ 7 cm) treatment‐naive hepatocellular carcinoma

Interventions

Proton beam radiotherapy versus radiofrequency ablation

Outcomes

Primary outcome measures:

• Local control rate (treatment in‐field control rate) (time frame: three years)

Secondary outcome measures:

• Overall survival rate

• Intrahepatic control rate

• Distant metastasis‐free survival rate

• Local control rate (treatment in‐field control rate) (time frame: five years).

• Number of participants with treatment‐related adverse events as assessed by CTCAE v4.0.

• Patient‐report outcome: quality of life as assessed by the FACT‐Hep.

Starting date

January 2016

Contact information

Bing‐Shen Huang, MD; [email protected]

Notes

Inclusion criteria:

• Pathologically confirmed hepatocellular carcinoma or lesion with typical triphasic computed tomography (CT) or MRI imaging features for hepatocellular carcinoma.

• Single tumour and tumour size > 3 cm, ≤ 7 cm in diameter.

• People unsuitable for resection or unwilling to accept surgery.

• Age ≥ 20 years old.

• ECOG performance status score of 0 or 1.

• Child‐Pugh score ≤ 8.

• Willing to sign informed consent regarding participation in this study.

Exclusion criteria:

• People who have received any prior treatment for hepatocellular carcinoma.

• Pregnant or breastfeeding women.

• Tumour adjacent to bowel < 1 cm.

• Extrahepatic metastasis.

• Extrahepatic invasion.

• Portal or hepatic vein tumour invasion/thrombosis.

• Uncontrolled ascites.

• Glomerular filtration rate < 30 mL/min.*

• Platelet count < 50,000/L.*

• Prior invasive malignancy (except non‐melanomatous skin cancer) unless disease‐free for a minimum of 5 years.

• Ongoing, medically significant active infection.

• MRI incompatible devices.

*Baseline laboratories results must be within the protocol range prior to signing informed consent. Repeat lab tests are permitted to evaluate eligibility during the screening period.

Trial name or title

Transarterial chemoembolisation compared with stereotactic body radiation therapy or stereotactic ablative radiation therapy in treating patients with residual or recurrent liver cancer undergone initial transarterial chemoembolisation

Methods

Phase III trial

Participants

People with residual or recurrent liver cancer who have undergone initial transarterial chemoembolisation

Interventions

Active comparator: Arm I ‐ transarterial chemoembolisation (TACE)

Experimental: Arm II (stereotactic body radiotherapy)

Outcomes

Primary objectives:

1. To determine the freedom from local progression of TACE versus stereotactic body radiotherapy in people with persistent hepatocellular carcinoma after TACE.

Secondary objectives:

1. To determine the progression‐free survival of TACE versus stereotactic body radiotherapy in people with persistent hepatocellular carcinoma after initial TACE.

2. To determine the overall survival of TACE versus stereotactic body radiotherapy for persistent hepatocellular carcinoma.

3. To determine the toxicities associated with TACE or stereotactic body radiotherapy for persistent hepatocellular carcinoma.

Starting date

May 2016

Contact information

Rachel Freiberg; [email protected]

Notes

Inclusion criteria:

• Confirmed hepatocellular carcinoma by 1 of the following: histopathology; 1 radiographic technique that confirms a lesion >= 1 cm with arterial hyper‐vascularisation with washout on delayed phase.

• Radiographic evidence of persistent, progressive, or recurrent disease in an area previously treated with TACE and determined from 3 months after initial TACE; this evaluation should be within 6 weeks of date of study eligibility.

• Unifocal liver tumours not to exceed 7.5 cm in greatest axial dimension; multifocal lesions will be restricted to lesions that can be treated within a single target volume within the same liver segment and to an aggregate of 10 cm as long as the dose constraints to normal tissue can be met.

• ECOG performance status 0, 1, or 2.

• People with liver disease classified as Child Pugh class A or B, with score =< 9.

• Life expectancy >= 6 months.

• Albumin >= 2.4 g/dL.

• Total bilirubin =< 3 mg/dL.

• International normalised ratio =< 1.5.

• Creatinine =< 2.0 mg/dL.

• Ability of the research participant or authorised legal representative to understand and be willing to sign a written informed consent document.

Exclusion criteria:

• Prior radiotherapy to the upper abdomen.

• Prior radioembolisation to the liver.

• Prior radiofrequency ablation to index lesion.

• Liver transplant.

• Active gastrointestinal bleed within 2 weeks of study enrolment.

• Ascites refractory to medical therapy (mild‐to‐moderate ascites is allowed).

• Women who are pregnant or breastfeeding.

• Administration of chemotherapy within the previous month.

• Extrahepatic metastases.

• Participation in another concurrent treatment protocol.

• Prior history of malignancy other than hepatocellular carcinoma, dermatologic basal cell or squamous cell carcinoma.

Trial name or title

Transarterial chemoembolisation (TACE) versus TACE + stereotactic body radiotherapy for unresectable hepatocellular cancer (TACE ‐ stereotactic body radiotherapy)

Methods

Phase III trial

Participants

People with unresectable hepatocellular carcinoma

Interventions

Active comparator: drug‐eluting beads ‐ TACE arm

Experimental: drug‐eluting beads ‐ TACE + stereotactic body radiotherapy arm

Outcomes

Primary outcome measures:

• In‐field progression‐free survival

Secondary outcome measures:

• Cause‐specific survival

• Response assessment after treatment

• Quality of life

• Toxicity assessment

Starting date

December 2014

Contact information

Supriya Chopra; [email protected]

Notes

Inclusion criteria:

• Diagnosis of hepatocellular carcinoma. While desirable, tissue diagnosis is not mandatory. In the absence of tissue diagnosis imaging findings characteristic of hepatocellular carcinoma will be used, i.e. in high‐risk population a nodule with arterial phase enhancement and washout during portovenous phase will be considered as diagnostic of hepatocellular carcinoma. In patients where 1 imaging is inconclusive, another imaging modality will be used. However, if second imaging is also inconclusive, and alpha‐fetoprotein is within the non‐diagnostic or borderline range, then tissue diagnosis will be deemed mandatory.

• Barcelona Stage B/Barcelona A not deemed suitable for surgery or refuse surgery. Child Pugh A/Select Child Pugh B (score 7/10).

• ECOG performance status 0 to 1.

• Total number of measurable target lesions ≤ 2, can be encompassed within a single hepatic field or 2 different hepatic fields without exceeding safe dose limit constraints.

• Optimal predicted liver volume reserve > 700 cc. No contraindication for TACE. Tumour considered to be sufficiently away from gastrointestinal structures to deliver safe radiation dose (> 1 cm).

• Consenting to molecular banking of tumour tissue (optional).

Exclusion criteria:

• Metastatic or nodal disease on staging investigations.

• Child C cirrhosis or previous history of liver failure. Expected life span < 6 months.

• Active variceal bleeding or other signs of hepatic decompensation.

• Portal venous thrombosis rendering patients unsuitable for TACE. However, if patient is suitable for superselective TACE, then can be considered for trial inclusion.