Effectiveness and Safety Study of TACE Plus Oral Sorafenib for Unresectable HCC

• Sponsor: University of Pittsburgh (Other)
• Overall Status: Terminated
• CT.gov ID: NCT00576056
• Collaborator: Bayer (Industry)
• Enrollment: 19
• Location: 1
• Arm: 1
• Duration (Months): 27
• Patients Per Site Per Month: 0.7

Study Details

Study Description

Brief Summary

The purpose of this study is to determine if TACE plus Sorafenib will improve outcome in patients with advanced hepatocellular carcinoma (HCC) not amenable to surgery.

Condition or Disease	Intervention/Treatment	Phase
Carcinoma, Hepatocellular	Drug: Sorafenib; Drug: TACE	Phase 2

Detailed Description

The proposed study will make an important contribution to understanding not only the safety and efficacy of sorafenib in addition to TACE in patients diagnosed with unresectable HCC, but this will also be the first clinical trial with sorafenib to assess the effects of this novel therapy on HRQL. Understanding the effects of sorafenib on HRQL is critical in the treatment of HCC secondary to the modest benefits in survival that have been reported with conventional therapies. Our team has one of the largest experiences in evaluating HRQL in patients diagnosed with unresectable hepatocellular carcinoma. We have previously reported on alternative methods of evaluating HRQL, solutions for missing data in clinical trials as well as tested statistical and clinically meaningful differences, within and between treatment groups, in clinical trials with patients diagnosed with hepatobiliary carcinoma.

Study Design

• Study Type: Interventional
• Actual Enrollment: 19 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Trial of Transcatheter Arterial Chemoembolization (TACE) Plus Oral Sorafenib (BAY 43-9006, Nexavar®) for Unresectable Hepatocellular Carcinoma (HCC)
• Study Start Date: Jan 1, 2008
• Actual Primary Completion Date: Mar 1, 2010
• Actual Study Completion Date: Apr 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Tace and Sorafenib Patients with unresectable HCC will be treated with TACE in combination with oral sorafenib administration. TACE will be accomplished with gelatin microspheres (Embospheres) following delivery of 125 mg/m2 of cisplatin. Oral sorafenib (400 mg BID) will start the next day after the first TACE treatment.	Drug: Sorafenib; Oral sorafenib (400 mg BID) will start the next day after the first TACE treatment until unacceptable toxicity occurs, or until study termination.; Other Names: Nexavar ; Drug: TACE; TACE will be accomplished with gelatin microspheres (Embospheres) following delivery of 125 mg/m2 of cisplatin.; Other Names: Transarterial Chemoembolization

Outcome Measures

Primary Outcome Measures

1. Determine Progression-free Survival in This Patient Population Treated With the Proposed Combination Treatment Modality [Up to 24 months (from initial treatment through 12 months follow-up)]

   Progression free survival (PFS) is calculated as the time interval between the date on which a patient first received protocol treatment and the documented date of disease progression or death. For a surviving and progression-free patient, PFS is censored by the last follow-up date when that patient is documented to be progression free. Progression is defined using RECIST v1.0, as a 20% increase in the sum of the longest diameter of target lesions, or a measureable increase in a non-target lesion, or the appearance of new lesions.

Secondary Outcome Measures

1. Determine the Overall Survival in Patients Treated With This Combination Regimen [From date of initial treatment until the date of death from any cause]

   Overall survival (OS) is calculated as the time interval between the date on which a patient first received protocol treatment and the documented date of death. For a surviving patient, OS is censored by the last follow-up date when that patient is documented to be alive.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 100 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Adult patients with HCC seen at UPMC will be enrolled in this study if they meet the following eligibility criteria:

• Adults patients (≥ 18 years of age) with a diagnosis of HCC which is not amenable to surgical resection or local ablative therapy

• Histological confirmed HCC or clinical/laboratory diagnosis of HCC or nodules larger than 2 cm with typical vascular features or AFP > 200

• Patient must have quantifiable disease limited to the liver

• Patients must have at least one tumor lesion that meets both of the following criteria:

• The lesion can be accurately measured in at least one dimension according to RECIST criteria

• The lesion has not been previously treated with surgery, radiation therapy, radiofrequency ablation, percutaneous ethanol or acetic acid injection, or cryoablation.

• ECOG performance status (PS) <2

• No prior targeted antiangiogenic therapy. Metronomic chemotherapies are allowed. At least 4 weeks since prior systemic chemotherapy

• At least 4 weeks since prior TACE

• At least 4 weeks since prior interferon

• Not pregnant

• No significant baseline liver dysfunction. Cirrhotic status of Child-Pugh class A only

• No significant renal impairment (creatinine clearance < 30 mL/minute) or patients on dialysis

• No current infections requiring antibiotic therapy

• Not on anticoagulation or suffering from a known bleeding disorder

• No unstable coronary artery disease or recent MI

• The following laboratory parameters:

• Platelet count ≥ 60,000/µL

• Hemoglobin ≥ 8.5 g/dL

• Total bilirubin ≤ 1.5 mg/dL

• ASL and AST ≤ 5 x upper limit of normal

• Serum creatinine ≤ 1.5 x upper limit of normal

• INR ≤ 1.5 or a Pt/PTT within normal limits

• Absolute neutrophil count (ANC) > 1,500/mm3

• Ability to understand the protocol and to agree to and sign a written informed consent document

Exclusion Criteria:

• Previous or concurrent cancer that is distinct in primary site or histology from HCC except cervical carcinoma in situ, treated basal-cell carcinoma of the skin, superficial bladder tumors (Ta, Tis & T1), and any cancer curatively treated > 3 years prior to entry is permitted

• Renal failure requiring hemo- or peritoneal dialysis

• Child-Pugh B & C hepatic impairment

• History of cardiac disease: > NY Heart Association (NYHA) class 2 congestive heart failure, active coronary artery disease, cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers or digoxin, and uncontrolled hypertension. Myocardial infarction more than 6 months prior to study entry is permitted.

• Active clinically serious infections (> CTCAEv3 grade 2)

• Known history of HIV

• Known central nervous system tumors including metastatic brain disease

• History of organ allograft

• Substance abuse (current), psychological, or social conditions that may interfere with the patient's participation in the study or evaluation of the study results.

• Known or suspected allergy to the investigational agents or any agent given in association with this trial.

• Patients unable to swallow oral medications.

• Pregnant or breast-feeding patients. Women of childbearing potential must have a negative pregnancy test performed within seven days prior to the start of the study drug. Both men and women enrolled in this trial must use adequate barrier birth control measures during the course of the trial.

• Cardiac ventricular arrhythmias requiring anti-arrhythmic therapy

• Uncontrolled hypertension defined as systolic blood pressure > 150 mmHg or diastolic blood pressure > 90 mmHg, despite optimal medical management

• Thrombolic or embolic events such as a cerebrovascular accident including transient ischemic attacks within the past 6 months

• Pulmonary hemorrhage/bleeding event > CTCAE Grade 2 within 4 weeks of first dose of study drug

• Any other hemorrhage/bleeding event > CTCAE Grade 3 within 4 weeks of first dose of study drug

• Serious non-healing wound, ulcer, or bone fracture

Excluded therapies and medications, previous and concomitant:

• Prior use of Raf-kinase inhibitors (RKI), VEGF inhibitors, MEK inhibitors, or farnesyl transferase inhibitors

• Major surgery within 6 weeks of start of study drug

• Radiotherapy during study or within 3 weeks prior to start of study drug.

• Use of biologic response modifiers such as granulocyte colony-stimulating factor (G-CSF) within 3 weeks prior to study entry.

• Autologous bone marrow transplant or stem cell rescue within four months of study drug initiation

• Concomitant treatment with rifampin or St. John's wort.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Pittsburgh Cancer Institute	Pittsburgh	Pennsylvania	United States	15232

Sponsors and Collaborators

• University of Pittsburgh
• Bayer

Investigators

• Principal Investigator: Thomas C Gamblin, MD, University of Pittsburgh

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Susan Lamson, RN, BA, RN BA, University of Pittsburgh
• ClinicalTrials.gov Identifier: NCT00576056
• Other Study ID Numbers: 07-047
• First Posted: Dec 18, 2007
• Last Update Posted: Feb 15, 2017
• Last Verified: Nov 1, 2016

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Susan Lamson, RN, BA, RN BA, University of Pittsburgh: Hepatocellular; Carcinoma; TACE; Sorafenib; Transcatheter Arterial Chemoembolization; Nexavar; Unresectable
• Additional relevant MeSH terms: Carcinoma; Carcinoma, Hepatocellular; Sorafenib

Study Results

Participant Flow

Arm/Group Title	Tace + Sorafenib
Arm/Group Description	Patients with unresectable HCC will be treated with TACE in combination with oral sorafenib administration. TACE will be accomplished with gelatin microspheres (Embospheres) following delivery of 125 mg/m2 of cisplatin. Oral sorafenib (400 mg BID) will start the next day after the first TACE treatment. TACE + Sorafenib: TACE will be accomplished with gelatin microspheres (Embospheres) following delivery of 125 mg/m2 of cisplatin. Oral sorafenib (400 mg BID) will start the next day after the first TACE treatment until unacceptable toxicity occurs, or until study termination.
Period Title: Overall Study
STARTED	19
COMPLETED	5
NOT COMPLETED	14

Baseline Characteristics

Arm/Group Title	Tace + Sorafenib
Arm/Group Description	Patients with unresectable HCC will be treated with TACE in combination with oral sorafenib administration. TACE will be accomplished with gelatin microspheres (Embospheres) following delivery of 125 mg/m2 of cisplatin. Oral sorafenib (400 mg BID) will start the next day after the first TACE treatment. TACE + Sorafenib: TACE will be accomplished with gelatin microspheres (Embospheres) following delivery of 125 mg/m2 of cisplatin. Oral sorafenib (400 mg BID) will start the next day after the first TACE treatment until unacceptable toxicity occurs, or until study termination.
Overall Participants	19
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	8 42.1%
>=65 years	11 57.9%
Gender (Count of Participants)
Female	4 21.1%
Male	15 78.9%
Region of Enrollment (participants) [Number]
United States	19 100%

Outcome Measures

1. Primary Outcome

Title	Determine Progression-free Survival in This Patient Population Treated With the Proposed Combination Treatment Modality
Description	Progression free survival (PFS) is calculated as the time interval between the date on which a patient first received protocol treatment and the documented date of disease progression or death. For a surviving and progression-free patient, PFS is censored by the last follow-up date when that patient is documented to be progression free. Progression is defined using RECIST v1.0, as a 20% increase in the sum of the longest diameter of target lesions, or a measureable increase in a non-target lesion, or the appearance of new lesions.
Time Frame	Up to 24 months (from initial treatment through 12 months follow-up)

Outcome Measure Data

Analysis Population Description

Patients who received at least one cycle of the entire treatment regimen (this did not include two patients who went on to receive liver transplants).

Arm/Group Title	Tace + Sorafenib
Arm/Group Description	Patients with unresectable HCC will be treated with TACE in combination with oral sorafenib administration. TACE will be accomplished with gelatin microspheres (Embospheres) following delivery of 125 mg/m2 of cisplatin. Oral sorafenib (400 mg BID) will start the next day after the first TACE treatment. TACE + Sorafenib: TACE will be accomplished with gelatin microspheres (Embospheres) following delivery of 125 mg/m2 of cisplatin. Oral sorafenib (400 mg BID) will start the next day after the first TACE treatment until unacceptable toxicity occurs, or until study termination.
Measure Participants	6
Median (Full Range) [days]	174.00

2. Secondary Outcome

Title	Determine the Overall Survival in Patients Treated With This Combination Regimen
Description	Overall survival (OS) is calculated as the time interval between the date on which a patient first received protocol treatment and the documented date of death. For a surviving patient, OS is censored by the last follow-up date when that patient is documented to be alive.
Time Frame	From date of initial treatment until the date of death from any cause

Outcome Measure Data

Analysis Population Description

Patients who received at least one cycle of the entire treatment regimen (this did not include two patients who went on to receive liver transplants).

Arm/Group Title	Tace + Sorafenib
Arm/Group Description	Patients with unresectable HCC will be treated with TACE in combination with oral sorafenib administration. TACE will be accomplished with gelatin microspheres (Embospheres) following delivery of 125 mg/m2 of cisplatin. Oral sorafenib (400 mg BID) will start the next day after the first TACE treatment. TACE + Sorafenib: TACE will be accomplished with gelatin microspheres (Embospheres) following delivery of 125 mg/m2 of cisplatin. Oral sorafenib (400 mg BID) will start the next day after the first TACE treatment until unacceptable toxicity occurs, or until study termination.
Measure Participants	6
Median (Full Range) [days]	156.000

Adverse Events

Adverse Event Reporting Description	Regular investigator assessment and laboratory testing in addition to participant self reporting
Arm/Group Title	Tace + Sorafenib
Arm/Group Description	Patients with unresectable HCC will be treated with TACE in combination with oral sorafenib administration. TACE will be accomplished with gelatin microspheres (Embospheres) following delivery of 125 mg/m2 of cisplatin. Oral sorafenib (400 mg BID) will start the next day after the first TACE treatment. TACE + Sorafenib: TACE will be accomplished with gelatin microspheres (Embospheres) following delivery of 125 mg/m2 of cisplatin. Oral sorafenib (400 mg BID) will start the next day after the first TACE treatment until unacceptable toxicity occurs, or until study termination.
All Cause Mortality
	Tace + Sorafenib
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Tace + Sorafenib
	Affected / at Risk (%)	# Events
Total	1/19 (5.3%)
Renal and urinary disorders
renal failure	1/19 (5.3%)	1
Other (Not Including Serious) Adverse Events
	Tace + Sorafenib
	Affected / at Risk (%)	# Events
Total	7/19 (36.8%)
Blood and lymphatic system disorders
Increased AST	5/19 (26.3%)	5
Anemia	1/19 (5.3%)	1
Cardiac disorders
Cardiac Arrhythmia	1/19 (5.3%)	1
Gastrointestinal disorders
nausea	1/19 (5.3%)	1
Diarrhea	2/19 (10.5%)	2
Constipation	3/19 (15.8%)	3
Bloating	2/19 (10.5%)	2
Flatulence	1/19 (5.3%)	1
Bleeding oral cavity	1/19 (5.3%)	1
Difficulty swallowing	1/19 (5.3%)	1
Dry mouth	1/19 (5.3%)	1
Bleeding varices	1/19 (5.3%)	1
dehydration	1/19 (5.3%)	1
General disorders
Fatigue	7/19 (36.8%)	7
Hiccups	2/19 (10.5%)	2
Hoarseness	5/19 (26.3%)	5
Abdominal Pain	5/19 (26.3%)	5
Fever	1/19 (5.3%)	1
Tremors	1/19 (5.3%)	1
Lower Extremity Edema	1/19 (5.3%)	1
Infections and infestations
Urinary Tract Infection	1/19 (5.3%)	1
Mouth Infection	1/19 (5.3%)	1
Investigations
Increased ALT	4/19 (21.1%)	4
Increased GGTP	5/19 (26.3%)	5
leukopenia	3/19 (15.8%)	3
thrombocytopenia	4/19 (21.1%)	4
Increased total bilirubin	5/19 (26.3%)	5
Increased Alkaline Phosphatase	2/19 (10.5%)	2
Hypophosphatemia	2/19 (10.5%)	2
Increased Lipase	5/19 (26.3%)	5
Weight Loss	2/19 (10.5%)	2
Metabolism and nutrition disorders
Hyperglycemia	4/19 (21.1%)	4
Hypocalcemia	1/19 (5.3%)	1
Hyponatremia	1/19 (5.3%)	1
Hypomagnesemia	3/19 (15.8%)	3
Hypokalemia	2/19 (10.5%)	2
Decreased Serum Albumin	1/19 (5.3%)	1
Elevated Amylase	1/19 (5.3%)	1
Musculoskeletal and connective tissue disorders
Muscle Aches	1/19 (5.3%)	1
Incisional hernia	1/19 (5.3%)	1
leg pain	1/19 (5.3%)	1
Psychiatric disorders
Anxiety	3/19 (15.8%)	3
Hallucination	1/19 (5.3%)	1
Renal and urinary disorders
Increased urination	1/19 (5.3%)	1
Creatinine	1/19 (5.3%)	1
Reproductive system and breast disorders
Breast Tenderness	1/19 (5.3%)	1
Respiratory, thoracic and mediastinal disorders
Shortness of Breath	3/19 (15.8%)	3
Skin and subcutaneous tissue disorders
Alopecia	2/19 (10.5%)	2
Rash	6/19 (31.6%)	6

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.