Sorafenib Tosylate With or Without Doxorubicin Hydrochloride in Treating Patients With Locally Advanced or Metastatic Liver Cancer

• ClinicalTrials.gov Identifier: NCT01015833
• Recruitment Status: Completed
• First Posted: November 18, 2009
• Results First Posted: May 2, 2018
• Last Update Posted: August 4, 2022
• Sponsor: National Cancer Institute (NCI)
• Information provided by (Responsible Party): National Cancer Institute (NCI)

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Single (Investigator); Primary Purpose: Treatment
• Conditions: Advanced Adult Hepatocellular Carcinoma; Recurrent Hepatocellular Carcinoma; Stage III Hepatocellular Carcinoma AJCC v7; Stage IIIA Hepatocellular Carcinoma AJCC v7; Stage IIIB Hepatocellular Carcinoma AJCC v7; Stage IIIC Hepatocellular Carcinoma AJCC v7; Stage IV Hepatocellular Carcinoma AJCC v7; Stage IVA Hepatocellular Carcinoma AJCC v7; Stage IVB Hepatocellular Carcinoma AJCC v7; Unresectable Hepatocellular Carcinoma
• Interventions: Drug: Doxorubicin Hydrochloride; Other: Laboratory Biomarker Analysis; Other: Pharmacogenomic Study; Drug: Sorafenib Tosylate
• Enrollment: 356

Participant Flow

Recruitment Details
Pre-assignment Details

Arm/Group Title	Arm I (Doxorubicin Hydrochloride, Sorafenib Tosylate)	Arm II (Sorafenib Tosylate)
Arm/Group Description	Patients receive 60 mg/m2 doxorubicin hydrochloride IV on day 1 and 400 mg sorafenib tosylate PO QD or BID on days 1-21. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. After 6 courses, patients may continue to receive sorafenib tosylate PO QD or BID in the absence of disease progression or unacceptable toxicity.	Patients receive 400 mg sorafenib tosylate PO QD or BID on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Period Title: Overall Study
Started	180	176
Completed	167	171
Not Completed	13	5
Reason Not Completed
Death	1	0
Withdrawal by Subject	3	2
Adverse Event	0	1
Physician Decision	2	0
Symptomatic deterioration	0	1
Other	5	1
Motor Vehicle Accidents	1	0
Did not start treatment	1	0

Baseline Characteristics

Arm/Group Title		Arm I (Doxorubicin Hydrochloride, Sorafenib Tosylate)	Arm II (Sorafenib Tosylate)	Total
Arm/Group Description		Patients receive 60 mg/m2 doxorubicin hydrochloride IV on day 1 and 400 mg sorafenib tosylate PO QD or BID on days 1-21. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. After 6 courses, patients may continue to receive sorafenib tosylate PO QD or BID in the absence of disease progression or unacceptable toxicity.	Patients receive 400 mg sorafenib tosylate PO QD or BID on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.	Total of all reporting groups
Overall Number of Baseline Participants		180	176	356
Baseline Analysis Population Description		[Not Specified]
Age, Continuous; Median (Full Range); Unit of measure: Years
	Number Analyzed	180 participants	176 participants	356 participants
		62; (22 to 81)	62; (31 to 85)	62; (22 to 85)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	180 participants	176 participants	356 participants
	Female	27 15.0%	23 13.1%	50 14.0%
	Male	153 85.0%	153 86.9%	306 86.0%
Region of Enrollment; Measure Type: Count of Participants; Unit of measure: Participants	Number Analyzed	180 participants	176 participants	356 participants
Canada		32 17.8%	29 16.5%	61 17.1%
United States		148 82.2%	147 83.5%	295 82.9%

Outcome Measures

1. Primary Outcome

Title	Overall Survival
Description	Overall survival is defined as the time from study entry to death from any cause. The median OS was estimated using the Kaplan-Meier method.
Time Frame	Up to 3 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm I (Doxorubicin Hydrochloride, Sorafenib Tosylate)	Arm II (Sorafenib Tosylate)
Arm/Group Description:	Patients receive 60 mg/m2 doxorubicin hydrochloride IV on day 1 and 400 mg sorafenib tosylate PO QD or BID on days 1-21. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. After 6 courses, patients may continue to receive sorafenib tosylate PO QD or BID in the absence of disease progression or unacceptable toxicity.	Patients receive 400 mg sorafenib tosylate PO QD or BID on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Overall Number of Participants Analyzed	180	176
Median (95% Confidence Interval); Unit of Measure: month
	8.9; (7.1 to 10.8)	10.5; (7.6 to 13.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm I (Doxorubicin Hydrochloride, Sorafenib Tosylate), Arm II (Sorafenib Tosylate)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.24
	Comments	[Not Specified]
	Method	t-test, 1 sided
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.06
	Confidence Interval	(2-Sided) 95%; 0.8 to 1.4
	Estimation Comments	[Not Specified]

2. Secondary Outcome

Title	Incidence of Toxicities, as Assessed by National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0
Description	Toxicity is defined as a grade 3 or higher adverse events that is classified as either possibly, probably, or definitely related to study treatment. The assignment of attribution to study treatment and grade (or degree of severity) of the adverse event are classified using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. The maximum grade for each type of adverse event will be recorded for each patient, and frequency tables will be reviewed to determine patterns. Additionally, the relationship of the adverse event(s) to the study treatment will be taken into consideration. The percentage of patients with a maximum grade 3 or higher adverse event at least possibly related to the study treatment are reported below.
Time Frame	Up to 3 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm I (Doxorubicin Hydrochloride, Sorafenib Tosylate)	Arm II (Sorafenib Tosylate)
Arm/Group Description:	Patients receive 60 mg/m2 doxorubicin hydrochloride IV on day 1 and 400 mg sorafenib tosylate PO QD or BID on days 1-21. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. After 6 courses, patients may continue to receive sorafenib tosylate PO QD or BID in the absence of disease progression or unacceptable toxicity.	Patients receive 400 mg sorafenib tosylate PO QD or BID on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Overall Number of Participants Analyzed	180	176
Measure Type: Number; Unit of Measure: percentage of patients
Fatigue	10	7
Hypertension	3	13
White blood cells	11	0
Neutrophils	33	0
Platelets	14	1
Hand Foot Syndrome	10	14

3. Secondary Outcome

Title	Progression Free Survival
Description	Progression free survival is defined as the time from study entry to earliest date of disease progression. Progression is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: The appearance of one or more new lesions is also considered progression).
Time Frame	Up to 3 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm I (Doxorubicin Hydrochloride, Sorafenib Tosylate)	Arm II (Sorafenib Tosylate)
Arm/Group Description:	Patients receive 60 mg/m2 doxorubicin hydrochloride IV on day 1 and 400 mg sorafenib tosylate PO QD or BID on days 1-21. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. After 6 courses, patients may continue to receive sorafenib tosylate PO QD or BID in the absence of disease progression or unacceptable toxicity.	Patients receive 400 mg sorafenib tosylate PO QD or BID on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Overall Number of Participants Analyzed	180	176
Median (95% Confidence Interval); Unit of Measure: months
	4.0; (3.2 to 5.0)	3.9; (2.9 to 4.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm I (Doxorubicin Hydrochloride, Sorafenib Tosylate), Arm II (Sorafenib Tosylate)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.98
	Comments	[Not Specified]
	Method	t-test, 1 sided
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.9
	Confidence Interval	(2-Sided) 95%; 0.72 to 1.2
	Estimation Comments	[Not Specified]

4. Secondary Outcome

Title	Time to Progression (TTP)
Description	Time to Progression (TTP) is defined as the time from on study to progression. Progression is defined by the RECIST criteria as Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: The appearance of one or more new lesions is also considered progression). Median and 95% confidence intervals are provided for each arm below.
Time Frame	Up to 3 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm I (Doxorubicin Hydrochloride, Sorafenib Tosylate)	Arm II (Sorafenib Tosylate)
Arm/Group Description:	Patients receive 60 mg/m2 doxorubicin hydrochloride IV on day 1 and 400 mg sorafenib tosylate PO QD or BID on days 1-21. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. After 6 courses, patients may continue to receive sorafenib tosylate PO QD or BID in the absence of disease progression or unacceptable toxicity.	Patients receive 400 mg sorafenib tosylate PO QD or BID on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Overall Number of Participants Analyzed	180	176
Median (95% Confidence Interval); Unit of Measure: months
	4.1; (3.25 to 5.00)	3.8; (2.92 to 4.50)

5. Secondary Outcome

Title	Best Overall Response Rate
Description	Best Overall Response Rate is defined as is the best response recorded from the start of the treatment until disease progression/recurrence. Complete Response: Disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to < 10 mm. Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: The appearance of one or more new lesions is also considered progression). Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as references the smallest sum diameters while on study.
Time Frame	Up to 3 years

Outcome Measure Data

Analysis Population Description

Patients who started treatment and had follow-up assessments were included in this analysis.

Arm/Group Title	Arm I (Doxorubicin Hydrochloride, Sorafenib Tosylate)	Arm II (Sorafenib Tosylate)
Arm/Group Description:	Patients receive 60 mg/m2 doxorubicin hydrochloride IV on day 1 and 400 mg sorafenib tosylate PO QD or BID on days 1-21. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. After 6 courses, patients may continue to receive sorafenib tosylate PO QD or BID in the absence of disease progression or unacceptable toxicity.	Patients receive 400 mg sorafenib tosylate PO QD or BID on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Overall Number of Participants Analyzed	150	150
Measure Type: Number; Unit of Measure: percentage of patients
	7.3	3.3

Adverse Events

Time Frame	Up to 3 years.
Adverse Event Reporting Description	Each CTCAE term is a unique representation of a specific event used for medical documentation and scientific analysis and is a single MedDRA Lowest Level Term (LLT). All graded AEs are reported for patients who completed the study. Serious AE (SAE) reports may include any secondary serious or non-serious events considered related to the primary event (the reason for filing an expedited report); collectively, these events are referred to as Expedited AEs, and appear in the SAE table.
Arm/Group Title	Arm I (Doxorubicin Hydrochloride, Sorafenib Tosylate)		Arm II (Sorafenib Tosylate)
Arm/Group Description	Patients receive 60 mg/m2 doxorubicin hydrochloride IV on day 1 and 400 mg sorafenib tosylate PO QD or BID on days 1-21. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. After 6 courses, patients may continue to receive sorafenib tosylate PO QD or BID in the absence of disease progression or unacceptable toxicity.		Patients receive 400 mg sorafenib tosylate PO QD or BID on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
All-Cause Mortality
	Arm I (Doxorubicin Hydrochloride, Sorafenib Tosylate)		Arm II (Sorafenib Tosylate)
	Affected / at Risk (%)		Affected / at Risk (%)
Total	12/167 (7.19%)		16/171 (9.36%)
Serious Adverse Events
	Arm I (Doxorubicin Hydrochloride, Sorafenib Tosylate)		Arm II (Sorafenib Tosylate)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	71/167 (42.51%)		57/171 (33.33%)
Blood and lymphatic system disorders
Anemia † 1	9/167 (5.39%)	10	4/171 (2.34%)	5
Febrile neutropenia † 1	7/167 (4.19%)	8	0/171 (0.00%)	0
Leukocytosis † 1	1/167 (0.60%)	1	0/171 (0.00%)	0
Spleen disorder † 1	0/167 (0.00%)	0	1/171 (0.58%)	1
Thrombotic thrombocytopenic purpura † 1	0/167 (0.00%)	0	1/171 (0.58%)	1
Cardiac disorders
Atrial fibrillation † 1	3/167 (1.80%)	3	1/171 (0.58%)	1
Cardiac disorder † 1	1/167 (0.60%)	1	0/171 (0.00%)	0
Chest pain - cardiac † 1	0/167 (0.00%)	0	1/171 (0.58%)	1
Left ventricular systolic dysfunction † 1	3/167 (1.80%)	3	0/171 (0.00%)	0
Myocardial infarction † 1	1/167 (0.60%)	1	0/171 (0.00%)	0
Palpitations † 1	1/167 (0.60%)	1	0/171 (0.00%)	0
Sinus bradycardia † 1	0/167 (0.00%)	0	1/171 (0.58%)	1
Sinus tachycardia † 1	1/167 (0.60%)	1	1/171 (0.58%)	1
Endocrine disorders
Hypothyroidism † 1	1/167 (0.60%)	1	1/171 (0.58%)	1
Eye disorders
Conjunctivitis † 1	1/167 (0.60%)	1	0/171 (0.00%)	0
Gastrointestinal disorders
Abdominal distension † 1	0/167 (0.00%)	0	1/171 (0.58%)	1
Abdominal pain † 1	22/167 (13.17%)	24	28/171 (16.37%)	33
Anal mucositis † 1	1/167 (0.60%)	1	0/171 (0.00%)	0
Ascites † 1	3/167 (1.80%)	3	2/171 (1.17%)	2
Colitis † 1	2/167 (1.20%)	2	0/171 (0.00%)	0
Constipation † 1	1/167 (0.60%)	1	0/171 (0.00%)	0
Diarrhea † 1	27/167 (16.17%)	28	13/171 (7.60%)	15
Dyspepsia † 1	1/167 (0.60%)	1	0/171 (0.00%)	0
Dysphagia † 1	3/167 (1.80%)	3	0/171 (0.00%)	0
Esophageal ulcer † 1	1/167 (0.60%)	2	0/171 (0.00%)	0
Esophageal varices hemorrhage † 1	1/167 (0.60%)	1	4/171 (2.34%)	4
Esophagitis † 1	2/167 (1.20%)	3	0/171 (0.00%)	0
Gastric hemorrhage † 1	0/167 (0.00%)	0	2/171 (1.17%)	2
Gastrointestinal disorders - Other, specify † 1	0/167 (0.00%)	0	1/171 (0.58%)	1
Hemorrhoidal hemorrhage † 1	0/167 (0.00%)	0	1/171 (0.58%)	1
Lower gastrointestinal hemorrhage † 1	1/167 (0.60%)	1	0/171 (0.00%)	0
Mucositis oral † 1	17/167 (10.18%)	17	4/171 (2.34%)	4
Nausea † 1	34/167 (20.36%)	36	24/171 (14.04%)	29
Pancreatitis † 1	2/167 (1.20%)	2	0/171 (0.00%)	0
Rectal hemorrhage † 1	1/167 (0.60%)	1	0/171 (0.00%)	0
Rectal mucositis † 1	1/167 (0.60%)	1	0/171 (0.00%)	0
Upper gastrointestinal hemorrhage † 1	1/167 (0.60%)	1	3/171 (1.75%)	4
Vomiting † 1	4/167 (2.40%)	4	6/171 (3.51%)	6
General disorders
Death NOS † 1	4/167 (2.40%)	4	7/171 (4.09%)	7
Edema limbs † 1	1/167 (0.60%)	1	0/171 (0.00%)	0
Edema trunk † 1	0/167 (0.00%)	0	1/171 (0.58%)	1
Fatigue † 1	49/167 (29.34%)	56	32/171 (18.71%)	38
Fever † 1	2/167 (1.20%)	2	1/171 (0.58%)	1
Localized edema † 1	0/167 (0.00%)	0	1/171 (0.58%)	1
Multi-organ failure † 1	1/167 (0.60%)	1	0/171 (0.00%)	0
Non-cardiac chest pain † 1	0/167 (0.00%)	0	2/171 (1.17%)	2
Pain † 1	1/167 (0.60%)	1	0/171 (0.00%)	0
Sudden death NOS † 1	1/167 (0.60%)	1	2/171 (1.17%)	2
Hepatobiliary disorders
Cholecystitis † 1	0/167 (0.00%)	0	1/171 (0.58%)	1
Gallbladder obstruction † 1	1/167 (0.60%)	1	1/171 (0.58%)	1
Hepatic failure † 1	3/167 (1.80%)	3	1/171 (0.58%)	1
Hepatic hemorrhage † 1	0/167 (0.00%)	0	2/171 (1.17%)	2
Hepatobiliary disorders - Other, specify † 1	0/167 (0.00%)	0	1/171 (0.58%)	2
Immune system disorders
Anaphylaxis † 1	1/167 (0.60%)	1	0/171 (0.00%)	0
Infections and infestations
Abdominal infection † 1	0/167 (0.00%)	0	1/171 (0.58%)	1
Bone infection † 1	1/167 (0.60%)	1	1/171 (0.58%)	1
Infections and infestations - Other, specify † 1	3/167 (1.80%)	3	1/171 (0.58%)	1
Lung infection † 1	6/167 (3.59%)	6	0/171 (0.00%)	0
Peritoneal infection † 1	1/167 (0.60%)	1	1/171 (0.58%)	1
Rash pustular † 1	1/167 (0.60%)	1	0/171 (0.00%)	0
Sepsis † 1	5/167 (2.99%)	5	2/171 (1.17%)	2
Skin infection † 1	2/167 (1.20%)	2	2/171 (1.17%)	3
Urinary tract infection † 1	1/167 (0.60%)	1	0/171 (0.00%)	0
Wound infection † 1	0/167 (0.00%)	0	1/171 (0.58%)	1
Injury, poisoning and procedural complications
Fall † 1	0/167 (0.00%)	0	2/171 (1.17%)	2
Fracture † 1	0/167 (0.00%)	0	1/171 (0.58%)	1
Wound complication † 1	1/167 (0.60%)	1	0/171 (0.00%)	0
Investigations
Activated partial thromboplastin time prolonged † 1	0/167 (0.00%)	0	1/171 (0.58%)	1
Alanine aminotransferase increased † 1	3/167 (1.80%)	3	3/171 (1.75%)	3
Alkaline phosphatase increased † 1	3/167 (1.80%)	3	4/171 (2.34%)	4
Aspartate aminotransferase increased † 1	4/167 (2.40%)	4	6/171 (3.51%)	6
Blood bilirubin increased † 1	8/167 (4.79%)	9	7/171 (4.09%)	7
Creatinine increased † 1	3/167 (1.80%)	3	0/171 (0.00%)	0
Ejection fraction decreased † 1	3/167 (1.80%)	3	1/171 (0.58%)	1
Haptoglobin decreased † 1	1/167 (0.60%)	1	0/171 (0.00%)	0
INR increased † 1	2/167 (1.20%)	2	1/171 (0.58%)	1
Leukocyte count decreased † 1	1/167 (0.60%)	1	0/171 (0.00%)	0
Lipase increased † 1	1/167 (0.60%)	1	0/171 (0.00%)	0
Lymphocyte count decreased † 1	6/167 (3.59%)	6	2/171 (1.17%)	3
Neutrophil count decreased † 1	31/167 (18.56%)	32	0/171 (0.00%)	0
Platelet count decreased † 1	35/167 (20.96%)	38	20/171 (11.70%)	24
Weight loss † 1	2/167 (1.20%)	2	1/171 (0.58%)	1
White blood cell decreased † 1	10/167 (5.99%)	10	0/171 (0.00%)	0
Metabolism and nutrition disorders
Anorexia † 1	5/167 (2.99%)	5	4/171 (2.34%)	4
Dehydration † 1	14/167 (8.38%)	14	5/171 (2.92%)	5
Hyperglycemia † 1	2/167 (1.20%)	2	2/171 (1.17%)	2
Hyperkalemia † 1	4/167 (2.40%)	4	1/171 (0.58%)	1
Hypernatremia † 1	0/167 (0.00%)	0	1/171 (0.58%)	1
Hypoalbuminemia † 1	4/167 (2.40%)	4	1/171 (0.58%)	1
Hypokalemia † 1	2/167 (1.20%)	2	0/171 (0.00%)	0
Hypomagnesemia † 1	0/167 (0.00%)	0	1/171 (0.58%)	1
Hyponatremia † 1	10/167 (5.99%)	10	4/171 (2.34%)	4
Hypophosphatemia † 1	4/167 (2.40%)	4	1/171 (0.58%)	1
Metabolism and nutrition disorders - Other, specify † 1	0/167 (0.00%)	0	1/171 (0.58%)	1
Serum phosphate decreased † 1	1/167 (0.60%)	1	0/171 (0.00%)	0
Musculoskeletal and connective tissue disorders
Back pain † 1	1/167 (0.60%)	1	1/171 (0.58%)	1
Bone pain † 1	0/167 (0.00%)	0	1/171 (0.58%)	1
Generalized muscle weakness † 1	1/167 (0.60%)	1	1/171 (0.58%)	1
Myalgia † 1	1/167 (0.60%)	1	0/171 (0.00%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specify † 1	1/167 (0.60%)	1	3/171 (1.75%)	3
Treatment related secondary malignancy † 1	2/167 (1.20%)	2	0/171 (0.00%)	0
Nervous system disorders
Amnesia † 1	1/167 (0.60%)	1	0/171 (0.00%)	0
Headache † 1	0/167 (0.00%)	0	1/171 (0.58%)	1
Intracranial hemorrhage † 1	0/167 (0.00%)	0	1/171 (0.58%)	1
Nervous system disorders - Other, specify † 1	1/167 (0.60%)	1	0/171 (0.00%)	0
Seizure † 1	0/167 (0.00%)	0	1/171 (0.58%)	1
Syncope vasovagal † 1	1/167 (0.60%)	1	0/171 (0.00%)	0
Psychiatric disorders
Anxiety † 1	1/167 (0.60%)	1	1/171 (0.58%)	1
Confusion † 1	1/167 (0.60%)	1	2/171 (1.17%)	2
Renal and urinary disorders
Acute kidney injury † 1	1/167 (0.60%)	1	0/171 (0.00%)	0
Hematuria † 1	2/167 (1.20%)	2	1/171 (0.58%)	1
Urogenital disorder † 1	1/167 (0.60%)	1	0/171 (0.00%)	0
Respiratory, thoracic and mediastinal disorders
Dyspnea † 1	4/167 (2.40%)	4	4/171 (2.34%)	4
Epistaxis † 1	1/167 (0.60%)	1	3/171 (1.75%)	3
Hypoxia † 1	1/167 (0.60%)	1	1/171 (0.58%)	1
Pulmonary edema † 1	0/167 (0.00%)	0	1/171 (0.58%)	1
Sore throat † 1	1/167 (0.60%)	2	0/171 (0.00%)	0
Skin and subcutaneous tissue disorders
Alopecia † 1	2/167 (1.20%)	2	0/171 (0.00%)	0
Erythema multiforme † 1	1/167 (0.60%)	1	0/171 (0.00%)	0
Palmar-plantar erythrodysesthesia syndrome † 1	13/167 (7.78%)	16	10/171 (5.85%)	11
Pruritus † 1	1/167 (0.60%)	1	0/171 (0.00%)	0
Rash maculo-papular † 1	1/167 (0.60%)	1	2/171 (1.17%)	2
Scalp pain † 1	0/167 (0.00%)	0	1/171 (0.58%)	1
Skin ulceration † 1	3/167 (1.80%)	3	3/171 (1.75%)	3
Stevens-Johnson syndrome † 1	1/167 (0.60%)	1	0/171 (0.00%)	0
Vascular disorders
Hypertension † 1	21/167 (12.57%)	25	16/171 (9.36%)	17
Hypotension † 1	2/167 (1.20%)	2	1/171 (0.58%)	1
Thromboembolic event † 1	0/167 (0.00%)	0	3/171 (1.75%)	3
1 Term from vocabulary, MedDRA 12; † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	0%
	Arm I (Doxorubicin Hydrochloride, Sorafenib Tosylate)		Arm II (Sorafenib Tosylate)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	146/167 (87.43%)		151/171 (88.30%)
Blood and lymphatic system disorders
Anemia † 1	10/167 (5.99%)	11	8/171 (4.68%)	8
Blood and lymphatic system disorders - Other, specify † 1	0/167 (0.00%)	0	1/171 (0.58%)	2
Febrile neutropenia † 1	5/167 (2.99%)	7	0/171 (0.00%)	0
Hemoglobin decreased † 1	1/167 (0.60%)	1	0/171 (0.00%)	0
Hemolysis † 1	1/167 (0.60%)	1	0/171 (0.00%)	0
Thrombotic thrombocytopenic purpura † 1	1/167 (0.60%)	1	0/171 (0.00%)	0
Cardiac disorders
Atrial fibrillation † 1	1/167 (0.60%)	5	0/171 (0.00%)	0
Chest pain - cardiac † 1	0/167 (0.00%)	0	2/171 (1.17%)	3
Left ventricular failure † 1	0/167 (0.00%)	0	1/171 (0.58%)	1
Left ventricular systolic dysfunction † 1	7/167 (4.19%)	7	0/171 (0.00%)	0
Sinus bradycardia † 1	0/167 (0.00%)	0	1/171 (0.58%)	1
Supraventricular tachycardia † 1	0/167 (0.00%)	0	1/171 (0.58%)	1
Ventricular tachycardia † 1	0/167 (0.00%)	0	1/171 (0.58%)	1
Ear and labyrinth disorders
Hearing impaired † 1	0/167 (0.00%)	0	1/171 (0.58%)	4
Endocrine disorders
Hypothyroidism † 1	5/167 (2.99%)	14	4/171 (2.34%)	18
Eye disorders
Conjunctivitis † 1	1/167 (0.60%)	1	0/171 (0.00%)	0
Eye disorders - Other, specify † 1	0/167 (0.00%)	0	1/171 (0.58%)	1
Eye pain † 1	0/167 (0.00%)	0	1/171 (0.58%)	1
Gastrointestinal disorders
Abdominal distension † 1	0/167 (0.00%)	0	1/171 (0.58%)	1
Abdominal pain † 1	59/167 (35.33%)	156	75/171 (43.86%)	205
Anal fistula † 1	1/167 (0.60%)	1	0/171 (0.00%)	0
Ascites † 1	3/167 (1.80%)	3	2/171 (1.17%)	2
Bloating † 1	0/167 (0.00%)	0	1/171 (0.58%)	1
Constipation † 1	1/167 (0.60%)	1	5/171 (2.92%)	6
Dental caries † 1	1/167 (0.60%)	2	0/171 (0.00%)	0
Diarrhea † 1	68/167 (40.72%)	203	73/171 (42.69%)	256
Dry mouth † 1	0/167 (0.00%)	0	2/171 (1.17%)	2
Dyspepsia † 1	1/167 (0.60%)	1	0/171 (0.00%)	0
Esophageal ulcer † 1	1/167 (0.60%)	1	0/171 (0.00%)	0
Esophageal varices hemorrhage † 1	0/167 (0.00%)	0	1/171 (0.58%)	2
Esophagitis † 1	2/167 (1.20%)	2	0/171 (0.00%)	0
Gastroesophageal reflux disease † 1	1/167 (0.60%)	1	0/171 (0.00%)	0
Hemorrhoids † 1	1/167 (0.60%)	1	0/171 (0.00%)	0
Mucositis oral † 1	54/167 (32.34%)	126	31/171 (18.13%)	45
Nausea † 1	59/167 (35.33%)	167	64/171 (37.43%)	179
Oral pain † 1	1/167 (0.60%)	1	0/171 (0.00%)	0
Upper gastrointestinal hemorrhage † 1	0/167 (0.00%)	0	1/171 (0.58%)	1
Vomiting † 1	5/167 (2.99%)	5	5/171 (2.92%)	5
General disorders
Chills † 1	0/167 (0.00%)	0	1/171 (0.58%)	1
Edema limbs † 1	4/167 (2.40%)	6	2/171 (1.17%)	2
Fatigue † 1	111/167 (66.47%)	427	104/171 (60.82%)	407
Fever † 1	1/167 (0.60%)	1	2/171 (1.17%)	2
Gait disturbance † 1	1/167 (0.60%)	1	0/171 (0.00%)	0
Localized edema † 1	1/167 (0.60%)	1	0/171 (0.00%)	0
Malaise † 1	1/167 (0.60%)	1	1/171 (0.58%)	2
Non-cardiac chest pain † 1	1/167 (0.60%)	1	0/171 (0.00%)	0
Pain † 1	4/167 (2.40%)	5	2/171 (1.17%)	2
Hepatobiliary disorders
Hepatic failure † 1	1/167 (0.60%)	1	0/171 (0.00%)	0
Hepatic hemorrhage † 1	0/167 (0.00%)	0	1/171 (0.58%)	1
Hepatobiliary disorders - Other, specify † 1	0/167 (0.00%)	0	1/171 (0.58%)	1
Infections and infestations
Cecal infection † 1	1/167 (0.60%)	1	0/171 (0.00%)	0
Gum infection † 1	1/167 (0.60%)	2	0/171 (0.00%)	0
Lung infection † 1	0/167 (0.00%)	0	1/171 (0.58%)	1
Papulopustular rash † 1	1/167 (0.60%)	2	1/171 (0.58%)	1
Periorbital infection † 1	1/167 (0.60%)	1	0/171 (0.00%)	0
Rash pustular † 1	1/167 (0.60%)	1	0/171 (0.00%)	0
Tooth infection † 1	1/167 (0.60%)	1	0/171 (0.00%)	0
Upper respiratory infection † 1	0/167 (0.00%)	0	1/171 (0.58%)	1
Urinary tract infection † 1	2/167 (1.20%)	2	1/171 (0.58%)	2
Injury, poisoning and procedural complications
Dermatitis radiation † 1	1/167 (0.60%)	1	0/171 (0.00%)	0
Fracture † 1	1/167 (0.60%)	1	1/171 (0.58%)	1
Investigations
Alanine aminotransferase increased † 1	6/167 (3.59%)	7	6/171 (3.51%)	10
Alkaline phosphatase increased † 1	5/167 (2.99%)	6	9/171 (5.26%)	13
Aspartate aminotransferase increased † 1	12/167 (7.19%)	15	15/171 (8.77%)	25
Blood bilirubin increased † 1	9/167 (5.39%)	10	10/171 (5.85%)	14
CD4 lymphocytes decreased † 1	1/167 (0.60%)	3	0/171 (0.00%)	0
Creatinine increased † 1	1/167 (0.60%)	1	1/171 (0.58%)	1
Ejection fraction decreased † 1	14/167 (8.38%)	29	0/171 (0.00%)	0
Electrocardiogram QT corrected interval prolonged † 1	1/167 (0.60%)	1	0/171 (0.00%)	0
Leukocyte count decreased † 1	3/167 (1.80%)	4	0/171 (0.00%)	0
Lipase increased † 1	1/167 (0.60%)	1	1/171 (0.58%)	1
Lymphocyte count decreased † 1	8/167 (4.79%)	15	9/171 (5.26%)	20
Neutrophil count decreased † 1	58/167 (34.73%)	110	11/171 (6.43%)	69
Platelet count decreased † 1	67/167 (40.12%)	199	62/171 (36.26%)	348
Weight loss † 1	1/167 (0.60%)	1	4/171 (2.34%)	6
White blood cell decreased † 1	11/167 (6.59%)	13	1/171 (0.58%)	1
Metabolism and nutrition disorders
Anorexia † 1	6/167 (3.59%)	8	11/171 (6.43%)	16
Blood glucose increased † 1	0/167 (0.00%)	0	1/171 (0.58%)	1
Dehydration † 1	1/167 (0.60%)	1	2/171 (1.17%)	3
Hypercalcemia † 1	1/167 (0.60%)	1	0/171 (0.00%)	0
Hyperglycemia † 1	9/167 (5.39%)	12	9/171 (5.26%)	11
Hyperkalemia † 1	1/167 (0.60%)	1	1/171 (0.58%)	1
Hypermagnesemia † 1	1/167 (0.60%)	3	0/171 (0.00%)	0
Hypernatremia † 1	0/167 (0.00%)	0	1/171 (0.58%)	1
Hyperuricemia † 1	1/167 (0.60%)	2	0/171 (0.00%)	0
Hypoalbuminemia † 1	2/167 (1.20%)	2	2/171 (1.17%)	3
Hypocalcemia † 1	1/167 (0.60%)	1	0/171 (0.00%)	0
Hypoglycemia † 1	1/167 (0.60%)	1	1/171 (0.58%)	1
Hypokalemia † 1	3/167 (1.80%)	7	2/171 (1.17%)	2
Hypomagnesemia † 1	3/167 (1.80%)	3	0/171 (0.00%)	0
Hyponatremia † 1	7/167 (4.19%)	13	11/171 (6.43%)	16
Hypophosphatemia † 1	6/167 (3.59%)	15	11/171 (6.43%)	16
Metabolism and nutrition disorders - Other, specify † 1	0/167 (0.00%)	0	1/171 (0.58%)	1
Serum albumin decreased † 1	2/167 (1.20%)	2	0/171 (0.00%)	0
Serum phosphate decreased † 1	1/167 (0.60%)	1	0/171 (0.00%)	0
Serum potassium decreased † 1	1/167 (0.60%)	1	0/171 (0.00%)	0
Serum sodium decreased † 1	0/167 (0.00%)	0	1/171 (0.58%)	1
Musculoskeletal and connective tissue disorders
Arthralgia † 1	1/167 (0.60%)	1	0/171 (0.00%)	0
Arthritis † 1	1/167 (0.60%)	1	0/171 (0.00%)	0
Back pain † 1	0/167 (0.00%)	0	3/171 (1.75%)	7
Chest wall pain † 1	1/167 (0.60%)	1	0/171 (0.00%)	0
Generalized muscle weakness † 1	2/167 (1.20%)	2	1/171 (0.58%)	1
Muscle weakness upper limb † 1	1/167 (0.60%)	1	0/171 (0.00%)	0
Musculoskeletal disorder † 1	1/167 (0.60%)	1	0/171 (0.00%)	0
Myalgia † 1	0/167 (0.00%)	0	1/171 (0.58%)	2
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specify † 1	0/167 (0.00%)	0	1/171 (0.58%)	5
Nervous system disorders
Dysgeusia † 1	0/167 (0.00%)	0	1/171 (0.58%)	1
Encephalopathy † 1	1/167 (0.60%)	1	0/171 (0.00%)	0
Headache † 1	1/167 (0.60%)	2	1/171 (0.58%)	1
Paresthesia † 1	1/167 (0.60%)	1	0/171 (0.00%)	0
Peripheral sensory neuropathy † 1	1/167 (0.60%)	1	2/171 (1.17%)	3
Psychiatric disorders
Confusion † 1	0/167 (0.00%)	0	2/171 (1.17%)	2
Depression † 1	2/167 (1.20%)	2	2/171 (1.17%)	3
Insomnia † 1	2/167 (1.20%)	2	2/171 (1.17%)	2
Renal and urinary disorders
Chronic kidney disease † 1	0/167 (0.00%)	0	1/171 (0.58%)	1
Hematuria † 1	5/167 (2.99%)	10	4/171 (2.34%)	5
Respiratory, thoracic and mediastinal disorders
Cough † 1	1/167 (0.60%)	2	0/171 (0.00%)	0
Dyspnea † 1	1/167 (0.60%)	1	6/171 (3.51%)	8
Epistaxis † 1	7/167 (4.19%)	8	12/171 (7.02%)	16
Hiccups † 1	0/167 (0.00%)	0	1/171 (0.58%)	1
Hypoxia † 1	1/167 (0.60%)	2	0/171 (0.00%)	0
Sore throat † 1	1/167 (0.60%)	1	0/171 (0.00%)	0
Skin and subcutaneous tissue disorders
Alopecia † 1	3/167 (1.80%)	5	1/171 (0.58%)	2
Dry skin † 1	0/167 (0.00%)	0	3/171 (1.75%)	5
Erythema multiforme † 1	0/167 (0.00%)	0	1/171 (0.58%)	1
Hand-and-foot syndrome † 1	0/167 (0.00%)	0	1/171 (0.58%)	1
Nail discoloration † 1	1/167 (0.60%)	2	0/171 (0.00%)	0
Palmar-plantar erythrodysesthesia syndrome † 1	57/167 (34.13%)	197	68/171 (39.77%)	215
Pruritus † 1	1/167 (0.60%)	1	0/171 (0.00%)	0
Rash acneiform † 1	1/167 (0.60%)	1	0/171 (0.00%)	0
Rash maculo-papular † 1	6/167 (3.59%)	7	3/171 (1.75%)	3
Scalp pain † 1	0/167 (0.00%)	0	1/171 (0.58%)	1
Skin and subcutaneous tissue disorders - Other, specify † 1	0/167 (0.00%)	0	1/171 (0.58%)	1
Skin disorder † 1	0/167 (0.00%)	0	1/171 (0.58%)	3
Skin ulceration † 1	8/167 (4.79%)	16	7/171 (4.09%)	9
Vascular disorders
Flushing † 1	0/167 (0.00%)	0	1/171 (0.58%)	1
Hypertension † 1	49/167 (29.34%)	172	68/171 (39.77%)	316
Hypotension † 1	1/167 (0.60%)	1	1/171 (0.58%)	1
Thromboembolic event † 1	3/167 (1.80%)	15	0/171 (0.00%)	0
Thrombosis † 1	1/167 (0.60%)	1	0/171 (0.00%)	0
1 Term from vocabulary, MedDRA 12; † Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

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

There IS 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.

Results Point of Contact

• Name/Title: Ghassan Abou-Alfa, MD
• Organization: Memorial Sloan-Kettering Cancer Center
• Phone: 646-888-4184
• EMail: abou-alg@mskcc.org

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Quintanilha JCF, Geyer S, Etheridge AS, Racioppi A, Hammond K, Crona DJ, Pena CE, Jacobson SB, Marmorino F, Rossini D, Cremolini C, Sanoff HK, Abou-Alfa GK, Innocenti F. KDR genetic predictor of toxicities induced by sorafenib and regorafenib. Pharmacogenomics J. 2022 Dec;22(5-6):251-257. doi: 10.1038/s41397-022-00279-3. Epub 2022 Apr 28.

Abou-Alfa GK, Shi Q, Knox JJ, Kaubisch A, Niedzwiecki D, Posey J, Tan BR Jr, Kavan P, Goel R, Lammers PE, Bekaii-Saab TS, Tam VC, Rajdev L, Kelley RK, El Dika I, Zemla T, Potaracke RI, Balletti J, El-Khoueiry AB, Harding JJ, Suga JM, Schwartz LH, Goldberg RM, Bertagnolli MM, Meyerhardt J, O'Reilly EM, Venook AP. Assessment of Treatment With Sorafenib Plus Doxorubicin vs Sorafenib Alone in Patients With Advanced Hepatocellular Carcinoma: Phase 3 CALGB 80802 Randomized Clinical Trial. JAMA Oncol. 2019 Nov 1;5(11):1582-1588. doi: 10.1001/jamaoncol.2019.2792. Erratum In: JAMA Oncol. 2019 Oct 10;:

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT01015833
• Other Study ID Numbers: NCI-2011-01989; NCI-2011-01989 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); CDR0000659348; CALGB-80802 ( Other Identifier: Alliance for Clinical Trials in Oncology ); CALGB-80802 ( Other Identifier: CTEP ); U10CA180821 ( U.S. NIH Grant/Contract ); U10CA031946 ( U.S. NIH Grant/Contract )
• First Submitted: November 17, 2009
• First Posted: November 18, 2009
• Results First Submitted: December 1, 2017
• Results First Posted: May 2, 2018
• Last Update Posted: August 4, 2022