Tivozanib in Treating Patients With Liver Cancer That Is Metastatic or Cannot Be Removed by Surgery

• Sponsor: Roswell Park Cancer Institute (Other)
• Overall Status: Completed
• CT.gov ID: NCT01835223
• Collaborator: National Comprehensive Cancer Network (Other), AVEO Pharmaceuticals, Inc. (Industry), National Cancer Institute (NCI) (NIH)
• Enrollment: 33
• Locations: 2
• Arms: 2
• Actual Duration (Months): 75.9
• Patients Per Site: 16.5
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

This phase I/II trial studies the side effects and best dose of tivozanib and to see how well it works in treating patients with liver cancer that has spread to other parts of the body or cannot be removed by surgery. Tivozanib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Condition or Disease	Intervention/Treatment	Phase
Advanced Adult Hepatocellular Carcinoma; Non-Resectable Hepatocellular Carcinoma	Drug: Tivozanib (1mg); Drug: Tivozanib (1.5mg)	Phase 1/Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. Progression free survival (PFS) at 24 weeks in patients with advanced hepatocellular carcinoma (HCC).

SECONDARY OBJECTIVES:

1. To determine the safety of tivozanib in HCC. II. To determine the overall survival (OS) and clinical benefit rate (complete response [CR], partial response [PR] and stable disease [SD]) by Response Evaluation Criteria in Solid Tumors (RECIST).

2. To determine the steady state pharmacokinetics (PK) and soluble vascular endothelial growth factor receptor 2 (VEGFR-2) baseline/change with tivozanib and use modeling to correlate exposure with biomarker change and the primary outcome measure of PFS.

3. To determine the change in viral load (hepatitis B virus [HBV] and hepatitis C virus [HCV]) during therapy in patients with HBV or HCV associated HCC.

4. To determine the change in tumor marker (alfa fetoprotein) with tivozanib therapy is in the effect of tivozanib on several tumor-associated immune response markers.

OUTLINE: This is a phase I, dose-escalation study followed by a phase II study.

Patients receive tivozanib orally (PO) once daily (QD) on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 6 months.

Study Design

• Study Type: Interventional
• Actual Enrollment: 33 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Multicenter Phase 1b/2 Study of Tivozanib in Patients With Advanced Inoperable Hepatocellular Carcinoma
• Actual Study Start Date: Jul 11, 2013
• Actual Primary Completion Date: Dec 24, 2018
• Actual Study Completion Date: Nov 8, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (tivozanib - 1 mg) Patients receive tivozanib PO QD on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.	Drug: Tivozanib (1mg); Given PO; Other Names: AV-951 TIVOZANIB
Experimental: Treatment (tivozanib - 1.5 mg) Patients receive tivozanib PO QD on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.	Drug: Tivozanib (1.5mg); Given PO; Other Names: AV-951 TIVOZANIB

Outcome Measures

Primary Outcome Measures

1. PFS, Assessed Using Standard RECIST Criteria [24 weeks]

   Will be descriptively analyzed using standard Kaplan-Meier estimation along with the corresponding descriptive statistics and 95% confidence intervals.

Secondary Outcome Measures

1. Clinical Benefit Rate (CR, PR, and SD) by RECIST [Up to 3 years]

   The number of patients achieving clinical benefit (CR, PR, or SD by RECIST).

2. Incidence of Adverse Events and Toxicities, Assessed Using National Cancer Institute Common Terminology Criteria for Adverse Events Version 4 [Up to 3 years]

   Toxicity frequency will be tabulated by grade across all dose levels and cycles for all patients in the safety sample and for the subset treated at the recommended phase 2 dose.

3. Overall Survival Rate [Up to 3 years]

   Overall survival is defined as the time from treatment until death or last follow-up.

Other Outcome Measures

1. AFP Response [Up to 3 years]

   Defined as an AFP decrease greater than 50%.

2. Antiviral Effects (if Any in Those With HBV or HCV Associated HCC) [Up to 3 years]

3. Drug Exposure, as Assessed by Steady State PK [Up to 3 years]

   Associations between drug exposure and response/survival and toxicity by quartiles of drug exposure.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Advanced staged HCC (unresectable and not amenable to local or regional therapy; or metastatic HCC); the diagnosis of HCC should be based on at least one of the following:

• Magnetic resonance imaging (MRI) or computed tomography (CT) consistent with liver cirrhosis AND at least one solid liver lesion measuring >= 2 cm, with characteristics arterial enhancement and venous washout regardless of alpha-fetoprotein (AFP) levels

• AFP >= 400 ng/mL AND evidence of at least one solid liver lesion >= 2 cm regardless of specific imaging characteristics on CT or MRI

• Histological/cytology biopsy confirming HCC

• Patients must have measurable disease per RECIST 1.1 criteria defined as at least one lesion that can be accurately measured in at least one dimension, and that has not been the target of local or regional therapy including transarterial chemoembolization, intra-arterial chemotherapy, ethanol or radiofrequency ablation

• Life expectancy of greater than 3 months

• Child-Pugh liver function class A

• Aspartate aminotransferase (AST) =< 5 x institutional upper limits of normal (ULN)

• Total bilirubin =< 3 mg/dL

• International normalized ratio (INR) =< 2.0 (unless due to therapeutic warfarin use)

• Serum albumin > 2.8 g/dL

• Creatinine =< 1.5 x institutional ULN

• Absolute neutrophil count (ANC) >= 1200/mm^3

• Platelets >= 60,000/mm^3

• Hemoglobin (Hgb) >= 8.5 g/dL

• Patients must not have any evidence of bleeding diathesis or active gastrointestinal bleeding

• Patients must not be known to be human immunodeficiency virus (HIV) positive

• Patients must not have other uncontrolled intercurrent illnesses (excluding HBV or HCV); this includes (but is not limited to) ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements

• Sexually active fertile patients (male and female), and their partners, must agree to use medically accepted methods of contraception during the course of the study and for 3 months after the last dose of the study drug

• Female patients of childbearing potential must have a negative pregnancy test at screening

• Have an Eastern Cooperative Oncology Group (ECOG) performance status of =< 2

• Subject or legal representative must understand the investigational nature of this study and sign an Independent Ethics Committee/Institutional Review Board approved written informed consent form prior to receiving any study related procedure

Exclusion Criteria:

• Patients who have had prior anti-angiogenic therapy, including but not limited to sorafenib, brivanib, bevacizumab, or sunitinib

• Patients who have had any prior line of systemic therapy including cytotoxic agents or molecularly targeted agents for advanced/unresectable disease; any number of prior regional therapies with transarterial chemoembolization (TACE), brachytherapy with yttrium-90 microsphere, intra-arterial chemotherapy, surgery, or ablative therapy are allowed

• Prior liver transplantation and on immunosuppression

• Known symptomatic or uncontrolled brain metastases or epidural disease

• Patient has a corrected QT interval (QTcF) > 500 ms at screening

• The patient is unable to swallow pills or diagnosed with a gastrointestinal disorder that are likely to interfere with the absorption of the study drug or with the patient's ability to take regular oral medication

• The patient is pregnant or breastfeeding

• Patients with second primary cancer (except adequately treated nonmelanoma skin cancer, curatively treated in-situ carcinoma of the cervix or superficial bladder cancer, or other solid tumors including lymphoma without bone marrow involvement curatively treated with no evidence of disease for >= 5 years)

• The patient has a previously-identified allergy or hypersensitivity to components of the study treatment formulation

• Patients receiving any medications or substances that are strong inducers of cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) are ineligible; moderate inducers of CYP3A4 should be used with caution

• Urine protein: creatinine ratio > 1

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Roswell Park Cancer Institute	Buffalo	New York	United States	14263
2	Case Western Reserve University	Cleveland	Ohio	United States	44106

Sponsors and Collaborators

• Roswell Park Cancer Institute
• National Comprehensive Cancer Network
• AVEO Pharmaceuticals, Inc.
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Renuka Iyer, Roswell Park Cancer Institute

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Mar 27, 2017

More Information

Publications

None provided.

• Responsible Party: Roswell Park Cancer Institute
• ClinicalTrials.gov Identifier: NCT01835223
• Other Study ID Numbers: I 229112; NCI-2013-00756; I 229112; P30CA016056
• First Posted: Apr 18, 2013
• Last Update Posted: Oct 28, 2020
• Last Verified: Oct 1, 2020

• Additional relevant MeSH terms: Carcinoma; Carcinoma, Hepatocellular

Study Results

Participant Flow

Arm/Group Title	Treatment (Tivozanib 1mg)	Treatment (Tivozanib 1.5mg)
Arm/Group Description	Patients receive tivozanib PO QD on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Laboratory Biomarker Analysis: Correlative studies Pharmacological Study: Correlative studies Tivozanib: Given PO	Patients receive tivozanib PO QD on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Laboratory Biomarker Analysis: Correlative studies Pharmacological Study: Correlative studies
Period Title: Overall Study
STARTED	30	3
COMPLETED	21	2
NOT COMPLETED	9	1

Baseline Characteristics

Arm/Group Title	Treatment (Tivozanib 1mg)	Treatment (Tivozanib 1.5mg)	Total
Arm/Group Description	Patients receive tivozanib PO QD on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Laboratory Biomarker Analysis: Correlative studies Pharmacological Study: Correlative studies Tivozanib: Given PO	Patients receive tivozanib PO QD on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Laboratory Biomarker Analysis: Correlative studies Pharmacological Study: Correlative studies Tivozanib: Given PO	Total of all reporting groups
Overall Participants	24	3	27
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	9 37.5%	1 33.3%	10 37%
>=65 years	15 62.5%	2 66.7%	17 63%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	66.2 (5.5)	65.5 (11.4)	65.6 (10.8)
Sex: Female, Male (Count of Participants)
Female	1 4.2%	0 0%	1 3.7%
Male	23 95.8%	3 100%	26 96.3%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	1 4.2%	0 0%	1 3.7%
White	22 91.7%	3 100%	25 92.6%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	1 4.2%	0 0%	1 3.7%
Region of Enrollment (participants) [Number]
United States	24 100%	3 100%	27 100%
ECOG Performance Status (participants) [Number]
0:Fully active, able to carry on all pre-disease performance without restriction.	14 58.3%	2 66.7%	16 59.3%
1: Restricted in physically strenuous, but able for work of light or sedentary nature	9 37.5%	1 33.3%	10 37%

Outcome Measures

1. Primary Outcome

Title	PFS, Assessed Using Standard RECIST Criteria
Description	Will be descriptively analyzed using standard Kaplan-Meier estimation along with the corresponding descriptive statistics and 95% confidence intervals.
Time Frame	24 weeks

Outcome Measure Data

Analysis Population Description

This outcome was only assessed as part of the Phase II study - which was conducted on the Tivozanib 1mg arm.

Arm/Group Title	Treatment (Tivozanib 1mg)	Treatment (Tivozanib 1.5mg)
Arm/Group Description	Patients receive tivozanib PO QD on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Laboratory Biomarker Analysis: Correlative studies Pharmacological Study: Correlative studies Tivozanib: Given PO	Patients receive tivozanib PO QD on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Laboratory Biomarker Analysis: Correlative studies Pharmacological Study: Correlative studies Tivozanib: Given PO
Measure Participants	19	0
Number (90% Confidence Interval) [percentage of participants]	58 241.7%

2. Secondary Outcome

Title	Clinical Benefit Rate (CR, PR, and SD) by RECIST
Description	The number of patients achieving clinical benefit (CR, PR, or SD by RECIST).
Time Frame	Up to 3 years

Outcome Measure Data

Analysis Population Description

This outcome was only assessed as part of the Phase II study - which was conducted on the Tivozanib 1mg arm. Only 19 subjects were evaluable for the primary or secondary end-points.

Arm/Group Title	Treatment (Tivozanib - 1 mg)	Treatment (Tivozanib - 1.5 mg)
Arm/Group Description	Patients receive tivozanib PO QD on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Tivozanib (1mg): Given PO	Patients receive tivozanib PO QD on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Tivozanib (1.5mg): Given PO
Measure Participants	19	0
Count of Participants [Participants]	12 50%

3. Secondary Outcome

Title	Incidence of Adverse Events and Toxicities, Assessed Using National Cancer Institute Common Terminology Criteria for Adverse Events Version 4
Description	Toxicity frequency will be tabulated by grade across all dose levels and cycles for all patients in the safety sample and for the subset treated at the recommended phase 2 dose.
Time Frame	Up to 3 years

Outcome Measure Data

Analysis Population Description

This outcome was only assessed as part of the Phase II study - which was conducted on the Tivozanib 1mg arm. Only 19 subjects were evaluable for the primary or secondary end-points.

Arm/Group Title	Treatment (Tivozanib 1mg)	Treatment (Tivozanib 1.5mg)
Arm/Group Description	Patients receive tivozanib PO QD on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Laboratory Biomarker Analysis: Correlative studies Pharmacological Study: Correlative studies Tivozanib: Given PO	Patients receive tivozanib PO QD on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Laboratory Biomarker Analysis: Correlative studies Pharmacological Study: Correlative studies Tivozanib: Given PO
Measure Participants	19	0
Count of Participants [Participants]	19 79.2%

4. Secondary Outcome

Title	Overall Survival Rate
Description	Overall survival is defined as the time from treatment until death or last follow-up.
Time Frame	Up to 3 years

Outcome Measure Data

Analysis Population Description

This outcome was only assessed as part of the Phase II study - which was conducted on the Tivozanib 1mg arm. Only 19 subjects were evaluable for the primary or secondary end-points.

Arm/Group Title	Treatment (Tivozanib 1mg)	Treatment (Tivozanib 1.5mg)
Arm/Group Description	Patients receive tivozanib PO QD on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Laboratory Biomarker Analysis: Correlative studies Pharmacological Study: Correlative studies Tivozanib: Given PO	Patients receive tivozanib PO QD on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Laboratory Biomarker Analysis: Correlative studies Pharmacological Study: Correlative studies Tivozanib: Given PO
Measure Participants	19	0
Number (90% Confidence Interval) [percent probability]	0.40

5. Other Pre-specified Outcome

Title	AFP Response
Description	Defined as an AFP decrease greater than 50%.
Time Frame	Up to 3 years

Outcome Measure Data

Analysis Population Description

This outcome was only assessed as part of the Phase II study - which was conducted on the Tivozanib 1mg arm. Only 19 subjects were evaluable for the primary or secondary end-points.

Arm/Group Title	Treatment (Tivozanib 1mg)	Treatment (Tivozanib 1.5mg)
Arm/Group Description	Patients receive tivozanib PO QD on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Laboratory Biomarker Analysis: Correlative studies Pharmacological Study: Correlative studies Tivozanib: Given PO	Patients receive tivozanib PO QD on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Laboratory Biomarker Analysis: Correlative studies Pharmacological Study: Correlative studies Tivozanib: Given PO
Measure Participants	19	0
Count of Participants [Participants]	4 16.7%

6. Other Pre-specified Outcome

Title	Antiviral Effects (if Any in Those With HBV or HCV Associated HCC)
Time Frame	Up to 3 years

Outcome Measure Data

Analysis Population Description

Due to funding limitations, this outcome was not assessed.

Arm/Group Title	Treatment (Tivozanib 1mg)	Treatment (Tivozanib 1.5mg)
Arm/Group Description	Patients receive tivozanib PO QD on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Laboratory Biomarker Analysis: Correlative studies Pharmacological Study: Correlative studies Tivozanib: Given PO	Patients receive tivozanib PO QD on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Laboratory Biomarker Analysis: Correlative studies Pharmacological Study: Correlative studies Tivozanib: Given PO
Measure Participants	0	0

7. Other Pre-specified Outcome

Title	Drug Exposure, as Assessed by Steady State PK
Description	Associations between drug exposure and response/survival and toxicity by quartiles of drug exposure.
Time Frame	Up to 3 years

Outcome Measure Data

Analysis Population Description

Due to funding issues, data were not completed.

Arm/Group Title	Treatment (Tivozanib 1mg)	Treatment (Tivozanib 1.5mg)
Arm/Group Description	Patients receive tivozanib PO QD on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Laboratory Biomarker Analysis: Correlative studies Pharmacological Study: Correlative studies Tivozanib: Given PO	Patients receive tivozanib PO QD on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Laboratory Biomarker Analysis: Correlative studies Pharmacological Study: Correlative studies Tivozanib: Given PO
Measure Participants	0	0

Adverse Events

Time Frame	Phase 1: Cycle 1 Day 15, Day 1 of Each Cycle After Cycle 1, Cycle 3 Day 1 (for phase 1 only), and to the End of Treatment. Phase II: From start of treatment until end of treatment.
Arm/Group Title	Treatment (Tivozanib 1mg)		Treatment (Tivozanib 1.5mg)
Arm/Group Description	Patients receive tivozanib PO QD on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Laboratory Biomarker Analysis: Correlative studies Pharmacological Study: Correlative studies Tivozanib: Given PO		Patients receive tivozanib PO QD on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Laboratory Biomarker Analysis: Correlative studies Pharmacological Study: Correlative studies Tivozanib: Given PO
All Cause Mortality
	Treatment (Tivozanib 1mg)		Treatment (Tivozanib 1.5mg)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	18/24 (75%)		3/3 (100%)
Serious Adverse Events
	Treatment (Tivozanib 1mg)		Treatment (Tivozanib 1.5mg)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	15/24 (62.5%)		3/3 (100%)
Cardiac disorders
Acute myocardial infarction	1/24 (4.2%)	1	0/3 (0%)	0
Cardiac failure congestive	1/24 (4.2%)	1	0/3 (0%)	0
Gastrointestinal disorders
Abdominal pain upper	1/24 (4.2%)	1	0/3 (0%)	0
Colitis	1/24 (4.2%)	1	0/3 (0%)	0
Gastrointestinal haemorrhage	1/24 (4.2%)	1	0/3 (0%)	0
Oesophageal ulcer haemorrhage	1/24 (4.2%)	1	0/3 (0%)	0
Pancreatitis	1/24 (4.2%)	1	0/3 (0%)	0
Stomatitis	0/24 (0%)	0	1/3 (33.3%)	1
General disorders
Pyrexia	1/24 (4.2%)	1	1/3 (33.3%)	1
Hepatobiliary disorders
Cholecystitis	1/24 (4.2%)	1	0/3 (0%)	0
Hepatic failure	2/24 (8.3%)	2	0/3 (0%)	0
Infections and infestations
Bacteraemia	0/24 (0%)	0	1/3 (33.3%)	1
Enterocolitis infectious	1/24 (4.2%)	1	0/3 (0%)	0
Infection	1/24 (4.2%)	1	0/3 (0%)	0
Pneumonia	0/24 (0%)	0	1/3 (33.3%)	1
Staphylococcal infection	1/24 (4.2%)	1	0/3 (0%)	0
Investigations
Blood bilirubin increased	2/24 (8.3%)	2	0/3 (0%)	0
Metabolism and nutrition disorders
Dehydration	1/24 (4.2%)	1	0/3 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasm malignant	1/24 (4.2%)	1	0/3 (0%)	0
Nervous system disorders
Cerebrovascular accident	1/24 (4.2%)	1	0/3 (0%)	0
Encephalopathy	1/24 (4.2%)	2	0/3 (0%)	0
Renal and urinary disorders
Acute kidney injury	1/24 (4.2%)	2	0/3 (0%)	0
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism	2/24 (8.3%)	2	0/3 (0%)	0
Vascular disorders
Hypertension	1/24 (4.2%)	1	1/3 (33.3%)	1
Hypotension	1/24 (4.2%)	1	0/3 (0%)	0
Other (Not Including Serious) Adverse Events
	Treatment (Tivozanib 1mg)		Treatment (Tivozanib 1.5mg)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	24/24 (100%)		3/3 (100%)
Blood and lymphatic system disorders
Increased tendency to bruise	1/24 (4.2%)	1	0/3 (0%)	0
Cardiac disorders
Palpitations	1/24 (4.2%)	1	0/3 (0%)	0
Ear and labyrinth disorders
Hypoacusis	1/24 (4.2%)	1	0/3 (0%)	0
Endocrine disorders
Hypothyroidism	1/24 (4.2%)	1	0/3 (0%)	0
Eye disorders
Vision blurred	0/24 (0%)	0	1/3 (33.3%)	1
Gastrointestinal disorders
Abdominal distension	3/24 (12.5%)	3	0/3 (0%)	0
Abdominal pain	7/24 (29.2%)	7	2/3 (66.7%)	2
Abdominal pain upper	4/24 (16.7%)	4	0/3 (0%)	0
Ascites	1/24 (4.2%)	1	0/3 (0%)	0
Constipation	6/24 (25%)	7	0/3 (0%)	0
Diarrhoea	14/24 (58.3%)	27	2/3 (66.7%)	7
Dyspepsia	1/24 (4.2%)	1	0/3 (0%)	0
Faeces discoloured	1/24 (4.2%)	1	0/3 (0%)	0
Flatulence	2/24 (8.3%)	2	0/3 (0%)	0
Gastrooesophageal reflux disease	3/24 (12.5%)	3	2/3 (66.7%)	2
Large intestinal haemorrhage	1/24 (4.2%)	1	0/3 (0%)	0
Lip swelling	1/24 (4.2%)	1	0/3 (0%)	0
Nausea	11/24 (45.8%)	23	1/3 (33.3%)	1
Rectal haemorrhage	1/24 (4.2%)	1	0/3 (0%)	0
Stomatitis	5/24 (20.8%)	12	1/3 (33.3%)	4
Varices oesophageal	1/24 (4.2%)	1	0/3 (0%)	0
Vomiting	9/24 (37.5%)	17	1/3 (33.3%)	1
General disorders
Chest pain	1/24 (4.2%)	1	1/3 (33.3%)	1
Chills	1/24 (4.2%)	1	0/3 (0%)	0
Fatigue	19/24 (79.2%)	45	2/3 (66.7%)	3
Infusion site extravasation	1/24 (4.2%)	1	0/3 (0%)	0
Oedema	2/24 (8.3%)	2	0/3 (0%)	0
Oedema peripheral	5/24 (20.8%)	5	0/3 (0%)	0
Pain	1/24 (4.2%)	1	0/3 (0%)	0
Pyrexia	1/24 (4.2%)	1	0/3 (0%)	0
Thirst	1/24 (4.2%)	1	0/3 (0%)	0
Hepatobiliary disorders
Cholangitis	1/24 (4.2%)	1	0/3 (0%)	0
Hepatic failure	1/24 (4.2%)	1	0/3 (0%)	0
Jaundice	1/24 (4.2%)	1	0/3 (0%)	0
Portal vein thrombosis	1/24 (4.2%)	1	0/3 (0%)	0
Immune system disorders
Hypersensitivity	1/24 (4.2%)	1	0/3 (0%)	0
Infections and infestations
Bronchitis	1/24 (4.2%)	1	0/3 (0%)	0
Candida infection	2/24 (8.3%)	2	0/3 (0%)	0
Cellulitis	2/24 (8.3%)	2	0/3 (0%)	0
Fungal skin infection	1/24 (4.2%)	1	0/3 (0%)	0
Nasopharyngitis	1/24 (4.2%)	1	0/3 (0%)	0
Oral candidiasis	1/24 (4.2%)	1	0/3 (0%)	0
Perichondritis	1/24 (4.2%)	1	0/3 (0%)	0
Pneumonia	1/24 (4.2%)	1	0/3 (0%)	0
Rhinitis	2/24 (8.3%)	2	0/3 (0%)	0
Sinusitis	1/24 (4.2%)	1	0/3 (0%)	0
Urinary tract infection	1/24 (4.2%)	1	0/3 (0%)	0
Viral infection	1/24 (4.2%)	1	0/3 (0%)	0
Injury, poisoning and procedural complications
Contusion	2/24 (8.3%)	2	1/3 (33.3%)	1
Fall	2/24 (8.3%)	2	0/3 (0%)	0
Investigations
Activated partial thromboplastin time prolonged	0/24 (0%)	0	1/3 (33.3%)	1
Alanine aminotransferase increased	6/24 (25%)	7	2/3 (66.7%)	2
Ammonia increased	1/24 (4.2%)	1	0/3 (0%)	0
Aspartate aminotransferase increased	5/24 (20.8%)	6	2/3 (66.7%)	5
Blood alkaline phosphatase increased	5/24 (20.8%)	8	2/3 (66.7%)	2
Blood bilirubin decreased	1/24 (4.2%)	1	0/3 (0%)	0
Blood bilirubin increased	6/24 (25%)	14	3/3 (100%)	6
Blood creatinine increased	0/24 (0%)	0	2/3 (66.7%)	2
Haemoglobin decreased	2/24 (8.3%)	2	1/3 (33.3%)	1
Lipase increased	1/24 (4.2%)	2	0/3 (0%)	0
Lymphocyte count decreased	3/24 (12.5%)	4	3/3 (100%)	8
Platelet count decreased	4/24 (16.7%)	5	2/3 (66.7%)	3
Urine viscosity increased	1/24 (4.2%)	1	0/3 (0%)	0
Weight decreased	8/24 (33.3%)	10	0/3 (0%)	0
Metabolism and nutrition disorders
Cachexia	1/24 (4.2%)	1	0/3 (0%)	0
Decreased appetite	15/24 (62.5%)	28	1/3 (33.3%)	1
Dehydration	4/24 (16.7%)	4	2/3 (66.7%)	3
Hypercalcaemia	1/24 (4.2%)	1	0/3 (0%)	0
Hyperkalaemia	2/24 (8.3%)	2	3/3 (100%)	4
Hypernatraemia	0/24 (0%)	0	2/3 (66.7%)	2
Hypoalbuminaemia	4/24 (16.7%)	7	3/3 (100%)	5
Hypoglycaemia	2/24 (8.3%)	2	0/3 (0%)	0
Hypokalaemia	2/24 (8.3%)	2	0/3 (0%)	0
Hypomagnesaemia	1/24 (4.2%)	1	1/3 (33.3%)	1
Hyponatraemia	1/24 (4.2%)	1	2/3 (66.7%)	4
Musculoskeletal and connective tissue disorders
Arthralgia	3/24 (12.5%)	4	0/3 (0%)	0
Back pain	3/24 (12.5%)	3	0/3 (0%)	0
Flank pain	3/24 (12.5%)	4	0/3 (0%)	0
Groin pain	1/24 (4.2%)	1	0/3 (0%)	0
Muscle spasms	2/24 (8.3%)	3	1/3 (33.3%)	1
Muscular weakness	3/24 (12.5%)	4	0/3 (0%)	0
Musculoskeletal pain	4/24 (16.7%)	5	0/3 (0%)	0
Myalgia	2/24 (8.3%)	3	0/3 (0%)	0
Neck pain	1/24 (4.2%)	1	0/3 (0%)	0
Pain in extremity	2/24 (8.3%)	2	0/3 (0%)	0
Spinal pain	1/24 (4.2%)	1	0/3 (0%)	0
Spinal stenosis	1/24 (4.2%)	1	0/3 (0%)	0
Nervous system disorders
Amnesia	1/24 (4.2%)	1	0/3 (0%)	0
Balance disorder	1/24 (4.2%)	1	0/3 (0%)	0
Cognitive disorder	1/24 (4.2%)	1	0/3 (0%)	0
Dizziness	10/24 (41.7%)	12	1/3 (33.3%)	1
Dysgeusia	1/24 (4.2%)	1	0/3 (0%)	0
Encephalopathy	4/24 (16.7%)	5	0/3 (0%)	0
Headache	5/24 (20.8%)	6	1/3 (33.3%)	1
Hepatic encephalopathy	1/24 (4.2%)	1	0/3 (0%)	0
Posterior reversible encephalopathy syndrome	0/24 (0%)	0	1/3 (33.3%)	1
Somnolence	2/24 (8.3%)	2	0/3 (0%)	0
Taste disorder	2/24 (8.3%)	2	0/3 (0%)	0
Psychiatric disorders
Anxiety	1/24 (4.2%)	1	0/3 (0%)	0
Confusional state	2/24 (8.3%)	3	0/3 (0%)	0
Delirium	1/24 (4.2%)	1	0/3 (0%)	0
Depressed mood	1/24 (4.2%)	1	0/3 (0%)	0
Depression	2/24 (8.3%)	2	0/3 (0%)	0
Disorientation	1/24 (4.2%)	1	0/3 (0%)	0
Insomnia	3/24 (12.5%)	3	0/3 (0%)	0
Nightmare	1/24 (4.2%)	1	0/3 (0%)	0
Renal and urinary disorders
Haematuria	2/24 (8.3%)	3	0/3 (0%)	0
Nephrolithiasis	1/24 (4.2%)	1	0/3 (0%)	0
Pollakiuria	1/24 (4.2%)	1	0/3 (0%)	0
Proteinuria	1/24 (4.2%)	1	0/3 (0%)	0
Renal disorder	1/24 (4.2%)	1	0/3 (0%)	0
Renal failure	0/24 (0%)	0	1/3 (33.3%)	1
Urinary incontinence	1/24 (4.2%)	1	0/3 (0%)	0
Urinary retention	0/24 (0%)	0	1/3 (33.3%)	1
Respiratory, thoracic and mediastinal disorders
Cough	4/24 (16.7%)	7	1/3 (33.3%)	1
Dysphonia	8/24 (33.3%)	13	2/3 (66.7%)	4
Dyspnoea	5/24 (20.8%)	6	2/3 (66.7%)	2
Epistaxis	3/24 (12.5%)	4	1/3 (33.3%)	1
Hiccups	1/24 (4.2%)	1	0/3 (0%)	0
Nasal congestion	3/24 (12.5%)	4	0/3 (0%)	0
Oropharyngeal pain	1/24 (4.2%)	3	0/3 (0%)	0
Productive cough	2/24 (8.3%)	3	0/3 (0%)	0
Pulmonary embolism	2/24 (8.3%)	2	0/3 (0%)	0
Upper respiratory tract congestion	1/24 (4.2%)	1	0/3 (0%)	0
Skin and subcutaneous tissue disorders
Dry skin	5/24 (20.8%)	5	0/3 (0%)	0
Erythema	2/24 (8.3%)	2	0/3 (0%)	0
Nail discolouration	1/24 (4.2%)	1	0/3 (0%)	0
Nail ridging	1/24 (4.2%)	1	0/3 (0%)	0
Night sweats	0/24 (0%)	0	1/3 (33.3%)	1
Palmar-plantar erythrodysaesthesia syndrome	3/24 (12.5%)	6	1/3 (33.3%)	1
Pruritus	4/24 (16.7%)	7	0/3 (0%)	0
Rash	2/24 (8.3%)	2	1/3 (33.3%)	1
Rash generalised	1/24 (4.2%)	1	0/3 (0%)	0
Rash papular	2/24 (8.3%)	4	0/3 (0%)	0
Skin discolouration	1/24 (4.2%)	1	0/3 (0%)	0
Skin exfoliation	1/24 (4.2%)	1	0/3 (0%)	0
Skin hyperpigmentation	1/24 (4.2%)	1	0/3 (0%)	0
Skin necrosis	1/24 (4.2%)	2	0/3 (0%)	0
Urticaria	1/24 (4.2%)	1	0/3 (0%)	0
Vascular disorders
Hot flush	1/24 (4.2%)	1	0/3 (0%)	0
Hypertension	4/24 (16.7%)	5	1/3 (33.3%)	2
Hypotension	2/24 (8.3%)	2	0/3 (0%)	0
Pelvic venous thrombosis	1/24 (4.2%)	1	0/3 (0%)	0
Peripheral coldness	1/24 (4.2%)	1	0/3 (0%)	0
Thrombophlebitis	1/24 (4.2%)	1	0/3 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE 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.