Sorafenib Tosylate and Yttrium Y 90 Glass Microspheres in Treating Patients With Liver Cancer That Cannot Be Removed by Surgery

• Sponsor: M.D. Anderson Cancer Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT01900002
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 40
• Location: 1
• Arm: 1
• Actual Duration (Months): 86.9
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

This phase II trial studies how well sorafenib tosylate and yttrium Y 90 glass microspheres work in treating patients with liver cancer that cannot be removed by surgery. Sorafenib tosylate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Yttrium Y 90 glass microspheres use glass beads to carry radiation directly to tumor cells without harming normal cells. Giving sorafenib tosylate with yttrium Y 90 glass microspheres may be an effective treatment for liver cancer.

Condition or Disease	Intervention/Treatment	Phase
Advanced Adult Hepatocellular Carcinoma; BCLC Stage C Hepatocellular Carcinoma; Recurrent Adult 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	Other: Laboratory Biomarker Analysis; Other: Quality-of-Life Assessment; Drug: Sorafenib; Drug: Sorafenib Tosylate; Radiation: Yttrium Y 90 Glass Microspheres	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. Median progression-free survival (PFS).

SECONDARY OBJECTIVES:

1. Overall survival (OS). II. Time to radiographic progression (TTRP). III. To evaluate the safety of the combination of sorafenib (sorafenib tosylate) and Yttrium-90; adverse events (National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 [NCI-CTAE v 4.0]).

OTHER OBJECTIVES:

1. Predictive biomarkers of response to therapy and survival: will assess pre-treatment plasma level of insulin-like growth factor 1 (IGF-1) as above, and assess its predictive ability of time to progression (TTP) and OS.

OUTLINE:

Patients receive sorafenib tosylate orally (PO) twice daily (BID). After 4 weeks, patients receive yttrium Y 90 glass microspheres intra-arterially (IA). Courses of sorafenib tosylate repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months.

Study Design

• Study Type: Interventional
• Actual Enrollment: 40 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Study of Sorafenib and Yttrium-90 Glass Microspheres for Advanced Hepatocellular Carcinoma, BCLC Stage C
• Actual Study Start Date: Sep 13, 2013
• Actual Primary Completion Date: Dec 10, 2020
• Actual Study Completion Date: Dec 10, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (sorafenib tosylate, TheraSphere) Patients receive sorafenib tosylate PO BID. After 4 weeks, patients receive yttrium Y 90 glass microspheres IA. Courses of sorafenib tosylate repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.	Other: Laboratory Biomarker Analysis; Correlative studies; Other: Quality-of-Life Assessment; Ancillary studies; Other Names: Quality of Life Assessment ; Drug: Sorafenib; Given PO; Other Names: BAY 43-9006 ; Drug: Sorafenib Tosylate; Given PO; Other Names: BAY 43-9006 Tosylate BAY 54-9085 Nexavar sorafenib ; Radiation: Yttrium Y 90 Glass Microspheres; Given IA; Other Names: TheraSphere

Outcome Measures

Primary Outcome Measures

1. Median Progression Free Survival (PFS) [From the start of therapy until failure to disease progression or death, assessed up to 4 years]

   Will be monitored using the method of Thall et al. Kaplan-Meier method will be used to estimate median progression free survival (PFS) and the 95% confidence interval. Log rank test, univariate and multivariate Cox proportional hazards regression models will be used to identify prognostic factors for progression free survival (PFS).

Secondary Outcome Measures

1. Median Time to Progression (TTP) [Up to 4 years]

   95% credible interval will be estimated. This will be analyzed using Kaplan-Meier method, Log rank test and Cox proportional hazards regression modeling.

2. Incidence of Adverse Events, Graded According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 4.0 [Up to 4 years]

   To evaluate the safety of the combination of sorafenib (sorafenib tosylate) and Yttrium-90; adverse events (National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 [NCI-CTAE v 4.0]) .

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Subjects must be able to understand and be willing to sign the written informed consent form; a signed informed consent form must be appropriately obtained prior to the conduct of any trial-specific procedure

• Life expectancy of at least 12 weeks (3 months)

• Patients with histological or cytologically documented hepatocellular carcinoma (HCC) (documentation of original biopsy for diagnosis is acceptable if tumor tissue is unavailable) or clinical diagnosis by American Association for the Study of Liver Diseases (AASLD) criteria in cirrhotic subjects is required; for subjects without cirrhosis histological confirmation is mandatory

• Patients must have at least one tumor lesion that meets the following criteria: the lesion can be accurately measured in at least one dimension according to Response Evaluation Criteria in Solid Tumor (RECIST)

• The target lesion(s) has not been previously treated with local therapy (such as surgery, radiation therapy, hepatic arterial therapy, chemoembolization, radiofrequency ablation, percutaneous ethanol injection or cryoablation)

• Patients who have received local therapy, such as surgery, radiation therapy, hepatic arterial embolization, chemoembolization, radiofrequency ablation, percutaneous ethanol injection or cryoablation are eligible if the previously treated lesions have progressed or recurred can be identified as target lesions; local therapy must have been completed at least 4 weeks prior to the baseline scan

• Patients who have received yttrium-90 microspheres are not eligible

• Patients who have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) =< 1

• Patients who are categorized under Barcelona-Clınic Liver Cancer (BCLC)-C stage

• Cirrhosis grade of Child-Pugh class A; Child-Pugh status should be calculated based on clinical findings and laboratory results during the screening period

• Platelet count >= 60 x 10^9/L

• Hemoglobin >= 8.5 g/dL

• Total bilirubin =< 2.5 mg/dl

• Alanine transaminase (ALT) and aspartate aminotransferase (AST) =< 5 x upper limit of normal

• Serum creatinine =< 1.5 x the upper limit of normal

• Prothrombin time (PT)-international normalized ratio (INR) =< 2.3 or PT =< 6 seconds above control

• All acute toxic effects of any prior treatment have resolved to National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) v4.0 grade 1 or less at the time of signing the informed consent form (ICF)

• Women of childbearing potential must have a negative serum pregnancy test performed within 7 days prior to the start of study drug; post-menopausal women (defined as no menses for at least 1 year) and surgically sterilized women are not required to undergo a pregnancy test

• Subjects (men and women) of childbearing potential must agree to use adequate contraception beginning at the signing of the ICF until at least 30 days after the last dose of study drug; the definition of adequate contraception will be based on the judgment of the principal investigator or a designated associate

• Subject must be able to swallow and retain oral medication

Exclusion Criteria:

• Main portal vein thrombosis (PVT)

• Patients who are eligible for curative treatment (ablation or resection or transplantation)

• Previous or concurrent cancer other than HCC unless without evidence of disease for 5 or more years prior to entry, except cervical cancer in-situ, treated basal cell carcinoma, or superficial bladder tumor

• Tumor replacement > 70% of total liver volume based on visual estimation by the investigator OR tumor replacement > 50% of total liver volume in the presence of albumin < 3 mg/dL

• Contraindications to angiography and selective visceral arterial catheterization

• Any known contraindications to sorafenib including allergic reaction, pill-swallowing difficulty, uncontrolled hypertension or history of cardiac disease, significant gastrointestinal (GI) bleed within 30 days, metastatic brain disease, renal failure requiring dialysis

• Concomitant treatment or within 28 days of one of the following:

• Any other systemic anticancer agent other than agents used for cancer prevention

• Subjects who have used strong cytochrome P450 3A4 (CYP3A4) inducers (e.g., phenytoin, carbamazepine, phenobarbital, St. John's Wort [hypericum perforatum], dexamethasone at a dose of greater than 16 mg daily, or rifampin [rifampicin], and/or rifabutin) within 28 days before treatment

• UDP glycosyltransferase 1 family, polypeptide A1 (UGT 1A1) and UDP glycosyltransferase 1 family, polypeptide A9 (UGT 1A9) substrates (e.g., irinotecan)

• P-glycoprotein (Gp) substrates (e.g., Digoxin)

• Prior radiation therapy to the liver

• Prior systemic therapy for the treatment of HCC, including sorafenib

• Any history of symptomatic pulmonary compromise, such as chronic obstructive pulmonary disease

• Any prior intervention for, or ongoing compromise of, the ampulla of Vater or biliary-enteric anastomosis

• Clinically evident ascites (trace ascites on imaging is acceptable)

• Pregnant or breast-feeding patients

• A positive serum pregnancy test within 14 days prior to treatment in women of childbearing potential

• Uncontrolled hypertension (systolic pressure > 140 mm Hg or diastolic pressure > 90 mm Hg [NCI-CTCAE v4.0] on repeated measurement) despite optimal medical management

• Active or clinically significant cardiac disease including:

• Congestive heart failure-New York Heart Association (NYHA) > class II

• Active coronary artery disease

• Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers or digoxin

• Unstable angina (anginal symptoms at rest), new-onset angina within 3 months before treatment, or myocardial infarction within 6 months before treatment

• Evidence or history of bleeding diathesis or uncontrolled coagulopathy

• Subject with any pulmonary hemorrhage/bleeding event of NCI-CTCAE v4.0 grade 2 or higher within 4 weeks before treatment; any other hemorrhage/bleeding event of NCI-CTCAE v4.0 grade 3 or higher within 4 weeks before treatment

• Subjects with thrombotic, embolic, venous, or arterial events, such as cerebrovascular accident (including transient ischemic attacks) within 6 months of informed consent

• Presence of a non-healing wound, non-healing ulcer, or bone fracture

• History of organ allograft. (Including corneal transplant)

• Known or suspected allergy or hypersensitivity to any of the study drugs, study drug classes, or excipients of the formulations given during the course of this trial

• Any malabsorption condition

• Inability to comply with the protocol and/or not willing or not available for follow-up assessments

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	M D Anderson Cancer Center	Houston	Texas	United States	77030

Sponsors and Collaborators

• M.D. Anderson Cancer Center
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Ahmed O Kaseb, M.D. Anderson Cancer Center

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jun 19, 2015

More Information

Additional Information:

• University of Texas MD Anderson Cancer Center Website

Publications

None provided.

• Responsible Party: M.D. Anderson Cancer Center
• ClinicalTrials.gov Identifier: NCT01900002
• Other Study ID Numbers: 2012-0870; NCI-2013-01667; Y-90; 2012-0870; P30CA016672
• First Posted: Jul 16, 2013
• Last Update Posted: Dec 30, 2021
• Last Verified: Dec 1, 2021

• Additional relevant MeSH terms: Carcinoma; Carcinoma, Hepatocellular; Sorafenib

Study Results

Participant Flow

Recruitment Details	September 2013 - December 2020. All participants were enrolled in MD Anderson

Arm/Group Title	Treatment (Sorafenib Tosylate, TheraSphere)
Arm/Group Description	Patients receive sorafenib tosylate PO BID. After 4 weeks, patients receive yttrium Y 90 glass microspheres IA. Courses of sorafenib tosylate repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.
Period Title: Overall Study
STARTED	40
COMPLETED	34
NOT COMPLETED	6

Baseline Characteristics

Arm/Group Title	Treatment (Sorafenib Tosylate, TheraSphere)
Arm/Group Description	Patients receive sorafenib tosylate PO BID. After 4 weeks, patients receive yttrium Y 90 glass microspheres IA. Courses of sorafenib tosylate repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.
Overall Participants	34
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	68.2
Sex: Female, Male (Count of Participants)
Female	9 26.5%
Male	25 73.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	5 14.7%
Not Hispanic or Latino	16 47.1%
Unknown or Not Reported	13 38.2%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	4 11.8%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	1 2.9%
White	21 61.8%
More than one race	0 0%
Unknown or Not Reported	8 23.5%
Region of Enrollment (participants) [Number]
United States	34 100%

Outcome Measures

1. Primary Outcome

Title	Median Progression Free Survival (PFS)
Description	Will be monitored using the method of Thall et al. Kaplan-Meier method will be used to estimate median progression free survival (PFS) and the 95% confidence interval. Log rank test, univariate and multivariate Cox proportional hazards regression models will be used to identify prognostic factors for progression free survival (PFS).
Time Frame	From the start of therapy until failure to disease progression or death, assessed up to 4 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Sorafenib Tosylate, TheraSphere)
Arm/Group Description	Patients receive sorafenib tosylate PO BID. After 4 weeks, patients receive yttrium Y 90 glass microspheres IA. Courses of sorafenib tosylate repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.
Measure Participants	34
Median (95% Confidence Interval) [months]	10.32

2. Secondary Outcome

Title	Median Time to Progression (TTP)
Description	95% credible interval will be estimated. This will be analyzed using Kaplan-Meier method, Log rank test and Cox proportional hazards regression modeling.
Time Frame	Up to 4 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Sorafenib Tosylate, TheraSphere)
Arm/Group Description	Patients receive sorafenib tosylate PO BID. After 4 weeks, patients receive yttrium Y 90 glass microspheres IA. Courses of sorafenib tosylate repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.
Measure Participants	34
Median (95% Confidence Interval) [months]	10.38

3. Secondary Outcome

Title	Incidence of Adverse Events, Graded According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 4.0
Description	To evaluate the safety of the combination of sorafenib (sorafenib tosylate) and Yttrium-90; adverse events (National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 [NCI-CTAE v 4.0]) .
Time Frame	Up to 4 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Sorafenib Tosylate, TheraSphere)
Arm/Group Description	Patients receive sorafenib tosylate PO BID. After 4 weeks, patients receive yttrium Y 90 glass microspheres IA. Courses of sorafenib tosylate repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.
Measure Participants	34
Fatigue	3 8.8%
Diarrhea	2 5.9%
Nausea	1 2.9%
Vomiting	2 5.9%
Hypertension	4 11.8%
Thrombocytopenia	1 2.9%
Hyperbilirubinemia	1 2.9%
Proteinuria	1 2.9%
ALT increase	1 2.9%
AST increase	1 2.9%

Adverse Events

Time Frame	adverse events were collected up to 4 years
Arm/Group Title	Treatment (Sorafenib Tosylate, TheraSphere)
Arm/Group Description	Patients receive sorafenib tosylate PO BID. After 4 weeks, patients receive yttrium Y 90 glass microspheres IA. Courses of sorafenib tosylate repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.
All Cause Mortality
	Treatment (Sorafenib Tosylate, TheraSphere)
	Affected / at Risk (%)	# Events
Total	0/34 (0%)
Serious Adverse Events
	Treatment (Sorafenib Tosylate, TheraSphere)
	Affected / at Risk (%)	# Events
Total	11/34 (32.4%)
Gastrointestinal disorders
Hepatic Hemorrhage	1/34 (2.9%)
Duodenal Ulcer	1/34 (2.9%)
Diarrhea	2/34 (5.9%)
Nausea	2/34 (5.9%)
Vomiting	2/34 (5.9%)
Rectal Bleed	1/34 (2.9%)
Abdominal Pain	1/34 (2.9%)
General disorders
Weakness	1/34 (2.9%)
Infections and infestations
Sepsis	1/34 (2.9%)
Investigations
Hyponatremia	3/34 (8.8%)
Hypophosphatemia	1/34 (2.9%)
Nervous system disorders
Dizziness	2/34 (5.9%)
Renal and urinary disorders
Hematuria	1/34 (2.9%)
Urinary Retention	1/34 (2.9%)
Acute Renal Failure	1/34 (2.9%)
Respiratory, thoracic and mediastinal disorders
Dyspnea	1/34 (2.9%)
Vascular disorders
Hypertenstion	1/34 (2.9%)
Hypotension	1/34 (2.9%)
Other (Not Including Serious) Adverse Events
	Treatment (Sorafenib Tosylate, TheraSphere)
	Affected / at Risk (%)	# Events
Total	27/34 (79.4%)
Gastrointestinal disorders
Diarrhea	2/34 (5.9%)
Nausea	1/34 (2.9%)
Vomiting	2/34 (5.9%)
Mucositis	1/34 (2.9%)
General disorders
Fatigue	3/34 (8.8%)
Investigations
Weight Loss	1/34 (2.9%)
Thrombocytopenia	1/34 (2.9%)
Hyperbilirubinemia	1/34 (2.9%)
Proteinuria	1/34 (2.9%)
Hyponatremia	1/34 (2.9%)
Hypophosphatemia	1/34 (2.9%)
ALT increase	2/34 (5.9%)
AST increase	4/34 (11.8%)
Nervous system disorders
Encephalopathy	1/34 (2.9%)
Skin and subcutaneous tissue disorders
Palmar-Planta Erythrodysesthesia	1/34 (2.9%)
Vascular disorders
Hypertension	4/34 (11.8%)

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.