Sorafenib Dose Ramp-Up in Hepatocellular Carcinoma (HCC)

Hepatocellular Carcinoma Clinical Trial

Official title:

Multicenter, Randomized Pilot Study of the Effect of Sorafenib Dosing Schedule on Tolerability and Drug Delivery

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01203787
• Other study ID #: ONC-2010-19
• Status: Completed
• Phase: Phase 4
• First received: September 10, 2010
• Last updated: February 13, 2015
• Start date: December 2010
• Est. completion date: March 2014

Study information

• Verified date: February 2015
• Source: University of Florida
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

Open-label study to evaluate the safety and tolerability of Sorafenib dose ramp-up (starting at a lower dose and then gradually increasing the dose) versus standard Sorafenib dosing in subjects with unresectable and/or metastatic hepatocellular carcinoma.

Description:

This is an open-label study that investigates the impact of a dose ramp-up strategy for sorafenib in patients with HCC. Clinical trial and post-marketing data suggest that sorafenib dose reductions and discontinuations due to adverse events are common and limit the drug's effectiveness. It is our hypothesis that a dose escalation strategy for sorafenib will improve the tolerability and allow a greater percentage of patients to remain on drug. The primary end-point of the study is the total accumulated and median daily dose of sorafenib delivered at month 2 and 4.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 120
• Est. completion date: March 2014
• Est. primary completion date: January 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 20 Years to 75 Years

Eligibility

Inclusion Criteria:

• HCC must be unresectable and/or metastatic

• CPT score <9 at the time of screening (that is all Child A and Child B with a score of 7 or 8)

• Age 20-75 years

• Signed informed consent

• EGD for variceal screening performed as per standard of care prophylaxis with non-selective beta-blockers or ligation

• ECOG Performance Status = 2.

• Adequate bone marrow, liver and renal function as assessed by the following:

1. Hemoglobin > 8.5 g/dl

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

3. Platelet count > 50,000/mm3

4. Total bilirubin < 3 mg/dl

5. ALT and AST ( < 5 x ULN)

6. Creatinine < 1.5 times ULN

• Women of childbearing potential must have a negative serum pregnancy test performed within 7 days prior to the start of treatment

• Women of childbearing potential and non-surgically sterile men must agree to use adequate contraception (barrier method of birth control) prior to study entry and for the duration of study participation. Men should use adequate birth control for at least three months after the last administration of sorafenib.

• Ability to understand and the willingness to sign a written informed consent. A signed informed consent must be obtained prior to any study specific procedures.

• INR< 2.3. Patients receiving anti-coagulation treatment with an agent such as warfarin or heparin may be allowed to participate. For patients on warfarin, the INR should be measured prior to initiation of sorafenib and monitored at least weekly, or as defined by the local standard of care, until INR is stable.

• Life expectancy of at least 24 weeks

Exclusion Criteria:

• Absence of informed consent

• Child-Pugh score >9

• ECOG PS >2

• Active alcohol dependence per PI discretion

• History of organ or bone marrow transplant

• Plans to relocate from the study center within the period of the trial

• Pregnancy or breastfeeding

• Contraindications to sorafenib

1. Cardiac disease: Congestive heart failure > class II NYHA. Patients must not have unstable angina (anginal symptoms at rest) or new onset angina (began within the last 3 months) or myocardial infarction within the past 6 months.

2. Cardiac ventricular arrhythmias requiring anti-arrhythmic therapy.

3. Known brain metastasis. Patients with neurological symptoms must undergo a CT scan/MRI of the brain to exclude brain metastasis.

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

• Known human immunodeficiency virus (HIV) infection

• Active clinically serious infection > CTCAE Grade 2.

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

• Bleeding

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

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

3. Evidence or history of bleeding diathesis or coagulopathy

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

• Major surgery, open biopsy or significant traumatic injury within 4 weeks prior to first study drug.

• Use of St. John's Wort or rifampin (rifampicin).

• Known or suspected allergy to sorafenib or any agent given in the course of this trial.

• Any condition that impairs patient's ability to swallow whole pills.

• Any malabsorption problem.

Study Design

Allocation: Randomized, Endpoint Classification: Safety Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Carcinoma
• Carcinoma, Hepatocellular
• Hepatocellular Carcinoma

Intervention

Drug:
• Sorafenib Standard Dosing Regimen
Sorafenib 400 mg twice daily until wk 24 or end of treatment
• Sorafenib Ramp-Up Regimen
200 mg daily, Day 0-Day 13 200 mg twice daily, Day 14-Day 20 600 mg daily, Day 21-Day 27 400 mg twice daily, Day 28 until end of treatment400 mg twice daily

Locations

Country	Name	City	State
United States	Henry Ford Health System	Detroit	Michigan
United States	University of Florida Hepatology	Gainesville	Florida
United States	University of Texas Health Science Center Houston	Houston	Texas
United States	Mayo Clinic	Jacksonville	Florida
United States	Loyola University Medical Center	Maywood	Illinois
United States	Florida Hospital Transplant Center	Orlando	Florida
United States	Drexel University College of Medicine	Philadelphia	Pennsylvania
United States	Brooke Army Medical Center	San Antonio	Texas
United States	Tampa General Hospital	Tampa	Florida

Sponsors (1)

Lead Sponsor	Collaborator
University of Florida

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Total (Cumulative) Dose Delivery of Sorafenib	This outcome measure table shows the median cumulative dose delivered to the subjects randomized to the standard dosing regimen (N=63) and ramp-up regimen (N=57) at 4 months of treatment.	4 months-1/12/2010-1/27/14	No
Primary	Cumulative Dose of Sorafenib	Table below shows mean cumulative dose of sorafenib for each of the dosing regimens.	11/22/2010-1/27/14	No
Secondary	Safety and Efficacy of Sorafenib Dosing Regimens	Safety of Sorafenib was assessed by the frequency and severity of adverse events according to NCI-CTCAE grading	Baseline-End of Treatment (11/22/2010-3/10/2014)	Yes
Secondary	Safety of Dosing Regimens as Assessed by the Frequency and Severity of Adverse Events According to National Cancer Institute- CTCAE	The total number of CTCAE (Common Terminology Criteria) grade 4 adverse events was collected for each dosing regimen beginning at baseline until Week 24/Early Termination Visit.	11/22/2010-3/10/2014	Yes
Secondary	Frequency and Severity of Adverse Events According to National Cancer Institute- CTCAE	The total number of CTCAE (Common Terminology Criteria) grade 5 adverse events was collected for each dosing regimen beginning at baseline through 6 months of treatment.	11/22/2010-3/10/2014	Yes
Secondary	Number of Subjects With Dose Interruptions		Baseline-End of Treatment (11/22/2010-3/10/2014)	Yes
Secondary	Number of Subjects With Dose Reductions		11/22/2010-3/10/2014	Yes