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Bevacizumab and Sorafenib as First-Line Therapy in Treating Patients With Locally Advanced or Metastatic Liver Cancer

Phase I/II Randomized Trial of Sorafenib and Bevacizumab as First-Line Therapy in Patients With Locally Advanced or Metastatic Hepatocellular Carcinoma

Status
Completed
Phases
Phase 1Phase 2
Study type
Interventional
Source
ClinicalTrials.gov
Registry ID
NCT00867321
Enrollment
24
Registered
2009-03-23
Start date
2009-04-30
Completion date
2013-05-31
Last updated
2022-04-19

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Liver Cancer

Keywords

adult primary hepatocellular carcinoma, advanced adult primary liver cancer, localized unresectable adult primary liver cancer, recurrent adult primary liver cancer

Brief summary

RATIONALE: Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Sorafenib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Bevacizumab and sorafenib may also stop the growth of liver cancer by blocking blood flow to the tumor. PURPOSE: This randomized phase I/II trial is studying the best dose of bevacizumab when given together with sorafenib as first-line therapy in treating patients with locally advanced or metastatic liver cancer.(Phase I closed to accrual as of 11/03/2010)

Detailed description

OBJECTIVES: Primary * Determine the maximum tolerated dose of bevacizumab in combination with sorafenib tosylate in patients with locally advanced or metastatic hepatocellular carcinoma. (Phase I closed to accrual as of 11/03/2010) * Determine time to progression in these patients. (Phase II) Secondary * Determine the safety of this regimen in these patients. (Phase I closed to accrual as of 11/03/2010) * Assess tolerability of this regimen in these patients. (Phase I closed to accrual as of 11/03/2010) * Determine overall survival of these patients. (Phase II) * Determine tumor response (at 6 months) in patients treated with this regimen. (Phase II) * Determine progression-free survival of these patients. (Phase II) * Determine response rate in patients treated with this regimen. (Phase II) * Assess the occurrence of adverse events in these patients. (Phase II) Tertiary * Determine the relationship between tumor biomarkers and circulating biomarkers of vascular response and clinical outcome in patients treated with this regimen. OUTLINE: This is a phase I, dose escalation study followed by a randomized phase II study. * Phase I (closed to accrual as of 11/03/2010): Patients receive oral sorafenib tosylate twice daily on days 1-28 and bevacizumab IV on days 1 and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. * Phase II: Patients are stratified according to gender (female vs male), ECOG performance status (0 vs 1), and Child-Pugh class (A vs B7). Patients are randomized to 1 of 2 treatment arms. * Arm I: Patients receive oral sorafenib tosylate on days 1-28 twice daily and bevacizumab IV on days 1 and 15. * Arm II: Patients receive oral sorafenib tosylate twice daily on days 1-28. In both arms, courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Blood samples are collected periodically for analysis of circulating endothelial cells and circulating endothelial progenitor cells and angiogenic proteins in plasma by ELISA. After completion of study treatment, patients are followed for 3 years.

Interventions

BIOLOGICALbevacizumab

Given IV

DRUGsorafenib tosylate

Given orally

Sponsors

National Cancer Institute (NCI)
CollaboratorNIH
Alliance for Clinical Trials in Oncology
Lead SponsorOTHER

Study design

Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE

Eligibility

Sex/Gender
ALL
Age
18 Years to 120 Years
Healthy volunteers
No

Inclusion criteria

DISEASE CHARACTERISTICS: * Histologically or cytologically confirmed hepatocellular carcinoma * Locally advanced or metastatic disease that is not amenable to treatment with surgery or to orthotopic liver transplant * Child Pugh class A or B7 disease * Measurable disease * No mixed cholangiocarcinoma/hepatocellular carcinoma * No current or previously resected brain metastases PATIENT CHARACTERISTICS: * ECOG performance status 0-1 * Life expectancy ≥ 3 months * ANC ≥ 1,200/mm³ * Platelet count ≥ 75,000/mm³ * Hemoglobin ≥ 9.0 g/dL * Total bilirubin ≤ 1.5 times upper limit of normal (ULN) * AST ≤ 5 times ULN * Alkaline phosphatase ≤ 5 times ULN * Urine protein ≤ 1+ by urine protein:creatinine ratio OR 24-hour urine protein \< 1 g * QTc interval ≤ 500 msec on baseline EKG * Not pregnant or nursing * Negative pregnancy test * Fertile patients must use effective contraception during and for ≥ 2 weeks after sorafenib tosylate and 6 months after bevacizumab * None of the following risk factors for decreased LVEF: * Prior treatment with anthracyclines * History of myocardial infarction within the past 12 months * No uncontrolled hypertension (defined as systolic blood pressure \[BP\] \> 150 mm Hg or diastolic BP \> 100 mm Hg) despite optimal medical management * No New York Heart Association class III-IV congestive heart failure * No cardiac ventricular arrhythmias requiring antiarrhythmic therapy * No history of hypertensive crisis or hypertensive encephalopathy * No cardiac ventricular arrhythmia requiring anti-arrhythmic therapy within the past 6 months * None of the following within the past 6 months: * Transient ischemic attack * Cerebrovascular accident * Unstable angina or angina * Clinically significant peripheral artery disease (i.e., claudication in less than one block) or any other arterial thrombotic event * Abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess * Significant vascular disease (e.g., aortic aneurysm, aortic dissection) or recent peripheral arterial thrombosis * No active or recent history of hemoptysis (≥ ½ teaspoon of bright red blood per episode) within the past 30 days * No evidence of bleeding diathesis (greater than normal risk of bleeding) or coagulopathy (in the absence of therapeutic anticoagulation) * No significant traumatic injury within the past 4 weeks * No serious or non-healing wound, ulcer, or bone fracture * No uncontrolled intercurrent illness, including, but not limited to, ongoing or active infection, or psychiatric illness/social situations that would limit compliance with study requirements * No other active malignancy within the past 3 years, except nonmelanotic skin cancer or carcinoma in situ of the cervix * No comorbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens * No history of allergic reactions attributed to compounds of similar chemical or biologic composition to bevacizumab or sorafenib tosylate PRIOR CONCURRENT THERAPY: * No prior systemic chemotherapy regimens for hepatocellular carcinoma * No prior external beam radiation to the primary site * No prior central thoracic radiation therapy (RT), including RT to the heart * No prior radiation (if given for another malignancy) to ≥ 25% of the bone marrow * At least 6 weeks since prior chemoembolization, radioembolization, radiofrequency ablation, or other local ablative therapies * More than 4 weeks since prior biologic, hormonal, or immune therapy * More than 4 weeks since prior and no concurrent major surgical procedure or open biopsy * More than 7 days since prior core biopsy or other minor surgical procedure (placement of a vascular access device allowed) * No concurrent investigational agent which would be considered as a treatment for the primary neoplasm * No concurrent anticoagulants, except low-dose warfarin or heparin for deep venous thrombosis prophylaxis * No other concurrent treatment for prior malignancy (other than hormonal therapy)

Design outcomes

Primary

MeasureTime frameDescription
Maximum Tolerated Dose (Phase I)From baseline up to 3 years post treatmentMTD is defined as the dose level below the lowest dose that induces dose limiting toxicity in at least one-third of patients (at least 2 of a maximum of 6 new patients). If dose level (-1) is not tolerable, but dose (-3) or (-2) is below or at MTD, testing of alternate dose levels (-2a, -3a, -3b) will occur as outlined in the table. The number of dose limiting toxicities will be reported here.
Time to Progression (TTP) (Phase II)From baseline up to 3 years post treatmentTime to progression is defined to be the length of time from study registration to a) date of disease progression as defined by section 11.0, or b) last follow-up. If a patient dies without documentation of disease progression, the patient will be considered to have had a tumor progression at the time of death unless there is sufficient documented evidence to conclude no progression occurred prior to death. Kaplan-Meier survival curves will be used to estimate the distribution of TTP.

Secondary

MeasureTime frameDescription
Overall SurvivalUp to 3 years post treatmentOverall survival (OS) is defined as the length of time from date of registration to a) date of death due to any cause or b) last follow-up. Kaplan-Meier survival curves will be used to estimate the distribution of OS.
Tumor Response at 6 Months6 monthsTumor response (at 6 months) is defined as the number of responses (complete or partial response per Section 11) over the number of eligible patients observed for at least 6 months. Tumor response will be evaluated using simple estimates of proportions.

Countries

United States

Participant flow

Participants by arm

ArmCount
Arm I (Phase II)
Patients receive oral sorafenib tosylate on days 1-28 twice daily and bevacizumab IV on days 1 and 15.
4
Arm II (Phase II)
Patients receive oral sorafenib tosylate twice daily on days 1-28.
3
All Phase I Patients
This includes all patients who participated in the phase I dose escalation portion of the trial.
17
Total24

Baseline characteristics

CharacteristicArm I (Phase II)Arm II (Phase II)All Phase I PatientsTotal
Age, Continuous58.5 years55 years66 years60.5 years
Region of Enrollment
United States
4 participants3 participants17 participants24 participants
Sex: Female, Male
Female
1 Participants1 Participants3 Participants5 Participants
Sex: Female, Male
Male
3 Participants2 Participants14 Participants19 Participants

Adverse events

Event typeEG000
affected / at risk
EG001
affected / at risk
EG002
affected / at risk
EG003
affected / at risk
EG004
affected / at risk
EG005
affected / at risk
deaths
Total, all-cause mortality
— / —— / —— / —— / —— / —— / —
other
Total, other adverse events
3 / 36 / 65 / 53 / 34 / 43 / 3
serious
Total, serious adverse events
0 / 31 / 60 / 50 / 30 / 40 / 3

Outcome results

Primary

Maximum Tolerated Dose (Phase I)

MTD is defined as the dose level below the lowest dose that induces dose limiting toxicity in at least one-third of patients (at least 2 of a maximum of 6 new patients). If dose level (-1) is not tolerable, but dose (-3) or (-2) is below or at MTD, testing of alternate dose levels (-2a, -3a, -3b) will occur as outlined in the table. The number of dose limiting toxicities will be reported here.

Time frame: From baseline up to 3 years post treatment

Population: All eligible patients were treated and analyzed.

ArmMeasureValue (COUNT_OF_PARTICIPANTS)
Phase I: Dose Level 0Maximum Tolerated Dose (Phase I)2 Participants
Phase I: Dose Level -1Maximum Tolerated Dose (Phase I)3 Participants
Phase I: Dose Level -2a (Maximum Tolerated Dose)Maximum Tolerated Dose (Phase I)0 Participants
Phase I: Dose Level -2Maximum Tolerated Dose (Phase I)0 Participants
Primary

Time to Progression (TTP) (Phase II)

Time to progression is defined to be the length of time from study registration to a) date of disease progression as defined by section 11.0, or b) last follow-up. If a patient dies without documentation of disease progression, the patient will be considered to have had a tumor progression at the time of death unless there is sufficient documented evidence to conclude no progression occurred prior to death. Kaplan-Meier survival curves will be used to estimate the distribution of TTP.

Time frame: From baseline up to 3 years post treatment

Population: 6 of 7 patients have had at least one post-baseline assessment of disease and were used for this endpoint.

ArmMeasureValue (MEDIAN)
Phase I: Dose Level 0Time to Progression (TTP) (Phase II)8.6 years
Phase I: Dose Level -1Time to Progression (TTP) (Phase II)13.3 years
Secondary

Overall Survival

Overall survival (OS) is defined as the length of time from date of registration to a) date of death due to any cause or b) last follow-up. Kaplan-Meier survival curves will be used to estimate the distribution of OS.

Time frame: Up to 3 years post treatment

ArmMeasureValue (MEDIAN)
Phase I: Dose Level 0Overall Survival13.3 Months
Secondary

Tumor Response at 6 Months

Tumor response (at 6 months) is defined as the number of responses (complete or partial response per Section 11) over the number of eligible patients observed for at least 6 months. Tumor response will be evaluated using simple estimates of proportions.

Time frame: 6 months

Population: No patients were analyzed for this endpoint because data was not collected for it

Source: ClinicalTrials.gov · Data processed: Mar 10, 2026