Adult Primary Hepatocellular Carcinoma, Advanced Adult Primary Liver Cancer, Localized Unresectable Adult Primary Liver Cancer, Recurrent Adult Primary Liver Cancer
Conditions
Keywords
doxorubicin, doxorubicin hydrochloride, bortezomib, hepatocellular carcinoma
Brief summary
This phase II trial is studying how well giving doxorubicin together with bortezomib works in treating patients with liver cancer. Drugs used in chemotherapy, such as doxorubicin, work in different ways to stop tumor cells from dividing so they stop growing or die. Bortezomib may stop the growth of tumor cells by blocking the enzymes necessary for their growth. Giving doxorubicin together with bortezomib may kill more tumor cells.
Detailed description
PRIMARY OBJECTIVES: I. To evaluate the tumor response rate in patients with hepatocellular carcinoma (HCC). SECONDARY OBJECTIVES: I. To determine other parameters of antitumor effect including time to tumor progression and overall survival in HCC patients treated with bortezomib and doxorubicin. II. To observe toxicity profile of bortezomib and doxorubicin in patients with hepatocellular carcinoma. III. To evaluate proteasome 20S inhibition in tumor tissue (including proteins such as p21, p27, p53, Bax and Bcl-2 which are affected by proteasome 26S) and compare them to clinical parameters using biopsy specimens obtained from patients with HCC treated with bortezomib. (Withdrawn as of 03-2007) IV. To measure phosphorylation of IkB in tumor tissue and compare to clinical parameters using biopsy specimens obtained from patients with HCC treated with bortezomib. (Withdrawn as of 03-2007) V. To evaluate the effect of bortezomib on 26S proteasome activity in peripheral white blood cells (WBC's) and patient serum. Direct measurement of 26S proteasome activity as well as proteins affected by proteasome 26S and Nuclear factor kappa-B (NF-kB) will be analyzed. (Withdrawn as of 03-2007) OUTLINE: This is a multicenter study. Patients receive doxorubicin intravenously (IV) over 5-15 minutes on days 1 and 8. Patients also receive bortezomib IV over 3-5 seconds on days 1, 4, 8, and 11. Treatment repeats every 21 days for up to 12 courses in the absence of disease progression or unacceptable toxicity. Patients with no disease progression may continue to receive bortezomib alone in the absence of disease progression or unacceptable toxicity. Patients are followed every 3 months for 2 years and then every 6 months for 1 year. PROJECTED ACCRUAL: A total of 40 patients will be accrued for this study within 13 months.
Interventions
DRUGdoxorubicin
Given IV
DRUGbortezomib
Given IV
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients must have microscopically confirmed hepatocellular carcinoma not amenable to curative resection; if patients have an isolated lesion in one lobe of the liver, a liver surgeon should determine resectability; central review is not required * Patients must have measurable disease as determined by Response Evaluation Criteria In Solid Tumors (RECIST) criteria, amenable to biopsy; patients are not mandated to allow biopsy, even though it is an important aspect of this clinical trial * Patients with history of malignancy treated within the past 5 years are not eligible; history of carcinoma-in-situ of cervix, squamous cell cancer of skin, basal cell cancer of skin, previously treated are allowed; others are excluded as recurrence of disease may confuse response rate and/or survival endpoints * Patients must have Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 * Patients must not have had prior systemic chemotherapy for HCC; patients on antineoplastics for non-malignant diseases, such as methotrexate for rheumatoid arthritis, are allowed, providing patients have been off these agents for at least 4 weeks and all related toxicities have resolved to baseline * Patients may have had prior embolization without chemotherapy; patients who have had chemoembolization are not eligible; patients may have had radiofrequency (RF) ablation, cryosurgery or ethanol injection; patients must have documented progression with the involved lesion or at least one previously untreated lesion amenable to biopsy * Platelet count must be \>= 100,000/mm\^3 in absence of splenomegaly; platelet count must be \>= 75,000/mm\^3 with splenomegaly * Absolute neutrophil count (ANC) must be \>= 1,500/mm\^3 in absence of splenomegaly; ANC must be =\< 1,000/mm\^3 with splenomegaly * Alkaline phosphate (ALT) must be =\< 5 x institutional upper limit of normal (ULN) * Aspartate aminotransferase (AST) must be =\< 5 x institutional ULN * Bilirubin must be =\< 2 mg/dl * Patients may not exhibit Child Pugh scale grade C cirrhosis * Serum creatinine=\< 2.0 mg/dl * All females of childbearing potential must have a blood test or urine study within 2 weeks prior to registration to rule out pregnancy * Women of childbearing potential and sexually active males are strongly advised to use an accepted and effective method of contraception * Patients must not have known bleeding diathesis, international normalized ratio (INR) \> 1.5 or Partial thromboplastin time (PTT) \> 1.5 x institutional ULN (required due to biopsy portion of study); use of vitamin K or fresh frozen plasma to correct values just prior to biopsy or enrollment is not allowed are not eligible
Exclusion criteria
* Patients have baseline peripheral neuropathy \> grade 1 * Patients with history of untreated malignancy other than HCC * Patients have had prior use of octreotide or tamoxifen as therapy for HCC * Patients with known allergy to boron, mannitol or bortezomib * Women are pregnant or breast-feeding (due to the uncertain effects of bortezomib in the developing fetus and young infants) * Patients have an underlying medical condition that precludes safe participation in this clinical trial * Patients have psychiatric illness or continued substance abuse that may impair the ability to provide informed consent or prevent safe administration of bortezomib * Patients with ejection fraction (EF) \< 50% measured by Echocardiography (ECHO) or Multiple gated acquisition (MUGA) * Patients on verapamil who cannot be switched to an alternative medication (due to the interaction with doxorubicin)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate Measured by Response Evaluation Criteria In Solid Tumors (RECIST) | assessed every 3 cycles while on treatment. After discontinuing treatment, assessed every 3 months for 2 years and then every 6 months for 1 year | Tumor response was measured by Response Evaluation Criteria In Solid Tumors (RECIST) v1.0. Objective response rate included complete response (disappearance of all tumor lesions) and partial response (At least a 30% decrease in the sum of the longest diameters of target lesions, taking as reference the baseline sum longest diameter.). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | assessed every 3 months for 2 years and then every 6 months for 1 year | Overall survival is defined as time from registration to death from any cause. Patients alive were censored at follow up. Analysis was conducted in the 38 eligible and treated patients. |
| Progression Free Survival | assessed every 3 cycles while on treatment. After discontinuing treatment, assessed every 3 months for 2 years and then every 6 months for 1 year. | Time from registration to disease progression or death, whichever occurred earlier. Patients alive and progression-free were censored at last follow up. 36 eligible and treated patients were included in the analysis. The other 2 eligible and treated patients had no disease status information. |
Countries
United States
Participant flow
Recruitment details
This study was activated on March 19, 2004 and terminated on February 12,2007 after meeting its accrual goal of 40 patients. The final accrual of the study was 42 patients, enrolled through 4 ECOG member institutions.
Participants by arm
| Arm | Count |
|---|---|
| Treatment (Doxorubicin+Bortezomib) Patients receive doxorubicin IV over 5-15 minutes on days 1 and 8. Patients also receive bortezomib IV over 3-5 seconds on days 1, 4, 8, and 11. Treatment repeats every 21 days for up to 12 courses in the absence of disease progression or unacceptable toxicity. Patients with no disease progression may continue to receive bortezomib alone in the absence of disease progression or unacceptable toxicity.
doxorubicin: Given IV
bortezomib: Given IV | 38 |
| Total | 38 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 9 |
| Overall Study | Death | 4 |
| Overall Study | ineligible or not receiving treatment | 4 |
| Overall Study | Lack of Efficacy | 19 |
| Overall Study | Other | 2 |
| Overall Study | Withdrawal by Subject | 4 |
Baseline characteristics
| Characteristic | Treatment (Doxorubicin+Bortezomib) |
|---|---|
| Age, Continuous | 57.1 years STANDARD_DEVIATION 11.1 |
| Region of Enrollment United States | 38 participants |
| Sex: Female, Male Female | 11 Participants |
| Sex: Female, Male Male | 27 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 36 / 39 |
| serious Total, serious adverse events | 28 / 39 |
Outcome results
Primary
Objective Response Rate Measured by Response Evaluation Criteria In Solid Tumors (RECIST)
Tumor response was measured by Response Evaluation Criteria In Solid Tumors (RECIST) v1.0. Objective response rate included complete response (disappearance of all tumor lesions) and partial response (At least a 30% decrease in the sum of the longest diameters of target lesions, taking as reference the baseline sum longest diameter.).
Time frame: assessed every 3 cycles while on treatment. After discontinuing treatment, assessed every 3 months for 2 years and then every 6 months for 1 year
Population: eligible and treated patients
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment (Doxorubicin+Bortezomib) | Objective Response Rate Measured by Response Evaluation Criteria In Solid Tumors (RECIST) | 3 percentage of participants |
Secondary
Overall Survival
Overall survival is defined as time from registration to death from any cause. Patients alive were censored at follow up. Analysis was conducted in the 38 eligible and treated patients.
Time frame: assessed every 3 months for 2 years and then every 6 months for 1 year
Population: eligible and treated
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (Doxorubicin+Bortezomib) | Overall Survival | 6.4 months |
Secondary
Progression Free Survival
Time from registration to disease progression or death, whichever occurred earlier. Patients alive and progression-free were censored at last follow up. 36 eligible and treated patients were included in the analysis. The other 2 eligible and treated patients had no disease status information.
Time frame: assessed every 3 cycles while on treatment. After discontinuing treatment, assessed every 3 months for 2 years and then every 6 months for 1 year.
Population: eligible and treated patients with progression status information
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (Doxorubicin+Bortezomib) | Progression Free Survival | 2.2 months |