Doxorubicin and Bortezomib in Treating Patients With Liver Cancer

Study Overview
=================
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 (Withdrawn as of 03-2007) IV.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 (Withdrawn as of 03-2007) V. To evaluate the effect of bortezomib on 26S proteasome activity in peripheral white blood cells (WBC's) and patient serum.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 (Withdrawn as of 03-2007) OUTLINE: This is a multicenter study.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.

Official Title
-----------------
A Phase II Trial of Bortezomib Plus Doxorubicin in Hepatocellular Carcinoma

Conditions
-----------------
Adult Primary Hepatocellular Carcinoma, Advanced Adult Primary Liver Cancer, Localized Unresectable Adult Primary Liver Cancer, Recurrent Adult Primary Liver Cancer

Intervention / Treatment
-----------------
* Drug: doxorubicin
* Drug: bortezomib


Participation Criteria
=================
Eligibility Criteria
-----------------
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)

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (doxorubicin+bortezomib)<br>Patients receive doxorubicin IV over 5-15 minutes on days 1 and 8. Patients also receive bortezomib at a dose of 1.3 mg/m^2 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. | Drug: doxorubicin<br>* Given IV<br>* Other names: Adriamycin RDF;Drug: bortezomib<br>* Given IV<br>* Other names: VELCADE;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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.). | 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 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | assessed every 3 months for 2 years and then every 6 months for 1 year | 
| 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. | 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. | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
doxorubicin, doxorubicin hydrochloride, bortezomib, hepatocellular carcinoma