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A Phase II Trial of Bortezomib Plus Doxorubicin in Hepatocellular Carcinoma

Phase 2
18 Years
Not Enrolling
Adult Primary Hepatocellular Carcinoma, Advanced Adult Primary Liver Cancer, Localized Unresectable Adult Primary Liver Cancer, Recurrent Adult Primary Liver Cancer

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Trial Information

A Phase II Trial of Bortezomib Plus Doxorubicin in Hepatocellular Carcinoma


I. To evaluate the tumor response rate in patients with hepatocellular carcinoma (HCC).


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 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(Withdrawn as of 03-2007) IV.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 (Withdrawn as of 03-2007) V. To evaluate the effect of bortezomib on 26S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
NF-kB will be analyzed. (Withdrawn as of 03-2007)

OUTLINE: This is a multicenter study.

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.

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.

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 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 untreated malignancy other than HCC are not eligible

- 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 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 must not have had prior use of octreotide or tamoxifen as therapy for HCC

- 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

- Platelet count must be >= 100,000/mm^3 in absence of splenomegaly; platelet count
must be >= 75,000/mm^3 with splenomegaly

- ANC must be >= 1,500/mm^3 in absence of splenomegaly; ANC must be =< 1,000/mm^3 with

- Alkaline phosphate must be =< 5 x institutional ULN

- 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

- Patients must have no baseline peripheral neuropathy > grade 1

- Patients with known allergy to boron, mannitol or bortezomib are not eligible

- Women must not be pregnant or breast-feeding due to the uncertain effects of
bortezomib in the developing fetus and young infants

- 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 an underlying medical condition that precludes safe
participation in this clinical trial

- Patients must not have psychiatric illness or continued substance abuse that may
impair the ability to provide informed consent or prevent safe administration of

- Patients must not have known bleeding diathesis, INR > 1.5 or 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

- Patients with EF < 50% measured by ECHO or MUGA are not eligible

- Patients on verapamil who cannot be switched to an alternative medication are not
eligible (due to the interaction with doxorubicin)

Type of Study:


Study Design:

Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Objective response rate as assessed by the Response Evaluation Criteria in Solid Tumors (RECIST)

Outcome Time Frame:

Up to 3 years

Safety Issue:


Principal Investigator

Jordan Berlin

Investigator Role:

Principal Investigator

Investigator Affiliation:

Eastern Cooperative Oncology Group


United States: Food and Drug Administration

Study ID:




Start Date:

March 2004

Completion Date:

Related Keywords:

  • Adult Primary Hepatocellular Carcinoma
  • Advanced Adult Primary Liver Cancer
  • Localized Unresectable Adult Primary Liver Cancer
  • Recurrent Adult Primary Liver Cancer
  • Carcinoma
  • Liver Neoplasms
  • Carcinoma, Hepatocellular



Eastern Cooperative Oncology Group Boston, Massachusetts  02215