Phase II and Pharmacodynamic Study of PS-341 in Patients With Unresectable or Metastatic Adenocarcinoma of the Bile Duct or Gallbladder
Phase II and Pharmacodynamic Study of PS-341 in Patients With Unresectable or Metastatic Adenocarcinoma of the Bile Duct or Gallbladder
This phase II trial is studying how well bortezomib works as first-line systemic therapy in treating patients with unresectable locally advanced or metastatic adenocarcinoma (cancer) of the bile duct or gallbladder. Bortezomib may stop the growth of tumor cells by blocking the enzymes necessary for their growth.
PRIMARY OBJECTIVES:
I. Determine the objective response rate in patients with unresectable locally advanced or metastatic adenocarcinoma of the bile duct or gallbladder treated with bortezomib.
SECONDARY OBJECTIVES:
I. Determine the time to disease progression in patients treated with this drug.
II. Determine the overall survival of patients treated with this drug. III. Correlate the degree of proteasome inhibition in peripheral blood with degree of proteasome inhibition in tumor specimens of patients treated with this drug.
IV. Correlate phenotypic expression of NF-kB, p53, and other molecular markers in biliary washings and tumor biopsies with clinical outcomes in patients treated with this drug.
V. Correlate treatment with this drug with changes in phenotypic expression of molecular markers in these patients.
OUTLINE: This is an open-label, multicenter study.
Patients receive bortezomib IV over 3-5 seconds on days 1, 4, 8, and 11. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Patients are followed every 3 months for 1 year.
Inclusion Criteria:
Absolute neutrophil count >= 1,500/mm3
No psychiatric illness or social situation that would preclude study compliance
Chemotherapy administered solely as a radiosensitizer or as adjuvant therapy and investigational or targeted therapies (i.e., inhibitors of the epidermal growth factor receptor) will not count toward the maximum of 2 prior regimens allowed
Histologically or cytologically confirmed adenocarcinoma of the intrahepatic or extrahepatic bile duct or gallbladder:
At least 1 unidimensionally measurable lesion >=20 mm by conventional techniques OR >= 10 mm by spiral CT scan
Not amenable to curative surgical resection
No known brain metastases
Performance status:
Life expectancy:
Platelet count >= 100,000/mm3
WBC >= 3,000/mm3
AST and ALT ≤ 2.5 times upper limit of normal (ULN) [Note: Biliary shunting or stenting allowed to achieve the required bilirubin and transaminase levels]
Bilirubin ≤ 1.5 times ULN [Note: Biliary shunting or stenting allowed to achieve the required bilirubin and transaminase levels]
Creatinine within ULN OR Creatinine clearance >= 60 mL/min
No symptomatic congestive heart failure
No unstable angina pectoris
No symptomatic cardiac arrhythmia within the past 4 weeks
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective contraception
No underlying neuropathy >= grade 2
No history of allergic reaction to boron, mannitol, or bortezomib
No active or ongoing infection
No concurrent uncontrolled illness
No medical or psychiatric condition that would preclude study participation
No prophylactic granulocyte or platelet growth factors (filgrastim [G-CSF] or sargramostim [GM-CSF])
Prior chemotherapy as a radiosensitizer (e.g., fluorouracil or gemcitabine) with radiotherapy is allowed as adjuvant therapy after resection for locally advanced disease provided there is evidence of disease progression
No more than 2 prior chemotherapy regimens for locally advanced or metastatic disease
No concurrent combination antiretroviral therapy for HIV-positive patients
No other concurrent anticancer agents or therapies
No other concurrent investigational agents