Adenocarcinoma of the Extrahepatic Bile Duct, Adenocarcinoma of the Gallbladder, Advanced Adult Primary Liver Cancer, Gastrointestinal Cancer, Localized Unresectable Adult Primary Liver Cancer, Recurrent Adult Primary Liver Cancer, Recurrent Extrahepatic Bile Duct Cancer, Recurrent Gallbladder Cancer, Unresectable Extrahepatic Bile Duct Cancer, Unresectable Gallbladder Cancer
Conditions
Brief summary
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.
Detailed description
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.
Interventions
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
* 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: * Locally advanced or metastatic disease * 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: * ECOG 0-2 * Life expectancy: * More than 12 weeks * 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate | Up to 1 year | Objective Response Rate (ORR) was determined by best response on radiologic assessment (computed tomography or magnetic resonance imaging) according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.0. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Disease Progression | Up to 1 year | Time from initiation of therapy to first progressive disease. |
| Overall Survival | Up to 1 year | The time from initiation of therapy to death or last follow-up. |
| Correlation of the Degree of Proteasome Inhibition in Peripheral Blood With the Degree of Proteasome Inhibition in Tumor Specimens | Once in the screening period (within 14 days of starting treatment) | Proteasome inhibition compared between tumor specimens and peripheral blood. Sufficient tissue samples are required for this analysis. |
| Correlation of Phenotypic Expression of NF-kB, p53, and Other Molecular Markers in Biliary Washings and Tumor Biopsies With Clinical Outcomes | Once in the screening period (within 14 days of starting treatment) | Evaluation of clinical outcomes with expression of molecular markers specified and others. Sufficient amount of biliary washings and tumor biopsies needed for analysis. |
| Correlation of Treatment With Changes in Phenotypic Expression of Molecular Markers | Duration of study treatment | Phenotypic expression of molecular markers before and after study treatment |
Countries
United States
Participant flow
Recruitment details
Participants were recruited through physician referral at: Fox Chase Cancer Center. The trial was discontinued early due to no confirmed partial responses.
Pre-assignment details
Twenty individuals were enrolled in this study over a four year period.
Participants by arm
| Arm | Count |
|---|---|
| Arm I Patients receive bortezomib IV over 3-5 seconds on days 1, 4, 8, and 11. | 20 |
| Total | 20 |
Baseline characteristics
| Characteristic | Arm I |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 7 Participants |
| Age, Categorical Between 18 and 65 years | 13 Participants |
| Eastern Cooperative Oncology Group Performance Status Grade 0 | 7 participants |
| Eastern Cooperative Oncology Group Performance Status Grade 1 | 13 participants |
| Previous Surgery No | 15 participants |
| Previous Surgery Yes: Cholecystectomy | 4 participants |
| Previous Surgery Yes: Liver section | 1 participants |
| Previous Treatment Chemotherapy only | 4 participants |
| Previous Treatment Chemotherapy/radiation therapy | 5 participants |
| Previous Treatment None | 10 participants |
| Previous Treatment Other | 1 participants |
| Region of Enrollment United States | 20 participants |
| Sex: Female, Male Female | 9 Participants |
| Sex: Female, Male Male | 11 Participants |
| Site of Metastases Liver | 14 participants |
| Site of Metastases Lung | 5 participants |
| Site of Metastases Lymph nodes | 7 participants |
| Site of Metastases Other | 2 participants |
| Site of Primary Tumor Gallbladder | 6 participants |
| Site of Primary Tumor Intrahepatic or extrahepatic cholangiocarcinoma | 14 participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 20 / 20 |
| serious Total, serious adverse events | 4 / 20 |
Outcome results
Primary
Objective Response Rate
Objective Response Rate (ORR) was determined by best response on radiologic assessment (computed tomography or magnetic resonance imaging) according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.0.
Time frame: Up to 1 year
Population: Per protocol
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm I | Objective Response Rate | Stable Disease | 10 Participants |
| Arm I | Objective Response Rate | Partial Response (Unconfirmed) | 1 Participants |
| Arm I | Objective Response Rate | Progressive Disease | 8 Participants |
| Arm I | Objective Response Rate | Withdrew Consent Before Evaluation | 1 Participants |
Secondary
Correlation of Phenotypic Expression of NF-kB, p53, and Other Molecular Markers in Biliary Washings and Tumor Biopsies With Clinical Outcomes
Evaluation of clinical outcomes with expression of molecular markers specified and others. Sufficient amount of biliary washings and tumor biopsies needed for analysis.
Time frame: Once in the screening period (within 14 days of starting treatment)
Population: Insufficient amount of patient samples collected for analysis
Secondary
Correlation of the Degree of Proteasome Inhibition in Peripheral Blood With the Degree of Proteasome Inhibition in Tumor Specimens
Proteasome inhibition compared between tumor specimens and peripheral blood. Sufficient tissue samples are required for this analysis.
Time frame: Once in the screening period (within 14 days of starting treatment)
Population: Insufficient amount of patient samples collected for analysis
Secondary
Correlation of Treatment With Changes in Phenotypic Expression of Molecular Markers
Phenotypic expression of molecular markers before and after study treatment
Time frame: Duration of study treatment
Population: Insufficient amount of patient samples collected for analysis
Secondary
Overall Survival
The time from initiation of therapy to death or last follow-up.
Time frame: Up to 1 year
Population: 1 patient who withdrew consent prior to the first disease evaluation was excluded.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm I | Overall Survival | 9 months |
Secondary
Time to Disease Progression
Time from initiation of therapy to first progressive disease.
Time frame: Up to 1 year
Population: 1 patient who withdrew consent prior to the first disease evaluation was excluded.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm I | Time to Disease Progression | 5.8 months |
Post Hoc
1-year Survival
The time from initiation of initiation of therapy to 1 year beyond.
Time frame: 1 year
Population: 1 patient who withdrew consent prior to the first disease evaluation was excluded.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm I | 1-year Survival | 38 percentage of patients |
Post Hoc
6-Month and 1-Year Survival for Patients Who Derived Clinical Benefit From Study Treatment
The time from initiation of therapy to 6 months beyond. Only patients who derived benefit from study treatment (stable disease, partial response, or complete response was best response) were included.
Time frame: Up to 1 year
Population: Patients who derived benefit from study treatment (stable disease, partial response, or complete response was best response)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm I | 6-Month and 1-Year Survival for Patients Who Derived Clinical Benefit From Study Treatment | 6-Month Survival | 90 percentage of patients |
| Arm I | 6-Month and 1-Year Survival for Patients Who Derived Clinical Benefit From Study Treatment | 1-Year Survival | 69 percentage of patients |
Post Hoc
6-Month and 1-Year Survival: Patients Who Did Not Derive Clinical Benefit From Study Treatment
The time from initiation of therapy to 6 months beyond. Only patients who did not derive clinical benefit from study treatment (progressive disease or unconfirmed partial response was best response) were included.
Time frame: Up to 1 year
Population: Patients who did not derive clinical benefit from study treatment (progressive disease was best response) only.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm I | 6-Month and 1-Year Survival: Patients Who Did Not Derive Clinical Benefit From Study Treatment | 6-Month Survival | 44 percentage of patients |
| Arm I | 6-Month and 1-Year Survival: Patients Who Did Not Derive Clinical Benefit From Study Treatment | 1-Year Survival | 11 percentage of patients |
Post Hoc
6-Month Survival
The time from initiation of therapy to 6 months beyond.
Time frame: 6 months
Population: 1 patient who withdrew consent prior to the first disease evaluation was excluded.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm I | 6-Month Survival | 70 percentage of patients |
Post Hoc
Clinical Benefit Rate
Best response to study treatment was confirmed complete response, partial response, or stable disease. Unconfirmed partial response was not included. The outcome measure data table is stratified into patients who a) received prior therapy b) did not receive prior therapy.
Time frame: Up to 1 year
Population: 1 patient who withdrew consent prior to the first disease evaluation was excluded.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm I | Clinical Benefit Rate | Patients who received prior therapy | 21 percentage of patients |
| Arm I | Clinical Benefit Rate | Patients who did not receive prior therapy | 32 percentage of patients |