Bortezomib and Paclitaxel in Treating Patients With Locally Advanced or Metastatic Solid Tumors

Study Overview
=================
Brief Summary
-----------------
Phase I trial to study the effectiveness of combining bortezomib with paclitaxel in treating patients who have advanced or metastatic solid tumors. Bortezomib may stop the growth of cancer cells by blocking the enzymes necessary for their growth. Drugs used in chemotherapy work in different ways to stop tumor cells from dividing so they stop growing or die. Combining bortezomib with paclitaxel may kill more tumor cells.

Detailed Description
-----------------
PRIMARY OBJECTIVES: I. Determine the maximum tolerated dose of bortezomib when given in combination with paclitaxel in patients with locally advanced or metastatic solid tumors. OUTLINE: This is a multicenter, dose-escalation study of bortezomib. Patients receive bortezomib IV on days 2 and 9 and paclitaxel IV over 1 hour on days 1 and 8. For the first course only, patients do not receive paclitaxel on day 1. Courses repeat every 3 weeks in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of bortezomib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity or greater than 80% 20S proteasome inhibition. Once the MTD is determined, an additional 6-9 patients are accrued and treated at that dose. Patients are followed at 21 days. PROJECTED ACCRUAL: A total of 45 patients will be accrued for this study.

Official Title
-----------------
A Phase I Study of PS-341 in Combination With Paclitaxel in Metastatic Solid Tumors

Conditions
-----------------
Unspecified Adult Solid Tumor, Protocol Specific

Intervention / Treatment
-----------------
* Drug: bortezomib
* Drug: paclitaxel
* Other: laboratory biomarker analysis


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histologically or cytologically confirmed locally advanced or metastatic solid tumor for which there is no curative treatment No known brain metastases Performance status - ECOG 0-2 Performance status - Karnofsky 60-100% WBC at least 3,000/mm^3 Absolute neutrophil count at least 1,500/mm^3 Platelet count at least 100,000/mm^3 Bilirubin normal AST/ALT no greater than 2.5 times upper limit of normal (ULN) Creatinine no greater than ULN Left ventricular function at least lower limit of normal if received prior doxorubicin No grade II or IV tilt-table test No symptomatic congestive heart failure No unstable angina pectoris No cardiac arrhythmia No thrombotic event within the past 6 months Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception No prior allergic reaction to compounds of similar chemical or biological composition to study drugs No other concurrent uncontrolled illness No ongoing or active infection No psychiatric illness or social situation that would preclude study compliance At least 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin) Prior paclitaxel allowed At least 2 weeks since prior hormonal therapy No concurrent steroids or hormonal therapy except steroids to prevent hypersensitivity reactions to paclitaxel or hormonal therapy for non-disease-related conditions (e.g., insulin for diabetes) At least 4 weeks since prior radiotherapy At least 4 weeks since prior surgery Recovered from prior therapy No other concurrent investigational agents No concurrent combination anti-retroviral therapy for HIV-positive patients No concurrent anticoagulation therapy Concurrent pamidronate or zoledronate allowed for treatment of hypercalcemia or for palliation of skeletal metastases

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 (bortezomib, paclitaxel)<br>Patients receive bortezomib IV on days 2 and 9 and paclitaxel IV over 1 hour on days 1 and 8. For the first course only, patients do not receive paclitaxel on day 1. Courses repeat every 3 weeks in the absence of disease progression or unacceptable toxicity. | Drug: bortezomib<br>* Given IV<br>* Other names: VELCADE;Drug: paclitaxel<br>* Given IV<br>* Other names: Taxol;Other: laboratory biomarker analysis<br>* Correlative studies<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose-limiting toxicity (DLT) defined as Common Terminology Criteria (CTC) version 2.0 grade 3 or greater non-hematologic toxicity or grade 4 hematologic toxicity with the exception of asymptomatic neutropenia [ANC < 500] |  | 21 days | 
| Maximum-tolerated dose (MTD) based on the incidence of DLT |  | 21 days | 
| Dose of PS-341 that results in not more than 70% to 80% 20S proteasome inhibition [20S-PI] in combination with a paclitaxel |  | At baseline and at 1 hour of weeks 1, 2 and 4 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response according to the Response Evaluation Criteria in Solid Tumors (RECIST) Committee | Reported descriptively using all eligible patients and evaluable patients separately. Response rates will include 95% confidence limits. | Up to 21 days | 
| Change in the level of p27 and Bax proteins in peripheral blood mononuclear cells | Descriptive data will be computed and compared using analysis of variance and non-parametric rank equivalents for continuous data and chi-square or Fisher's exact test for discrete data. | From baseline to 6 hours of day 1 (week 1) and day 2 (week 2) | 
| Change in plasma levels of TNF, IL-1, IL-6, and C-reactive protein | Descriptive data will be computed and compared using analysis of variance and non-parametric rank equivalents for continuous data and chi-square or Fisher's exact test for discrete data. | From baseline to 6 hours of day 2 (weeks 1 and 2) | 
| Change in NF-kb biomarkers TRAP I and c-IAP-2 in tumor tissue blocks | Descriptive data will be computed and compared using analysis of variance and non-parametric rank equivalents for continuous data and chi-square or Fisher's exact test for discrete data. | From baseline to 6 hours of day 2 (weeks 1 and 2) | 
| Change in phosphorylation of c-Jun and JNK in tumor tissue blocks | Descriptive data will be computed and compared using analysis of variance and non-parametric rank equivalents for continuous data and chi-square or Fisher's exact test for discrete data. | From baseline to 6 hours of day 2 (weeks 1 and 2) |