Bortezomib and Combination Chemotherapy in Treating Patients With Advanced Solid Tumors

Study Overview
=================
Brief Summary
-----------------
Bortezomib may stop the growth of tumor cells by blocking the enzymes necessary for their growth. Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Phase I trial to study the effectiveness of combining bortezomib with carboplatin and etoposide in treating patients who have advanced solid tumors that have not responded to previous treatment

Detailed Description
-----------------
PRIMARY OBJECTIVES: I. Determine the maximum tolerated dose (MTD) of bortezomib, carboplatin, and etoposide in patients with advanced solid tumors refractory to standard therapy. II. Evaluate biologic effects of bortezomib on relevant targets in the tumor tissues of patients treated with this regimen. OUTLINE: This is a dose-escalation study of bortezomib, etoposide, and carboplatin. Patients receive bortezomib IV on days 1 and 8, carboplatin IV over 30 minutes on day 1, and etoposide IV over 60 minutes on days 1-3. Treatment repeats every 21 days for at least 2 courses 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 or more of 6 patients experience dose-limiting toxicity. Once the MTD is determined, 6 additional patients with newly diagnosed, chemotherapy-naive extensive stage small cell lung cancer, and 6 patients with other tumor types, are treated at that dose. PROJECTED ACCRUAL: A total of 12-27 patients will be accrued for this study within 6-14 months.

Official Title
-----------------
A Phase I Study of PS-341 (NSC 681239), Carboplatin, and Etoposide in Patients With Advanced Solid Tumors Refractory to Standard Therapy

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

Intervention / Treatment
-----------------
* Drug: bortezomib
* Drug: carboplatin
* Drug: etoposide
* Other: laboratory biomarker analysis
* Other: pharmacological study


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histologically confirmed advanced solid tumor cancer for which no curativetherapy exists Clinically stable CNS disease is allowed provided the following criteria are met: No uncontrolled brain metastases or CNS involvement No active seizures On stable dose of antiseizure or steroid medication for at least 7 days before study enrollment Performance status - ECOG 0-2 At least 12 weeks Absolute neutrophil count at least 1,500/mm^3 Hemoglobin at least 9 g/dL Platelet count at least 100,000/mm^3 Bilirubin no greater than 1.5 mg/dL AST/ALT no greater than 2.5 times upper limit of normal Creatinine no greater than 1.5 mg/dL Creatinine clearance at least 60 mL/min Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception No active infection No other serious concurrent systemic disorders (including other malignancy) No prior bone marrow or peripheral blood stem cell transplantation No concurrent immunotherapy See Disease Characteristics At least 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin) and recovered Prior carboplatin and/or etoposide allowed No more than 2 prior courses of mitomycin See Disease Characteristics No concurrent hormonal therapy At least 4 weeks since prior radiotherapy and recovered Palliative radiotherapy involving less than 35% bone marrow reserve allowed if completed at least 2 weeks before study enrollment No prior wide-field radiotherapy to 35% or more of bone marrow No prior pelvic radiotherapy No concurrent radiotherapy At least 28 days since prior investigational agents No other concurrent experimental medications

Ages Eligible for Study
-----------------
Minimum Age: 16 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, carboplatin, and etoposide)<br>Patients receive bortezomib IV on days 1 and 8, carboplatin IV over 30 minutes on day 1, and etoposide IV over 60 minutes on days 1-3. Treatment repeats every 21 days for at least 2 courses in the absence of disease progression or unacceptable toxicity. | Drug: bortezomib<br>* Given IV<br>* Other names: VELCADE;Drug: carboplatin<br>* Given IV<br>* Other names: Paraplatin;Drug: etoposide<br>* Given IV<br>* Other names: VP-16-213;Other: laboratory biomarker analysis<br>* Correlative studies<br>Other: pharmacological study<br>* Correlative studies<br>* Other names: pharmacological studies;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MTD defined as the dose level below the dose level that results in DLT in >= 2 of 6 new patients assessed using NCI CTC version 2.0 |  | 21 days | 
| Biological data | The variation of these samples as a function of dose and time will be analyzed to define the mathematical function (e.g. linear, exponential, logistic) that best fits and models the data. | Up to 4 years |