Paclitaxel and Bortezomib in Treating Patients With Metastatic or Unresectable Malignant Solid Tumors

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Bortezomib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving paclitaxel together with bortezomib may kill more tumor cells. PURPOSE: This phase I trial is studying the side effects and best dose of paclitaxel and bortezomib in treating patients with metastatic or unresectable malignant solid tumors.

Detailed Description
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OBJECTIVES: Primary To identify the maximum tolerated dose of paclitaxel in combination with bortezomib in patients with metastatic or unresectable solid tumor malignancies that involve an activated Ras/Raf/MAPK pathway. Secondary To assess the toxicity of this regimen. To assess tumor response in these patients. To determine whether Bim is upregulated in peripheral blood mononuclear cells obtained from patients treated with this regimen. To correlate markers of Ras/Raf/MAPK pathway activation in fresh or archived tumor tissue with clinical response in these patients. To perform pharmacokinetic (PK) studies to determine whether bortezomib alters paclitaxel PK parameters. OUTLINE: Patients receive paclitaxel IV over 1 hour and bortezomib IV on days 1, 8, and 15. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity. Blood samples are collected at baseline and periodically during course 1 for pharmacokinetic and biomarker studies. Blood samples are analyzed for plasma concentrations of paclitaxel by high performance liquid chromatography and for Bim protein levels and phosphorylation status by western blotting. Tumor tissue samples, if available, are analyzed to evaluate the presence of an activated Ras/Raf/MAPK pathway. Tumor tissue samples are analyzed for Ras and/or Raf mutations by nucleic acid extraction and direct sequencing; Ras and/or Raf overexpression by western blotting; Ras activation assay; and/or phospho-ERK by western blotting and IHC.

Official Title
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Phase I Study of Paclitaxel (Taxol) and Bortezomib (Velcade) in Patients With Refractory Solid Tumor Malignancies Involving an Activated MAPK Pathway

Conditions
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Breast Cancer, Colorectal Cancer, Head and Neck Cancer, Lung Cancer, Melanoma (Skin), Ovarian Cancer, Pancreatic Cancer, Prostate Cancer, Unspecified Adult Solid Tumor, Protocol Specific

Intervention / Treatment
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* Drug: bortezomib
* Drug: paclitaxel


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed malignant solid tumor that involves an activated Ras/Raf/MAPK pathway, including the following: Breast cancer Prostate cancer Colon cancer Pancreatic cancer Ovarian cancer Non-small cell lung cancer Melanoma Papillary thyroid cancer Metastatic or unresectable disease Standard curative or palliative measures do not exist or are no longer effective No newly diagnosed, untreated, or uncontrolled brain metastases PATIENT CHARACTERISTICS: ECOG performance status 0-2 ANC ≥ 1,500/μL WBC ≥ 3,500/μL Platelet count ≥ 100,000/μL Total bilirubin ≤ 1.5 times upper limit of normal (ULN) AST/ALT ≤ 2.5 times ULN (≤ 5 times ULN for tumor involvement of the liver) Creatinine ≤ 2 times ULN Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception No neuropathy ≥ grade 1 with pain within the past 14 days No active infections No myocardial infarction within the past 6 months No NYHA class III or IV heart failure No uncontrolled angina No severe uncontrolled ventricular arrhythmias No evidence of acute ischemia or active conduction system abnormalities by ECG Any ECG abnormality at screening must be documented by the investigator as not medically relevant No hypersensitivity to bortezomib, boron, or mannitol No serious medical or psychiatric illness likely to interfere with study participation PRIOR CONCURRENT THERAPY: Prior paclitaxel or bortezomib allowed At least 4 weeks since prior chemotherapy and/or radiotherapy More than 14 days since other prior investigational drugs No other concurrent investigational agents No other concurrent anticancer agents, including chemotherapy and biologic agents No concurrent recombinant interleukin-11 (Neumega®)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: bortezomib|Starting dose level 0.70mg/m2|
|Drug: paclitaxel|Starting dose level 40mg/m2|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose of paclitaxel in combination with bortezomib |  | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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unspecified adult solid tumor, protocol specific, recurrent breast cancer, stage IV breast cancer, recurrent prostate cancer, stage IV prostate cancer, recurrent colon cancer, stage IV colon cancer, recurrent pancreatic cancer, stage IV pancreatic cancer, recurrent ovarian epithelial cancer, stage IV ovarian epithelial cancer, recurrent ovarian germ cell tumor, stage IV ovarian germ cell tumor, recurrent non-small cell lung cancer, stage IV non-small cell lung cancer, recurrent melanoma, stage IV melanoma, stage IV papillary thyroid cancer, recurrent thyroid cancer