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

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

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.

Study Overview

• Status: Completed
• Conditions: Breast Cancer; Head and Neck Cancer; Colorectal Cancer; Pancreatic Cancer; Ovarian Cancer; Lung Cancer; Prostate Cancer; Unspecified Adult Solid Tumor, Protocol Specific; Melanoma (Skin)
• Intervention / Treatment: Drug: bortezomib; Drug: paclitaxel

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 16
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • New Jersey
    • New Brunswick, New Jersey, United States, 08903
      • Cancer Institute of New Jersey at UMDNJ - Robert Wood Johnson Medical School

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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®)

Study Plan

How is the study designed?

Design Details

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

What is the study measuring?

Primary Outcome Measures

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

Collaborators and Investigators

• Sponsor: University of Medicine and Dentistry of New Jersey
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Vassil Karantza-Wadsworth, MD, Rutgers Cancer Institute of New Jersey

Publications and helpful links

Helpful Links

• Clinical trial summary from the National Cancer Institute's PDQ® database

Study record dates

Study Major Dates

• Study Start: March 1, 2007
• Primary Completion (Actual): February 1, 2009
• Study Completion (Actual): February 1, 2009

Study Registration Dates

• First Submitted: April 25, 2008
• First Submitted That Met QC Criteria: April 25, 2008
• First Posted (Estimate): April 28, 2008

Study Record Updates

• Last Update Posted (Estimate): May 10, 2011
• Last Update Submitted That Met QC Criteria: May 9, 2011
• Last Verified: May 1, 2011

More Information

Terms related to this study

• Keywords: stage IV breast cancer; recurrent breast cancer; recurrent non-small cell lung cancer; stage IV prostate cancer; recurrent prostate cancer; stage IV non-small cell lung cancer; unspecified adult solid tumor, protocol specific; stage IV colon cancer; recurrent colon cancer; recurrent pancreatic cancer; stage IV ovarian epithelial cancer; recurrent ovarian epithelial cancer; recurrent melanoma; stage IV melanoma; stage IV pancreatic cancer; recurrent ovarian germ cell tumor; stage IV ovarian germ cell tumor; stage IV papillary thyroid cancer; recurrent thyroid cancer
• Additional Relevant MeSH Terms: Digestive System Diseases; Skin Diseases; Respiratory Tract Diseases; Neoplasms by Histologic Type; Neoplasms; Lung Diseases; Urogenital Neoplasms; Neoplasms by Site; Endocrine System Diseases; Digestive System Neoplasms; Endocrine Gland Neoplasms; Genital Neoplasms, Male; Breast Diseases; Prostatic Diseases; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Pancreatic Diseases; Neuroendocrine Tumors; Nevi and Melanomas; Breast Neoplasms; Prostatic Neoplasms; Lung Neoplasms; Pancreatic Neoplasms; Melanoma; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Paclitaxel; Bortezomib
• Other Study ID Numbers: CDR0000592905; P30CA072720 (U.S. NIH Grant/Contract); CINJ-050608; MILLENNIUM-CINJ-050608; CINJ-IRB-0220060270