Clinical trial NCT00667641: Paclitaxel and Bortezomib in Treating Patients With Metastatic or Unresectable Malignant Solid Tumors
Official title: Phase I Study of Paclitaxel (Taxol) and Bortezomib (Velcade) in Patients With Refractory Solid Tumor Malignancies Involving an Activated MAPK Pathway
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Breast Cancer
Colorectal Cancer
Head and Neck Cancer
Lung Cancer
Melanoma (Skin)
Ovarian Cancer
Pancreatic Cancer
Prostate Cancer
Unspecified Adult Solid Tumor, Protocol Specific
Keywords: 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
Lead sponsor: Rutgers, The State University of New Jersey
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2008-04-28
Enrollment: 16
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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®)

Primary outcomes:
measure: Maximum tolerated dose of paclitaxel in combination with bortezomib
timeFrame: 2 years
Secondary outcomes:
Other outcomes:
Locations:
city: New Brunswick
country: United States
facility: Cancer Institute of New Jersey at UMDNJ - Robert Wood Johnson Medical School
state: New Jersey
Study officials:
affiliation: Rutgers Cancer Institute of New Jersey
name: Vassil Karantza-Wadsworth, MD
role: PRINCIPAL_INVESTIGATOR
References: