SB-715992 in Treating Patients With Advanced or Metastatic Colorectal Cancer

Study Overview
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Brief Summary
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This randomized phase II trial is studying how well SB-715992 works in treating patients with advanced or metastatic colorectal cancer. Drugs used in chemotherapy, such as SB-715992, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine the objective response rate in patients with advanced or metastatic colorectal cancer treated with SB-715992 once a week for 3 weeks, every 28 days and SB-715992 once every 21 days. SECONDARY OBJECTIVES: I. To determine the time to tumor progression, progression free and overall survival of patients and toxicity in patients with advanced or metastatic colorectal cancer treated with SB-715992 once a week for 3 weeks, every 28 days and SB-715992 once every 21 days. II. To characterize the population pharmacokinetic (PK) parameters of SB-715992 including an assessment of significant covariates on SB-715992 PK and an assessment of the potential relationships between the pharmacokinetics of SB-715992 and relevant safety and efficacy endpoints. IV. To examine cytoskeletal morphology changes in response to SB-715992 in peripheral blood mononuclear cells and tumors by fluorescent immunohistochemistry. V. To evaluate mRNA expression of betaΙΙΙ-tubulin and KSP in archival tumor tissue. VI. To determine the frequency of genomic polymorphisms in genes targeted by SB-715992 (measured in peripheral blood mononuclear cells) and to assess whether germline polymorphisms (DNA) of genes targeted by SB-715992 (KSP inhibitor) are associated with toxicity and clinical outcome in patients with colorectal cancer. Further, whether genes involved with the metabolism (CYP3A4) and resistance (MDR1) affect the outcome in these patients. OUTLINE: This is a randomized, multicenter study. Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive SB-715992 IV over 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. ARM II: Patients receive SB-715992 IV over 1 hour on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed every 3 months for 2 years, every 6 months for 2 years, and then annually thereafter.

Official Title
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A Randomized Phase II Non-Comparative Study of SB-715992 Given Weekly or Every Three Weeks in Advanced or Metastatic Colorectal Cancer

Conditions
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Recurrent Colon Cancer, Recurrent Rectal Cancer, Stage IIIA Colon Cancer, Stage IIIA Rectal Cancer, Stage IIIB Colon Cancer, Stage IIIB Rectal Cancer, Stage IIIC Colon Cancer, Stage IIIC Rectal Cancer, Stage IVA Colon Cancer, Stage IVA Rectal Cancer, Stage IVB Colon Cancer, Stage IVB Rectal Cancer

Intervention / Treatment
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* Drug: ispinesib
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have histologically or cytologically confirmed advanced/metastatic colorectal cancer Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as >= 20 mm with conventional techniques or as >= 10 mm with spiral CT scan Patients must have received prior therapy (in any setting) with 5-FU, CPT-11, and oxaliplatin; patients may have received prior erbitux and bevacizumab, but it is not required Patients must have received at least one prior chemotherapy regimen for advanced disease Tumor must be accessible for biopsy or paraffin embedded tissue must be available for review of their biopsy specimen Life expectancy of > 12 weeks ECOG performance status 0-2 (Karnofsky >= 50%) Leukocytes >= 3,000/μL Absolute neutrophil count >= 1,500/μL Platelets >= 100,000/μL Hemoglobin >= 9 mg/dL Total bilirubin within normal institutional limits AST(SGOT)/ALT(SGPT) =< 2.5 X institutional upper limit of normal Creatinine =< 1.5 X institutional upper limit of normal OR creatinine clearance >= 60 mL/min/1.73 m^2 Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from AEs due to agents administered more than 4 weeks earlier Patients may not have received any other investigational agents within 28 days of study entry Patients may not receive other anti-cancer therapy (cytotoxic, biologic, radiation, or hormonal other than for replacement) while on this study Prohibited medications; SB-715992 is a moderate to significant in vitro inhibitor of CYP3A4; the following lists of medications/substances are moderate to significant inhibitors/inducers of CYP3A4 that, if administered concomitantly with SB-715992, may alter study drug exposure; the use of these medications/substances within 14 days (> 6 months for amiodarone) prior to the administration of the first dose of SB-715992 through discontinuation from the study is prohibited Inhibitors of CYP3A4: Antibiotics: clarithromycin, erythromycin, troleandomycin Antifungals: itraconazole, ketoconazole, fluconazole (doses > 200 mg/day), voriconazole Antidepressants: nefazodone, fluovoxamine Calcium channel blockers: verapamil, diltiazem Miscellaneous: amiodarone*, grapefruit juice, bitter orange Use of amiodarone within 6 months prior to the administration of the first dose of SB-715992 is prohibited Inducers of CYP3A4: Anticonvulsants: phenytoin, carbamazepine, Phenobarbital, oxcarbazepine Antibiotics: rifampin, rifabutin, rifapentine Miscellaneous: St. John's wort, modafinil Patients with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events History of allergic reactions attributed to compounds of similar chemical or biologic composition to SB-715992 Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with SB-715992 HIV-positive patients receiving combination anti-retroviral therapy are excluded from the study

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: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I<br>Patients receive SB-715992 IV over 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. | Drug: ispinesib<br>* Given IV<br>Other: laboratory biomarker analysis<br>* Correlative studies<br>|
| Experimental: Arm II<br>Patients receive SB-715992 IV over 1 hour on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. | Drug: ispinesib<br>* Given IV<br>Other: laboratory biomarker analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response (CR or PR) as Determined by the RECIST Criteria | Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR | Up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival | Will be estimated using the product-limit method of Kaplan and Meier by arm. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. | From the date of registration to the date of documented PSA progression, assessed up to 6 months | 
| Overall Survival | Will be estimated using the product-limit method of Kaplan and Meier by arm. | From the date of registration to the date of death, assessed up to 12 months |