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

Phase 2

Completed

Conditions: Recurrent Colon Cancer
Stage IIIA Rectal Cancer
Stage IIIB Rectal Cancer
Stage IIIC Rectal Cancer
Stage IVA Colon Cancer
Recurrent Rectal Cancer
Stage IIIC Colon Cancer
Stage IIIA Colon Cancer
Stage IIIB Colon Cancer
Stage IVA Rectal Cancer

Interventions: Drug: ispinesib
Other: laboratory biomarker analysis

Registration Number: NCT00103311

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 64

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm II	laboratory biomarker analysis	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.
Arm I	laboratory biomarker analysis	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 I	ispinesib	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	ispinesib	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.

Primary Outcome Measures

Name	Time	Method
Objective Response (CR or PR) as Determined by the RECIST Criteria	Up to 5 years	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

Secondary Outcome Measures

Name	Time	Method
Progression-free Survival	From the date of registration to the date of documented PSA progression, assessed up to 6 months	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.
Overall Survival	From the date of registration to the date of death, assessed up to 12 months	Will be estimated using the product-limit method of Kaplan and Meier by arm.

Trial Locations

Locations (1): University of Southern California, Norris
🇺🇸
Los Angeles, California, United States
University of Southern California, Norris
🇺🇸Los Angeles, California, United States