Dasatinib in Treating Patients With Previously Treated Metastatic Colorectal Cancer

Study Overview
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Brief Summary
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This phase II trial is studying dasatinib to see how well it works in treating patients with previously treated metastatic colorectal cancer. Dasatinib may stop the growth of tumor cells by blocking some of the enzymes needed for their growth.

Detailed Description
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PRIMARY OBJECTIVES: I. Determine the progression-free survival of patients with metastatic colorectal cancer who have progressed on or following two prior chemotherapy regimens and are then treated with dasatinib. SECONDARY OBJECTIVES: I. Determine the objective response rates in patients treated with dasatinib. II. Determine the overall survival of patients treated with dasatinib. III. Determine the toxicity in patients treated with dasatinib. TERTIARY OBJECTIVES: I. Determine the incidence of somatic mutations in c-src, c-yes, fyn, lck, hck, lyn, yrk and csk in archival primary and metastatic colorectal cancer tissues from these patients and to correlate this with clinical outcome. II. Determine the incidence of total c-src and phosphorylated c-src expression in archival primary and metastatic colorectal cancer specimens from these patients, and to correlate this with clinical outcome. III. Evaluate the effect of dasatinib on serum VEGF levels. OUTLINE: This is a multicenter study. Patients receive oral dasatinib twice daily on days 1-28. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. Blood is collected on days 1 (prior to the first dose of dasatinib) and 15 of course 1 for measurement of VEGF pre-and post-dasatinib administration. Archived tumor tissue (tumor or core biopsy; primary or metastatic lesion) is collected for identification of the incidence of somatic mutations and polymorphisms by polymerase chain reaction and electrophoresis and for measurement of total c-src and phosphorylated src expression by immunohistochemistry. After completion of study treatment, patients are followed for at least 8 weeks.

Official Title
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A Phase II Study of Dasatinib (NSC 732517) in Previously-Treated Patients With Metastatic Colorectal Cancer

Conditions
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Recurrent Colon Cancer, Recurrent Rectal Cancer, Stage IV Colon Cancer, Stage IV Rectal Cancer

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed colorectal cancer Metastatic disease Not curable by surgical resection Archival tumor tissue available Measurable disease, defined as at least one unidimensionally measurable lesion ≥ 20 mm by conventional techniques or ≥ 10 mm by spiral CT scan Measurable disease must be outside of a prior radiation port Documented disease progression either during or after prior chemotherapy treatment No more than 2 prior chemotherapy regimens in the adjuvant or metastatic setting Prior chemotherapy regimens must have contained a fluoropyrimidine (e.g., fluorouracil or capecitabine), oxaliplatin, and irinotecan Patients who received no prior adjuvant therapy must have received 2 prior chemotherapy regimens for metastatic disease (e.g., FOLFOX followed by FOLFIRI) Patients who received prior adjuvant therapy with a fluoropyrimidine plus oxaliplatin must have received no more than 1 chemotherapy regimen for metastatic disease that must have contained irinotecan VEGF or EGFR inhibitors with prior chemotherapy allowed No known brain metastases Life expectancy > 3 months ECOG performance status (PS) 0-2 or Karnofsky PS ≥ 60% WBC ≥ 3,000/mm³ ANC ≥ 1,500/mm³ Platelet count ≥ 100,000/mm³ Total bilirubin ≤ 1.5 times upper limit of normal (ULN) AST/ALT ≤ 2.5 times ULN (5 times ULN with liver metastases) Creatinine normal or creatinine clearance ≥ 60 mL/min Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception No history of allergic reactions attributed to compounds of similar chemical or biological composition to dasatinib No QTc prolongation, defined as a QTc interval ≥ 480 msecs (Bazett correction) No condition (e.g., gastrointestinal tract disease resulting in an inability to take oral medication or a requirement for IV alimentation, or active peptic ulcer disease) that would impair ability to swallow and retain dasatinib tablets Prior partial colectomy is not considered an exclusion factor No clinically significant cardiovascular disease including any of the following: Myocardial infarction or ventricular tachyarrhythmia within the past 6 months New York Heart Association class II -IV congestive heart failure Major conduction abnormality (unless a cardiac pacemaker is present) No uncontrolled intercurrent illness including, but not limited to, any of the following: Ongoing or active infection History of significant bleeding disorder (including congenital [e.g., von Willebrand's disease] or acquired [e.g., anti-factor VIII antibodies] disorders) Large pleural effusions Psychiatric illness or social situations that would limit compliance with study requirements No currently active second malignancy other than non-melanoma skin cancer or carcinoma in situ of the cervix Patients are not considered to have a currently active malignancy if they have completed therapy and have no evidence of recurrence for at least 5 years At least 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin C) and recovered At least 4 weeks since prior radiation therapy and recovered No prior surgical procedures affecting absorption No prior treatment with inhibitors of src, PDGFR, KIT, or EPHA2 More than 1 week since prior and no concurrent medications or substances that are potent inhibitors or inducers of CYP3A4 More than 1 week since prior and no concurrent medications that inhibit platelet function (e.g., aspirin, dipyridamole, epoprostenol, eptifibatide, clopidogrel, cilostazol, abciximab, ticlopidine, or any non-steroidal anti-inflammatory drug) More than 1 week since prior and no concurrent agents that are generally accepted to have a risk of causing Torsades de Pointes, including quinidine, procainamide, disopyramide, amiodarone, sotalol, ibutilide, dofetilide, erythromycins, clarithromycin, chlorpromazine, haloperidol, mesoridazine, thioridazine, pimozide, cisapride, bepridil, droperidol, methadone, arsenic, chloroquine, domperidone, halofantrine, levomethadyl, pentamidine, sparfloxacin, or lidoflazine No concurrent anticoagulants (e.g., warfarin, heparin/low molecular weight heparin [e.g., danaparoid, dalteparin, tinzaparin, or enoxaparin]) No concurrent combination antiretroviral therapy for HIV-positive patients No concurrent grapefruit or grapefruit juice No other concurrent investigational agents or commercial agents or therapies

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (tyrosine Kinase Inhibitor)<br>Patients receive oral dasatinib twice daily on days 1-28. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. | Drug: dasatinib<br> <br> * Other names: Sprycel;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 |
| --- | --- | --- |
| Progression-free Survival Rate | Progression will be evaluated in this study using the new international criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee. Patients who are still alive and have not progressed will be censored at the date of the last negative examination. A Simon (1989), optimal, two-stage design will be employed. The progression-free survival count will be the proportion of subjects who are alive and progression-free at 4 months. | From the start of treatment to the time of disease progression or death from any cause, assessed at 4 months after completion of treatment (i.e., up to 12 months.) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response Rate (RR) (Complete or Partial Responders) | Response will be evaluated in this study using the new international criteria proposed by the RECIST Committee. The response rate is the proportion of subjects who experienced a complete or partial response. | Every 2 courses, assessed up to 8 weeks after completion of study treatment (i.e., up to 10 months) | 
| Incidence of Somatic Mutations | Multivariable analysis of progression-free survival duration will be performed using the Cox (1972) regression model to evaluate the prognostic value of somatic mutations. For the mutational analysis endpoints, genetic mutations will also be correlated with drug activity via Fisher's exact test for comparisons of responders with non-responders and for comparison of patients progression-free and 4 months vs. those with early progression or death | 1 year | 
| Association Between the Incidence of Total C-src and Phosphorylated C-src Expression and Response | Examined by comparing expression in those who have an objective response versus those who do not and in those with and without disease progression at 4 months using Fisher's exact test. | 4 months | 
| Change in Plasma Vascular Endothelial Growth Factor (VEGF) Levels Over 15 Days | Changes of VEGF will be correlated with response rates and 4-month progression-free survival utilizing the Wilcoxon rank-sum test. | At baseline and day 15 |