Dasatinib in Treating Patients With Previously Treated Metastatic Colorectal Cancer

• ClinicalTrials.gov Identifier: NCT00504153
• Recruitment Status: Completed
• First Posted: July 19, 2007
• Results First Posted: September 10, 2013
• Last Update Posted: May 19, 2014
• Sponsor: National Cancer Institute (NCI)
• Information provided by (Responsible Party): National Cancer Institute (NCI)

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Recurrent Colon Cancer; Recurrent Rectal Cancer; Stage IV Colon Cancer; Stage IV Rectal Cancer	Drug: dasatinib; Other: laboratory biomarker analysis	Phase 2

Detailed Description:

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 19 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Study of Dasatinib (NSC 732517) in Previously-Treated Patients With Metastatic Colorectal Cancer
• Study Start Date: July 2007
• Actual Primary Completion Date: June 2011
• Actual Study Completion Date: June 2011

Arms and Interventions

Arm	Intervention/treatment
Experimental: Treatment (tyrosine Kinase Inhibitor); 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; Other Names: BMS-354825; Sprycel; Other: laboratory biomarker analysis; Correlative studies

Outcome Measures

Primary Outcome Measures :

1. Progression-free Survival Rate [ Time Frame: 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.) ]
   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.

Secondary Outcome Measures :

1. Response Rate (RR) (Complete or Partial Responders) [ Time Frame: Every 2 courses, assessed up to 8 weeks after completion of study treatment (i.e., up to 10 months) ]
   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.
2. Incidence of Somatic Mutations [ Time Frame: 1 year ]
   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
3. Association Between the Incidence of Total C-src and Phosphorylated C-src Expression and Response [ Time Frame: 4 months ]
   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. Change in Plasma Vascular Endothelial Growth Factor (VEGF) Levels Over 15 Days [ Time Frame: At baseline and day 15 ]
   Changes of VEGF will be correlated with response rates and 4-month progression-free survival utilizing the Wilcoxon rank-sum test.

Eligibility Criteria

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

Criteria

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

Contacts and Locations

Locations

United States, Illinois

University of Chicago

Chicago, Illinois, United States, 60637

Sponsors and Collaborators

National Cancer Institute (NCI)

Investigators

• Principal Investigator: Hedy Kindler; University of Chicago

More Information

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT00504153
• Other Study ID Numbers: NCI-2009-00223; NCI-2009-00223 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); UCCRC-NCI-7786; CDR0000557036; 15431A ( Other Identifier: University of Chicago ); 7786 ( Other Identifier: CTEP ); N01CM62201 ( U.S. NIH Grant/Contract ); P30CA014599 ( U.S. NIH Grant/Contract )
• First Posted: July 19, 2007
• Results First Posted: September 10, 2013
• Last Update Posted: May 19, 2014
• Last Verified: October 2011

Additional relevant MeSH terms:

Rectal Neoplasms; Colonic Neoplasms; Colorectal Neoplasms; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases; Dasatinib; Antineoplastic Agents; Protein Kinase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action