Phase II Study Evaluating The Safety And Response To Neoadjuvant Dasatinib In Early Stage Non-Small Cell Lung Cancer (TOP0706)
Src expression has been identified in a majority of Non-Small Cell Lung Cancer (NSCLC) cell lines and there is preclinical evidence that Src family kinases may be important in hypoxic growth and angiogenesis in NSCLC. We hypothesize that the inhibition of Src pathway with dasatinib will demonstrate anti-tumor activity in early stage NSCLC, with a tolerable safety profile.
Patients will receive dasatinib, a Src inhibitor, for 3 weeks prior to surgical resection for early stage NSCLC. Fresh frozen tumor tissue is needed for genomic analysis. If fresh frozen tumor tissue is not available from the initial diagnosis, a biopsy will be required to participate in this trial. A second tumor sample will be obtained at time of surgical resection to evaluate for changes in genomic expression profiles.
Patients will be eligible to receive 3 months of adjuvant dasatinib therapy after completion of standard adjuvant therapy or after recovery from surgery if no standard adjuvant therapy is given, if there is evidence of neoadjuvant tumor response (radiologic and/or pathologic) to dasatinib.
Many patients who present with NSCLC are active smokers. Patients who are smoking up until the time of their surgery experience increased peri-operative complications compared to patients who have not smoked cigarettes immediately prior to surgery. While this trial will not be limited to active smokers, the period of smoking cessation prior to surgery is an attractive window of opportunity during which the potentially active novel anticancer therapy dasatinib can be offered to the patient.
|Study Design:||Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Phase II Study Evaluating The Safety And Response To Neoadjuvant Dasatinib In Early Stage Non-Small Cell Lung Cancer (NSCLC).|
- Response Rate [ Time Frame: First progression and survival every 3 months for 2 years, then every 6 months until 5 years, then yearly. ] [ Designated as safety issue: No ]Response rate (radiologic and pathologic) in Stage IB and II to neoadjuvant dasatinib
- Safety and Tolerability of Neoadjuvant Dasatinib [ Time Frame: Screening / Baseline; Neoadjuvant dasatinib Cycle 1 Day 1 and Day 22 ] [ Designated as safety issue: Yes ]Determine the safety and tolerability of neoadjuvant dasatinib in early stage NSCLC.
- Gene Expression Profile Activation of Src Pathways [ Time Frame: Baseline and after 3 weeks of dasatinib therapy at the time of definitive surgical resection. ] [ Designated as safety issue: No ]Determine whether gene expression profile activation of Src pathways is correlated with anti-tumor activity of dasatinib in early stage NSCLC.
- Safety and Tolerability of Adjuvant Dasatinib [ Time Frame: Duration of adjuvant treatment plus 30 days. ] [ Designated as safety issue: Yes ]Determine the safety and tolerability of adjuvant dasatinib in early stage NSCLC.
|Study Start Date:||November 2007|
|Study Completion Date:||September 2009|
|Primary Completion Date:||September 2009 (Final data collection date for primary outcome measure)|
Neoadjuvant dasatinib is to be administered as an oral dose of 70 mg PO twice daily on a continuous basis for 3 weeks prior to surgery. Patients will begin adjuvant dasatinib (70 mg PO twice daily) between 4-6 weeks after standard adjuvant therapy is complete or 4-8 weeks after surgery for those patients that do not receive adjuvant chemotherapy. Adjuvant dasatinib will be given on a continuous basis for up to 3 months after adjuvant chemotherapy or after surgery if no adjuvant chemotherapy is given.
Fresh frozen tumor tissue must be available prior to initiating dasatinib. Eligible patients will receive neoadjuvant dasatinib 70 mg PO twice daily for 3 weeks followed by surgery. The surgical specimen will be evaluated for pathologic response. The second tumor sample will be obtained after 3 weeks of dasatinib therapy at the time of definitive surgical resection which will be evaluated for changes in genomic expression profiles. Patients with at least a 15% decrease or better objective response, without evidence of progression (per tumor evaluation pre-surgery) or pathologic response (as defined as ≥30% tumor necrosis or cell death) to neoadjuvant dasatinib therapy will be eligible to receive dasatinib 70 mg twice daily for 90 days after the completion of standard adjuvant therapy.
Other Name: Sprycel
This is a phase II study of dasatinib, a targeted biologic agent, known to inhibit Src. It is difficult to assess outcome in phase II adjuvant trials because there is no measurable disease to evaluate efficacy and there are many variables that could confound comparing survival of subjects on trial to historical controls. Therefore, after a fresh frozen tumor tissue sample is obtained for genomic analysis, we plan to treat subjects with neoadjuvant dasatinib and then measure tumor response to therapy prior to surgery. Resected tumor will also be assessed for pathologic response as well as for changes in genomic expression patterns.
Subjects will be treated with neoadjuvant dasatinib 70 mg PO twice daily for 3 weeks, with a mandatory minimum of 3 days (72 hours) off of study drug prior to surgical resection. Imaging studies will be done pre-treatment and pre-surgery to assess radiologic response to therapy. The surgical specimen will be evaluated for pathologic response. A tumor tissue sample will be obtained from the surgical specimen for genomic analysis and will be evaluated for changes in genomic expression profiles.
Patients whose tumors have a response to neoadjuvant dasatinib therapy might benefit with better cancer control if they receive a potentially therapeutic course of adjuvant dasatinib. Patients that have at least a 15% decrease or better objective response, without evidence of progression to neoadjuvant dasatinib (per tumor evaluation pre-surgery) or pathologic response (as defined as ≥30% tumor necrosis or cell death) to neoadjuvant dasatinib therapy will be eligible to receive dasatinib 70 mg twice daily for 90 days after the completion of standard adjuvant therapy or after recovery from surgery if no standard adjuvant therapy is given. Patients will be followed for approximately 30 days after the last dose of dasatinib to assess toxicity.
Response will be evaluated in Src regulated and Src deregulated cohorts of tumors. If responses to neoadjuvant dasatinib occur, then accrual to either or both cohorts will be expanded. If there are no responses to neoadjuvant dasatinib in the cohort groups, then accrual to either or both cohorts will be stopped. The results of this study may be useful in designing future studies in early stage NSCLC using dasatinib alone or in combination with chemotherapy.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00564876
|United States, North Carolina|
|Duke University Medical Center|
|Durham, North Carolina, United States, 27710|
|Principal Investigator:||Neal Ready, M.D.||Duke University|