Phase II Study Evaluating The Safety And Response To Neoadjuvant Dasatinib In Early Stage Non-Small Cell Lung Cancer

NCT00564876 | Terminated Phase 2 Results DMC

• 1 other identifier: Pro00001278
• Study Type: interventional
• Target: 2
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Carcinoma, Non-Small-Cell Lung

Keywords

Non Small Cell Lung Cancer (NSCLC); carcinoma; dasatinib; neoadjuvant; adjuvant; resection; genomic signature; predictor; microarray

Outcome Measures

Primary Outcomes (1)

• Response Rate

  Response rate (radiologic and pathologic) in Stage IB and II to neoadjuvant dasatinib

  First progression and survival every 3 months for 2 years, then every 6 months until 5 years, then yearly.

Secondary Outcomes (3)

• Safety and Tolerability of Neoadjuvant Dasatinib

  Screening / Baseline; Neoadjuvant dasatinib Cycle 1 Day 1 and Day 22

• Gene Expression Profile Activation of Src Pathways

  Baseline and after 3 weeks of dasatinib therapy at the time of definitive surgical resection.

• Safety and Tolerability of Adjuvant Dasatinib

  Duration of adjuvant treatment plus 30 days.

Study Arms (1)

Treatment

EXPERIMENTAL

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.

Drug: Dasatinib

Interventions

Dasatinib DRUG

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.

Also known as: Sprycel

Treatment

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Suspected or histological/cytological diagnosis of Non-Small Cell Lung Cancer (NSCLC), Stage IB (≥4 cm per CT) or Stage IIA or IIB, amenable to surgical resection
• Must be deemed a surgical candidate
• Tumors ≥2 cm in maximum diameter without radiographic, bronchoscopic or pathologic evidence of nodal metastases are eligible for biopsy
• Fresh tissue biopsy material must be available for genomics analysis prior to initiating dasatinib therapy
• Age ≥18 years
• Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2
• No prior chemotherapy, immunotherapy, radiation therapy or biologic/targeted therapy for any malignancy
• Adequate Organ Function:
• Total bilirubin \<institutional upper limit normal (ULN)
• Hepatic enzymes (AST, ALT) ≤2.5x institutional ULN
• Serum creatinine \<1.5x institutional ULN
• Hemoglobin ≥9 gm/dL
• Neutrophil count (ANC or AGC) ≥1500 per μL
• Platelets ≥100,000 per μL
• Prothrombin time (PT)/a partial thromboplastin time (PTT) ≤1.5x control

You may not qualify if:

• Previous or concomitant malignancy in the past 2 years other than curatively treated carcinoma in situ of the cervix, basal cell or squamous cell carcinoma of the skin
• Prior dasatinib therapy
• Evidence of pleural or pericardial effusion of any grade
• Cardiac Symptoms:
• Uncontrolled angina, congestive heart failure (CHF), or myocardial infarction (MI) within 6 months
• Diagnosed congenital long QT syndrome
• Any history of clinically significant ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or Torsades de Pointes)
• Prolonged QT corrected (QTc) interval on pre-entry EKG (\>450 msec)
• Uncontrolled hypertension defined as \>160/90 on a regimen of antihypertensive therapy
• Subjects with hypokalemia or hypomagnesaemia if it cannot be corrected
• History of diagnosed congenital acquired bleeding disorders (e.g., von Willebrand's disease)
• Ongoing or recent (≤3 months) significant (≥grade 3) gastrointestinal bleeding
• Concomitant Medications:
• Drugs that are generally accepted to have a risk of causing Torsades de Pointes including: (Patients must discontinue drug 7 days prior to starting dasatinib)
• \*\*quinidine, procainamide, disopyramide, amiodarone, sotalol, ibutilide, dofetilide, erythromycin, clarithromycin, chlorpromazine, haloperidol, mesoridazine, thioridazine, pimozide, cisapride, bepridil, droperidol, methadone, arsenic, chloroquine, domperidone, halofantrine, levomethadyl, pentamidine, sparfloxacin, lidoflazine

Sponsors & Collaborators

• Duke University: lead
• Bristol-Myers Squibb: collaborator

Study Sites (1)

Duke University Medical Center

Durham, North Carolina, 27710, United States

Location

Related Publications (3)

• Potti A, Dressman HK, Bild A, Riedel RF, Chan G, Sayer R, Cragun J, Cottrill H, Kelley MJ, Petersen R, Harpole D, Marks J, Berchuck A, Ginsburg GS, Febbo P, Lancaster J, Nevins JR. Genomic signatures to guide the use of chemotherapeutics. Nat Med. 2006 Nov;12(11):1294-300. doi: 10.1038/nm1491. Epub 2006 Oct 22.

  PMID: 17057710 BACKGROUND

• Potti A, Mukherjee S, Petersen R, Dressman HK, Bild A, Koontz J, Kratzke R, Watson MA, Kelley M, Ginsburg GS, West M, Harpole DH Jr, Nevins JR. A genomic strategy to refine prognosis in early-stage non-small-cell lung cancer. N Engl J Med. 2006 Aug 10;355(6):570-80. doi: 10.1056/NEJMoa060467.

  PMID: 16899777 BACKGROUND

• Huang E, Ishida S, Pittman J, Dressman H, Bild A, Kloos M, D'Amico M, Pestell RG, West M, Nevins JR. Gene expression phenotypic models that predict the activity of oncogenic pathways. Nat Genet. 2003 Jun;34(2):226-30. doi: 10.1038/ng1167.

  PMID: 12754511 BACKGROUND

Related Links

• Clinical Trials at Duke Comprehensive Cancer Center

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung; Carcinoma

Interventions

Dasatinib

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type

Intervention Hierarchy (Ancestors)

Thiazoles; Sulfur Compounds; Organic Chemicals; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Pyrimidines

Limitations and Caveats

Limitations for this trial were the trial was stopped due to poor enrollment.

Results Point of Contact

• Title: Neal Ready, MD
• Organization: Duke University Medical Center

neal.ready@duke.edu

919-668-6688

Study Officials

• Neal Ready, M.D.

  Duke University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 26, 2007
• First Posted: November 28, 2007
• Study Start: November 1, 2007
• Primary Completion: September 1, 2009
• Study Completion: September 1, 2009
• Last Updated: February 23, 2015
• Results First Posted: March 8, 2013

Record last verified: 2015-01

Locations

US (1)