Phase II Study of Dasatinib in Previously Treated Patients With Advanced NSCLC (TOP0801)

Study Description

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Brief Summary:

On this study patients will receive dasatinib, a targeted therapy, for advanced NSCLC that has progressed after previous therapy. Safety and response to dasatinib will be assessed.

Fresh frozen tumor tissue must be available for genomics analysis prior to initiating dasatinib therapy. A biopsy must be obtained after any prior chemotherapy. If fresh frozen tumor tissue is not available, a biopsy will be required to participate in this trial.

Condition or disease	Intervention/treatment	Phase
Non Small Cell Lung Cancer	Drug: Dasatinib	Phase 2

Detailed Description:

Lung cancer is the leading cause of cancer death in the United States. Twenty to seventy-five percent of patients initially treated with surgery or radiotherapy recur and become candidates for systemic therapy. Src expression has been identified in a majority of NSCLC cell lines and may be important in hypoxic growth and angiogenesis of NSCLC.

This phase II trial will investigate the activity of the oral Src inhibitor dasatinib in advanced stage NSCLC. We hypothesize that the inhibition of Src pathway with dasatinib will show anti-tumor activity in advanced NSCLC, with a tolerable safety profile.

Fresh frozen tissue is needed for the genomics analysis, thus a biopsy will be required to participate in this trial. The genomic analysis will determine if the tumor is Src-active or Src-inactive and responses to dasatinib compared. In stage I, 40 patients will be treated without prior knowledge of their tumoral Src-activity. If all stage I responses are observed in the Src-active patients, the second stage will only accrue that cohort. If all responses are observed in the Src-inactive cohort, the activity of dasatinib and genomic determination of dasatinib response will be re-evaluated. Otherwise, if during Stage I, responses are observed in both cohorts, they will be accrued separately and evaluated in a two-stage manner.

Dasatinib will be give orally twice daily and continue until progression of disease, intolerable toxicity or patient withdrawal. Imaging studies will be done pre-treatment then every 6 weeks to assess radiologic response to therapy.

Patients will be followed for 30 days after the last dose of dasatinib to assess toxicity.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	37 participants
Intervention Model:	Single Group Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	Phase II Study of Dasatinib in Previously Treated Patients With Advanced Non-Small Cell Lung Cancer (NSCLC)
Study Start Date :	September 2008
Actual Primary Completion Date :	June 2013
Actual Study Completion Date :	June 2013

Arms and Interventions

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Arm

Intervention/treatment

Experimental: Dasatinib; After a biopsy is done to obtain fresh frozen tumor tissue (Stage I), dasatinib is to be administered as an oral dose of 70 mg twice daily on a continuous basis for 6 weeks. Every 6 weeks radiologic exam will be done to assess response. Treatment will continue until progression of disease, intolerable toxicity or patient withdrawal. For Stage II, a biopsy to obtain fresh frozen tumor tissue will also be done. Depending on results from Stage I and results of biopsy, treatment with dasatinib will be determined.

Drug: Dasatinib; 70 mg PO twice daily until progression. Re-assess radiographically every 6 weeks.; Other Name: Sprycel

Outcome Measures

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Primary Outcome Measures :

1. Tumor Response [ Time Frame: 2 years ]

   Tumor response rate was defined by RECIST criteria:

   CR (complete response) = disappearance of all target lesions taking as reference the baseline sum of the longest diameter (LD); PR (partial response) = at least a 30% decrease in the sum of the longest diameter of target lesions; PD (progressive disease) = at least a 20% increase in the sum of the longest diameter of target lesions as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions; SD (stable disease) = Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as reference the smallest sum LD since the treatment started

Secondary Outcome Measures :

1. Overall Survival [ Time Frame: Progression and survival every 6 months ]
   Overall survival (OS) is the duration from date of consent to date of death from any cause.
2. Grade 3-5 Toxicity Associated With Dasatinib Treatment [ Time Frame: Duration of dasatinib treatment plus 30 days ]
   Number of subjects with Grade 3-5 toxicity as assessed using NCI CTCAE criteria with the attribution of possibly, probably, or definitely related to protocol treatment.
3. Describe Change in Serum Levels of C-terminal Cross-linked Collagen I Between Pre-treatment and 6 Weeks After Starting Dasatinib. [ Time Frame: 2 years ]
4. Determine Relationship Between K-ras Gene Mutation and Response to Dasatinib. [ Time Frame: 2 years ]

Eligibility Criteria

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

Criteria

Inclusion Criteria:

1. Histological/cytological documented non-small cell lung cancer (NSCLC). Documentation of recurrence required if treated with surgical resection and/or external beam radiation therapy (XRT) with curative intent and now have recurrent disease.
2. Fresh tissue biopsy material for genomics analysis prior to initiating dasatinib. If prior XRT, tissue biopsy must be outside XRT field. Biopsy must be after any prior chemotherapy.

3. Prior treatment (tx) to include one of the following:

   • At least 1 prior systemic regimen (IV or oral agent) for Stage IV NSCLC or for recurrent disease.
   • Recurrence within 12 months after completion of systemic neoadjuvant/adjuvant chemotherapy for early stage NSCLC.
   • Combined modality platinum-based tx for Stage III NSCLC.
4. Prior XRT permitted if ≥1 week since completion, XRT must be <25% of bone marrow reserve.
5. At least one, non-radiated, measurable lesion (per RECIST).
6. Age ≥18 years.
7. Eastern Cooperative Oncology Group (ECOG) 0-2.

8. Adequate Organ Function:

   1. Total bilirubin < Upper limit normal (ULN)
   2. Hepatic enzymes (AST, ALT) ≤2.5x ULN
   3. Serum creatinine <1.5x ULN
   4. Hemoglobin ≥9 gm/dL
   5. Neutrophil count (ANC/AGC) ≥1500 per μL
   6. Platelets ≥100,000 per μL
   7. Prothrombin time (PT)/a Partial thromboplastin time (PTT) ≤1.5x control
9. No other serious medical or psychiatric illness.
10. Ability to take oral medication (dasatinib must be swallowed whole).
11. Women of childbearing potential must have negative serum pregnancy test ≤72 hours and not >7 days prior to starting study drug.
12. Sexually active males and females of reproductive potential must agree to use adequate method of contraception during tx and for at least 4 weeks after study drug stopped.
13. Signed, written informed consent including Health Insurance Portability and Accountability Act (HIPAA) according to institutional guidelines.

Exclusion Criteria:

1. Previous or concomitant malignancy in past 2 years other than curatively treated carcinoma in situ of cervix, or basal cell/squamous cell carcinoma of the skin.
2. Prior tx with dasatinib or other agents that inhibit Src.
3. Evidence of symptomatic pleural effusions (grade 2) unless undergo therapeutic thoracentesis as part of non-study care. Successful pleurodesis allowed. Patients who require supplemental oxygen or with oxygen saturation on room air <89% are not eligible. Pericardial effusions of any grade are not eligible.
4. Untreated documented symptomatic central nervous system (CNS) metastases.

5. Cardiac Symptoms:

   1. Uncontrolled angina, congestive heart failure(CHF)or myocardial infarction within 6 months
   2. Diagnosed congenital long QT syndrome
   3. Any h/o clinically significant ventricular arrhythmias
   4. Prolonged QT corrected (QTc) interval on pre-entry EKG (>450 msec)
   5. Uncontrolled B/P as defined as >160/90 on B/P therapy
6. Hypokalemia or hypomagnesaemia if it cannot be corrected.
7. H/o diagnosed congenital acquired bleeding disorders.
8. Ongoing or recent (≤3 months) significant (≥grade 3) GI bleeding.

9. Con Meds:

   1. Drugs having risk of causing Torsades de Pointes (must stop drug 7 days before dasatinib);
   2. Current therapeutic dose unfractionated heparin, low-molecular weight heparin, or coumadin therapy;
   3. St. John's Wort must be stopped while on dasatinib;
   4. IV bisphosphonates stopped 2 weeks pre/6 weeks post dasatinib.
10. Prisoners/subjects compulsorily detained for tx of psychiatric and/or physical illness.
11. Pregnant or breastfeeding.
12. Active or uncontrolled infection requiring IV antibiotics.
13. Impairment of GI function/disease that may alter absorption of dasatinib (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection).
14. Received investigational drugs ≤4 weeks prior to starting study drug and/or not recovered from side effects of such therapy. Any other anti-neoplastic and/or molecular therapy must be discontinued 7 days prior to starting dasatinib.

Contacts and Locations

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Locations

United States, North Carolina
Durham VA Medical Center
Durham, North Carolina, United States, 27705
Duke University Medical Center
Durham, North Carolina, United States, 27710
Duke Raleigh
Raleigh, North Carolina, United States, 27609

Sponsors and Collaborators

Duke University

Bristol-Myers Squibb

Investigators

Principal Investigator:	Michael Kelley, MD	Duke University

More Information

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Additional Information:

Duke Institute for Genome Sciences &amp; Policy 

Publications:

Downward J. Cancer biology: signatures guide drug choice. Nature. 2006 Jan 19;439(7074):274-5.

Responsible Party:	Duke University
ClinicalTrials.gov Identifier:	NCT00787267 History of Changes
Other Study ID Numbers:	Pro00008303
First Posted:	November 7, 2008
Results First Posted:	January 1, 2015
Last Update Posted:	June 30, 2016
Last Verified:	May 2016

Keywords provided by Duke University:

NSCLC; Lung Cancer; Dasatinib	Genomics; Genomics analysis; Genomic signature

Additional relevant MeSH terms:

Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases	Carcinoma, Bronchogenic; Bronchial Neoplasms; Dasatinib; Antineoplastic Agents; Protein Kinase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action