TOP0801: Phase II Study of Dasatinib in Previously Treated Patients With Advanced NSCLC
Study Details
Study Description
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 |
|---|---|---|
| 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
Arms and Interventions
| 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 Names:
|
Outcome Measures
Primary Outcome Measures
- Tumor Response [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
- Overall Survival [Progression and survival every 6 months]
Overall survival (OS) is the duration from date of consent to date of death from any cause.
- Grade 3-5 Toxicity Associated With Dasatinib Treatment [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.
- Describe Change in Serum Levels of C-terminal Cross-linked Collagen I Between Pre-treatment and 6 Weeks After Starting Dasatinib. [2 years]
- Determine Relationship Between K-ras Gene Mutation and Response to Dasatinib. [2 years]
Eligibility Criteria
Criteria
Inclusion Criteria:
-
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.
-
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.
-
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.
-
Prior XRT permitted if ≥1 week since completion, XRT must be <25% of bone marrow reserve.
-
At least one, non-radiated, measurable lesion (per RECIST).
-
Age ≥18 years.
-
Eastern Cooperative Oncology Group (ECOG) 0-2.
-
Adequate Organ Function:
-
Total bilirubin < Upper limit normal (ULN)
-
Hepatic enzymes (AST, ALT) ≤2.5x ULN
-
Serum creatinine <1.5x ULN
-
Hemoglobin ≥9 gm/dL
-
Neutrophil count (ANC/AGC) ≥1500 per μL
-
Platelets ≥100,000 per μL
-
Prothrombin time (PT)/a Partial thromboplastin time (PTT) ≤1.5x control
-
No other serious medical or psychiatric illness.
-
Ability to take oral medication (dasatinib must be swallowed whole).
-
Women of childbearing potential must have negative serum pregnancy test ≤72 hours and not >7 days prior to starting study drug.
-
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.
-
Signed, written informed consent including Health Insurance Portability and Accountability Act (HIPAA) according to institutional guidelines.
Exclusion Criteria:
-
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.
-
Prior tx with dasatinib or other agents that inhibit Src.
-
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.
-
Untreated documented symptomatic central nervous system (CNS) metastases.
-
Cardiac Symptoms:
-
Uncontrolled angina, congestive heart failure(CHF)or myocardial infarction within 6 months
-
Diagnosed congenital long QT syndrome
-
Any h/o clinically significant ventricular arrhythmias
-
Prolonged QT corrected (QTc) interval on pre-entry EKG (>450 msec)
-
Uncontrolled B/P as defined as >160/90 on B/P therapy
-
Hypokalemia or hypomagnesaemia if it cannot be corrected.
-
H/o diagnosed congenital acquired bleeding disorders.
-
Ongoing or recent (≤3 months) significant (≥grade 3) GI bleeding.
-
Con Meds:
-
Drugs having risk of causing Torsades de Pointes (must stop drug 7 days before dasatinib);
-
Current therapeutic dose unfractionated heparin, low-molecular weight heparin, or coumadin therapy;
-
St. John's Wort must be stopped while on dasatinib;
-
IV bisphosphonates stopped 2 weeks pre/6 weeks post dasatinib.
-
Prisoners/subjects compulsorily detained for tx of psychiatric and/or physical illness.
-
Pregnant or breastfeeding.
-
Active or uncontrolled infection requiring IV antibiotics.
-
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).
-
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
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Durham VA Medical Center | Durham | North Carolina | United States | 27705 |
| 2 | Duke University Medical Center | Durham | North Carolina | United States | 27710 |
| 3 | Duke Raleigh | Raleigh | North Carolina | United States | 27609 |
Sponsors and Collaborators
- Duke University
- Bristol-Myers Squibb
Investigators
- Principal Investigator: Michael Kelley, MD, Duke University
Study Documents (Full-Text)
None provided.More Information
Additional Information:
Publications
- Pro00008303
Study Results
Participant Flow
| Recruitment Details | This study opened to enrollment in November 2008 and closed in October 2011 due to slow accrual. Subjects were enrolled at 3 sites: Duke University Medical Center, Durham VA Medical Center, and the University of Minnesota. All subjects were enrolled in Stage 1, in which prior knowledge of each subject's tumoral Src-activity was not known. |
|---|---|
| Pre-assignment Detail |
| Arm/Group Title | Dasatinib |
|---|---|
| Arm/Group Description | Dasatinib: 70 mg PO twice daily until progression. |
| Period Title: Overall Study | |
| STARTED | 37 |
| COMPLETED | 25 |
| NOT COMPLETED | 12 |
Baseline Characteristics
| Arm/Group Title | Dasatinib |
|---|---|
| Arm/Group Description | Dasatinib: 70 mg PO twice daily until progression. |
| Overall Participants | 37 |
| Age (years) [Mean (Standard Deviation) ] | |
| Mean (Standard Deviation) [years] |
61.7
(8.0)
|
| Sex: Female, Male (Count of Participants) | |
| Female |
18
48.6%
|
| Male |
19
51.4%
|
| Race (NIH/OMB) (Count of Participants) | |
| American Indian or Alaska Native |
0
0%
|
| Asian |
1
2.7%
|
| Native Hawaiian or Other Pacific Islander |
0
0%
|
| Black or African American |
8
21.6%
|
| White |
28
75.7%
|
| More than one race |
0
0%
|
| Unknown or Not Reported |
0
0%
|
| Region of Enrollment (participants) [Number] | |
| United States |
37
100%
|
Outcome Measures
| Title | Tumor Response |
|---|---|
| Description | 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 |
| Time Frame | 2 years |
Outcome Measure Data
| Analysis Population Description |
|---|
| Unable to determine the response for 9 subjects. |
| Arm/Group Title | Dasatinib |
|---|---|
| Arm/Group Description | Dasatinib: 70 mg PO twice daily until progression. |
| Measure Participants | 16 |
| Complete Response |
0
0%
|
| Partial Response |
0
0%
|
| Stable Disease |
5
13.5%
|
| Progression of Disease |
11
29.7%
|
| Title | Overall Survival |
|---|---|
| Description | Overall survival (OS) is the duration from date of consent to date of death from any cause. |
| Time Frame | Progression and survival every 6 months |
Outcome Measure Data
| Analysis Population Description |
|---|
| All subjects who received at least one dose of dasatinib were included in the analysis. |
| Arm/Group Title | Dasatinib |
|---|---|
| Arm/Group Description | Dasatinib: 70 mg PO twice daily until progression. |
| Measure Participants | 25 |
| Median (95% Confidence Interval) [months] |
3.7
|
| Title | Grade 3-5 Toxicity Associated With Dasatinib Treatment |
|---|---|
| Description | 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. |
| Time Frame | Duration of dasatinib treatment plus 30 days |
Outcome Measure Data
| Analysis Population Description |
|---|
| All subjects who received at least one dose of dasatinib were included in the analysis. |
| Arm/Group Title | Dasatinib |
|---|---|
| Arm/Group Description | Dasatinib: 70 mg PO twice daily until progression. |
| Measure Participants | 25 |
| Number [participants] |
12
32.4%
|
| Title | Describe Change in Serum Levels of C-terminal Cross-linked Collagen I Between Pre-treatment and 6 Weeks After Starting Dasatinib. |
|---|---|
| Description | |
| Time Frame | 2 years |
Outcome Measure Data
| Analysis Population Description |
|---|
| Assays were not run because no objective tumor response was observed. |
| Arm/Group Title | Dasatinib |
|---|---|
| Arm/Group Description | Dasatinib: 70 mg PO twice daily until progression. |
| Measure Participants | 0 |
| Title | Determine Relationship Between K-ras Gene Mutation and Response to Dasatinib. |
|---|---|
| Description | |
| Time Frame | 2 years |
Outcome Measure Data
| Analysis Population Description |
|---|
| Assays were not run because no objective tumor response was observed. |
| Arm/Group Title | Dasatinib |
|---|---|
| Arm/Group Description | Dasatinib: 70 mg PO twice daily until progression. |
| Measure Participants | 0 |
Adverse Events
| Time Frame | ||
|---|---|---|
| Adverse Event Reporting Description | ||
| Arm/Group Title | Evalulable Patients That Received Dasatinib | |
| Arm/Group Description | Dasatinib: 70 mg PO twice daily until progression. | |
All Cause Mortality |
||
| Evalulable Patients That Received Dasatinib | ||
| Affected / at Risk (%) | # Events | |
| Total | / (NaN) | |
Serious Adverse Events |
||
| Evalulable Patients That Received Dasatinib | ||
| Affected / at Risk (%) | # Events | |
| Total | 17/25 (68%) | |
| Blood and lymphatic system disorders | ||
| decreased hemoglobin | 1/25 (4%) | |
| decreased leukocytes | 1/25 (4%) | |
| Gastrointestinal disorders | ||
| nausea | 2/25 (8%) | |
| vomiting | 1/25 (4%) | |
| General disorders | ||
| anorexia | 1/25 (4%) | |
| dehydration | 1/25 (4%) | |
| fatigue | 5/25 (20%) | |
| hyponatremia - metabolic/lab | 1/25 (4%) | |
| muscle weakness (generalized) | 1/25 (4%) | |
| neuro-motor (generalized weakness) | 1/25 (4%) | |
| pericardial effusion | 1/25 (4%) | |
| Respiratory, thoracic and mediastinal disorders | ||
| dyspnea | 6/25 (24%) | |
Other (Not Including Serious) Adverse Events |
||
| Evalulable Patients That Received Dasatinib | ||
| Affected / at Risk (%) | # Events | |
| Total | 25/25 (100%) | |
| Blood and lymphatic system disorders | ||
| decreased hemoglobin | 8/25 (32%) | |
| decreased neutrophils | 1/25 (4%) | |
| elevated AST | 2/25 (8%) | |
| neutrophils (neutropenia) | 1/25 (4%) | |
| Cardiac disorders | ||
| pulmonary edema | 1/25 (4%) | |
| Gastrointestinal disorders | ||
| diarrhea | 3/25 (12%) | |
| flatulence | 1/25 (4%) | |
| nausea | 6/25 (24%) | |
| taste alteration | 3/25 (12%) | |
| vomiting | 2/25 (8%) | |
| General disorders | ||
| anorexia | 6/25 (24%) | |
| dizziness (lightheadedness) | 1/25 (4%) | |
| edema (periorbital/face) | 1/25 (4%) | |
| elevated LDH | 1/25 (4%) | |
| fatigue | 8/25 (32%) | |
| insomnia | 1/25 (4%) | |
| leukocytosis | 1/25 (4%) | |
| muscle weakness - lower extremity (leg weakness) | 1/25 (4%) | |
| muscle weakness (generalized) | 1/25 (4%) | |
| pain extremity (legs) | 1/25 (4%) | |
| pedal edema | 1/25 (4%) | |
| weight loss | 2/25 (8%) | |
| Musculoskeletal and connective tissue disorders | ||
| myalgias (generalized) | 1/25 (4%) | |
| pain-joint | 1/25 (4%) | |
| Renal and urinary disorders | ||
| elevated creatinine | 1/25 (4%) | |
| renal/genitourinary other (slow starting urinary stream) | 1/25 (4%) | |
| Respiratory, thoracic and mediastinal disorders | ||
| bronchospasm (wheezing) | 2/25 (8%) | |
| dyspnea | 2/25 (8%) | |
| hypoxia | 1/25 (4%) | |
| pleural effusion | 2/25 (8%) | |
| pleural effusion, bilateral | 1/25 (4%) | |
| Skin and subcutaneous tissue disorders | ||
| hair loss (alopecia) | 1/25 (4%) | |
| rash | 6/25 (24%) | |
| ulcers (scrotal) | 1/25 (4%) | |
Limitations/Caveats
More Information
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
| Name/Title | Michael Kelley , MD |
|---|---|
| Organization | Duke University Medical Center |
| Phone | 919-286-0411 ext 7326 |
| kelleym@duke.edu |
- Pro00008303