Neoplasms

Respiratory Tract (Lung and Bronchial) Diseases

All Conditions

Lung Neoplasms

Carcinoma, Non-Small-Cell Lung

Carcinoma

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

Carcinoma, Bronchogenic

Bronchial Neoplasms

Antineoplastic Agents

All Drugs and Chemicals

Amino Acids

Dasatinib

Tyrosine Kinase Inhibitors

Protein Kinase Inhibitors

Enzyme Inhibitors

Tyrosine

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.

70 mg PO twice daily until progression. Re-assess radiographically every 6 weeks.

Michael Kelley, MD

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.

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.

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

Phase II Study of Dasatinib in Previously Treated Patients With Advanced Non-Small Cell Lung Cancer (NSCLC)

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

Overall survival (OS) is the duration from date of consent to date of death from any cause.

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.

Bristol-Myers Squibb

Duke University

Dasatinib: 70 mg PO twice daily until progression.

Evalulable Patients That Received Dasatinib

Age, Continuous

Sex: Female, Male

Race (NIH/OMB)

United States

Region of Enrollment

All consented subjects included in baseline analysis.

Michael Kelley , MD

Complete Response

Partial Response

Stable Disease

Progression of Disease

Unable to determine the response for 9 subjects.

Tumor Response

All subjects who received at least one dose of dasatinib were included in the analysis.

Overall Survival

Grade 3-5 Toxicity Associated With Dasatinib Treatment

Assays were not run because no objective tumor response was observed.

Describe Change in Serum Levels of C-terminal Cross-linked Collagen I Between Pre-treatment and 6 Weeks After Starting Dasatinib.

Determine Relationship Between K-ras Gene Mutation and Response to Dasatinib.

Overall Study

Micronutrients

Hematinics

Vitamins

Gemcitabine

Pemetrexed

Docetaxel

Cisplatin

Antimetabolites

Tubulin Modulators

Antimitotic Agents

Folic Acid

Vitamin B Complex

Folic Acid Antagonists

Folinic Acid

Folate

Vitamin B9

Assignment to Treatment Group based on histology and tumor genomics analysis:

Squamous Cell NSCLC-Cisplatin day 1, Gemcitabine days 1 \& 8 Non-Squamous Cell NSCLC-Cisplatin day 1, Pemetrexed day 1

Per an amendment dated 1/25/2010, post-amendment treatment assignment refers to the further separation of patients into sub-groups, within the cisplatin sensitive arm, based on histology (squamous/non-squamous).

Assignment to Treatment Group based on histology and tumor genomics analysis:

Squamous Cell NSCLC-Docetaxel day 1, Gemcitabine days 1 \& 8 Non-Squamous Cell NSCLC-Pemetrexed day 1, Gemcitabine days 1 \& 8

Per an amendment dated 1/25/2010, post-amendment treatment assignment refers to the further separation of patients into sub-groups, within the cisplatin resistant arm, based on histology (squamous/non-squamous).

Assignment to Treatment Group based on tumor genomics analysis:

Cisplatin day 1, Gemcitabine days 1 \& 8

Assignment to Treatment Group based on tumor genomics analysis:

Pemetrexed day 1, Gemcitabine days 1 \& 8

Squamous Cell NSCLC:

Gemcitabine 1250 mg/m2 IV over 30 minutes day 1 and 8, followed by Cisplatin 75 mg/m2 IV over 60 minutes day 1; repeat every 21 days for up to 6 cycles

Cisplatin & Gemcitabine

Non-Squamous Cell NSCLC:

Pemetrexed 500 mg/m2 IV over approximately 10 minutes day 1, followed by Cisplatin 75 mg/m2 IV over 60 minutes day 1; repeat every 21 days for up to 6 cycles

Cisplatin & Pemetrexed

Squamous Cell NSCLC:

Docetaxel 75 mg/m2 IV over 60 minutes day 1, followed by Gemcitabine 1250 mg/m2 IV over 30-60 minutes day 1 and alone day 8; repeat every 21 days for up to 6 cycles

Docetaxel & Gemcitabine

Non-Squamous Cell NSCLC:

Pemetrexed 500 mg/m2 IV over approximately 10 minutes day 1, followed by Gemcitabine 1250 mg/m2 IV over 30-60 minutes day 1 and alone day 8; repeat every 21 days for up to 6 cycles

Pemetrexed & Gemcitabine

Gordana Vlahovic, MD, MHS

In this trial, subjects with chemo-naive advanced non-small cell lung cancer (NSCLC) were assigned to chemotherapy using a genomic-based predictor for platinum sensitivity. After an amendment dated 1/25/2010, subjects with squamous cell NSCLC sensitive to cisplatin received cisplatin/gemcitabine and if resistant to cisplatin received docetaxel/gemcitabine. Subjects with non-squamous cell NSCLC sensitive to cisplatin received cisplatin/pemetrexed and if resistant to cisplatin received pemetrexed/gemcitabine. The primary objective of this trial was to prospectively validate the genomic-based prediction model through separate evaluation of the one-year progression-free survival (PFS) of the cisplatin-sensitive and cisplatin-resistant cohorts. Secondary objectives included: assessment of overall time to progressive disease, quality of life and evaluation of drug sensitivity patterns of cisplatin and pemetrexed.

Lung cancer is the leading cause of cancer death in both men and women. The majority of patients with lung cancer have non-small cell type (NSCLC). The current standard of care for treating select stage IIIB and stage IV NSCLC is a doublet chemotherapy regimen, such as cisplatin plus gemcitabine, carboplatin plus paclitaxel, or a platinum agent plus vinorelbine. All of these regimens have comparable response rates as first-line therapy. In addition, the combination of cisplatin plus pemetrexed has recently been approved for non-squamous histology, based on results of a large randomized prospective trial in advanced stage NSCLC. Alternative doublet therapy for first-line treatment of NSCLC per ASCO and NCCN guidelines also include a non-platinum doublet or single agent therapy.

An individual patient's response to chemotherapy is the result of complex interactions between the drug(s) and the patient's genetics and environment. Using Affymetrix gene expression data with corresponding drug response data for cisplatin from the NCI60 lines panel, a gene expression based model predicative of cisplatin-resistant has been developed. However, reevaluation of the genomics-based prediction model showed that it was irreproducible, suggesting inaccurate patient assignments into the two cisplatin cohorts. As a result, it would be inappropriate to separately analyze outcomes for the different treatment groups. Instead, information from both cisplatin cohorts will be combined to reflect the overall measure of one-year progression-free survival in this study. Secondary outcomes will also reflect the overall measures of median time to disease progression and quality of life.

Study Using a Genomic Predictor of Platinum Resistance to Guide Therapy in Stage IIIB/IV Non-Small Cell Lung Cancer

Phase II Prospective Study Evaluating the Role of Personalized Chemotherapy Regimens for Chemo-Naive Select Stage IIIB and IV Non-Small Cell Lung Cancer (NSCLC) in Patients Using a Genomic Predictor of Platinum Resistance to Guide Therapy

One-year progression-free survival was defined from the time from initiation of study treatment to the first date of disease progression or death as a result of any cause. Progression was defined as at least a 20% increase in the sum of the longest diameter (LD) of target lesions taking as references the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. Time was censored at the date of the last follow-up visit for patients who were still alive and have not progressed. The one-year progression free survival rate is a percentage, representing the fraction of treated patients who, after one-year, are disease free or alive.

Median time to progressive disease was defined as the time from enrollment to the the time at which 50% of patients had experienced disease progression. Enrollment is defined as having successful genomic analysis and start of chemotherapy. Time was censored at date of death for patients who have not had documented disease progression, at first available date of other anti-tumor therapy for patients who were either administered other anti-tumor therapy prior to documented disease progression or administered other anti-tumor therapy without documented disease progression, and at last date of followup if neither non-protocol therapy was administered nor progression documented.

The outcome measure is mean change in the Trial Outcome Index (TOI) between baseline and each follow-up assessment measured by the Functional Assessment of Cancer Therapy-Lung (FACT-L). The FACT-L instrument consists of 34 items to assess physical (PWB), social and family (SWB), emotional (EWB), functional well-being (FWB) and additional lung specific concerns (LCS). Using a 5-point Likert type scale, responses to individual items range from 0 (not at all) to 4 (Very Much) with higher scores indicating better quality of life. The TOI is the sum of PWB (7 items), FWB (7 items) and LCS scores (7 items), which each have a possible range between 0 and 28. Therefore, TOI ranges from 0 to 84.

Using genomics-based prediction models previously developed separately for cisplatin and pemetrexed, the probability that each patient was sensitive or would respond to treatment was computed. Quartiles describe the patterns of drug sensitivity probabilities. The 1st, 2nd, and 3rd quartiles are the sensitivity levels at which 25%, 50%, and 75% of patients have lower sensitivity.

Eli Lilly and Company

Pre-amendment cisplatin sensitive refers to patients who experienced adverse events and treated with cisplatin-sensitive protocol based therapy per the amendment dated 1/25/2010.

Cisplatin Sensitive (Pre-Amendment)

Post-amendment cisplatin sensitive refers to patients who experienced adverse events and treated with cisplatin-sensitive protocol based therapy per the amendment dated AFTER 1/25/2010.

Cisplatin Sensitive (Post-Amendment)

Pre-amendment cisplatin resistant refers to patients who experienced adverse events and treated with cisplatin-resistant protocol based therapy per the amendment dated 1/25/2010.

Cisplatin Resistant (Pre-Amendment)

Pre-amendment cisplatin sensitive refers to patients who experienced adverse events and treated with cisplatin-sensitive protocol based therapy per the amendment dated AFTER 1/25/2010.

Cisplatin Resistant (Post-Amendment)

Screen failures constitute patients who were registered into the study and underwent protocol-based procedure (e.g. biopsy, genomic screening), but were not enrolled to genomics-directed, protocol-based therapy. From the participant flow, 9 of the 54 screen failures did not have adverse event follow-up, resulting in a final count of 45 screen failures with adverse event follow-up.

Screen Failure

Cisplatin Sensitive patients were registered at the start of the study, assigned to cisplatin/gemcitabine protocol-based treatment consistent with histology, and treated during the course of the study.

Cisplatin + Gemcitabine

Cisplatin Sensitive patients were registered at the start of the study, assigned to cisplatin/pemetrexed protocol-based treatment consistent with histology, and treated during the course of the study.

Cisplatin + Pemetrexed

Cisplatin Resistant patients were registered at the start of the study, assigned to cisplatin/gemcitabine resistant protocol-based treatment consistent with histology, and treated during the course of the study.

Pemetrexed + Gemcitabine

Cisplatin Resistant patients were registered at the start of the study, assigned to docetaxel/gemcitabine resistant protocol-based treatment consistent with histology, and treated during the course of the study.

Docetaxel + Gemcitabine

Screen failures constitute patients who were registered into the study but were not assigned to treatment due to unsuccessful genomic analysis or those who were assigned treatment but not treated after reevaluation of their eligibility.

Total

The number of participants in each group reflects the number of participants at the end of the study period (COMPLETED) in the Participant Flow Analysis, with the exception of 3 patients who were assigned treatment, but not treated, and were added to the number of screen failures.

The microarray-based prediction model of chemotherapy sensitivity, used to allocate patients into the cisplatin treatment arms, was irreproducible and inaccurate. Quality of life measurements were incomplete and could not be analyzed.

Neal Ready, MD, PhD

Treatment refers to the combined cisplatin sensitive and resistant arms of the study. Due to the irreproducibility of the genomics-based prediction model for assigning patients into the original cisplatin treatment arms, patients from both arms were combined for analysis.

Treatment

Due to the irreproducible nature of the genomic signatures of cisplatin sensitivity, analyses based on separate treatment groups were inappropriate. Therefore, all enrolled participants (initiated for treatment) from both treatment arms were analyzed together.

1-year Progression Free Survival Rate in Chemo-naive Select Stage IIIB or Stage IV NSCLC Patients

Median Time to Progressive Disease

Change from baseline to Cycle 1

Change from baseline to Cycle 2

Change from baseline to Cycle 3

Change from baseline to Cycle 4

Change from baseline to Cycle 5

Change from baseline to Cycle 6

Treatment refers to the combined cisplatin sensitive (cisplatin/pemetrexed or cisplatin/gemcitabine) and resistant (pemetrexed/gemcitabine or docetaxel/gemcitabine) arms of the study. Due to the irreproducibility of the genomics-based prediction model for assigning patients into the original cisplatin treatment arms, patients from both arms were combined for analysis.

Of the 50 patients assigned treatment, only 32 patients completed the FACT-L assessment at baseline and at least one follow-up.

Mean Change From Baseline to Follow-up Cycle in Quality of Life - Functional Assessment of Cancer Therapy-Lung (FACT-L)

Treatment refers to the combined cisplatin sensitive and resistant arms of the study.

This outcome is not summarized due to irreproducibility of the genomics-based prediction model and resulting probability estimates.

Drug Sensitivity Quartiles for Cisplatin and Pemetrexed

Cisplatin Sensitive patients were registered at the start of the study and assigned to cisplatin + gemcitabine protocol-based treatment consistent with histology. One patient who was assigned to this arm withdrew from the study. This patient did not receive protocol treatment and was classified as a screen failure.

Cisplatin Sensitive patients were registered at the start of the study and assigned to cisplatin + pemetrexed protocol-based treatment consistent with histology. One patient who was assigned to this arm was deemed ineligible due to the discover of brain metastasis. This patient did not receive protocol treatment and was classified as a screen failure.

Cisplatin Resistant patients were registered at the start of the study and assigned to pemetrexed + gemcitabine protocol-based treatment consistent with histology. One patient who was assigned to this arm was later deemed ineligible before initiating protocol treatment and was classified as a screen failure.

Cisplatin Resistant patients were registered at the start of the study and assigned to docetaxel+ gemcitabine protocol-based treatment consistent with histology.

Screen failures constitute patients who were registered into the study but were not assigned to treatment due to unsuccessful genomic analysis. Nine patients did not undergo biopsy. Eight experienced complications from biopsy. The remaining 34 were deemed ineligible after genomic screening. Note that three patients who were assigned protocol-based treatment (2 in the cisplatin sensitive group and 1 in the cisplatin resistant group) did not receive the treatment and were added to the 51 initially identified as screen failures within the summary of baseline characteristics and outcome measures.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Phase II Study of Dasatinib in Previously Treated Patients With Advanced NSCLC	NCT00787267	Non Small Cell ...	Dasatinib	18 Years -	Duke University
Phase II Study of Dasatinib in Previously Treated Patients With Advanced NSCLC	NCT00787267	Non Small Cell ...	Dasatinib	18 Years -	Duke University
Study Using a Genomic Predictor of Platinum Resistance to Guide Therapy in Stage IIIB/IV Non-Small Cell Lung Cancer	NCT00509366	Non Small Cell ...	Cisplatin & Gem... Cisplatin & Pem... Docetaxel & Gem... Pemetrexed & Ge...	18 Years -	Duke University

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