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

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Rare Diseases

Prostatic Neoplasms

Genital Neoplasms, Male

Urogenital Neoplasms

Genital Diseases

Genital Diseases, Male

Urogenital Diseases

Prostatic Diseases

Male Urogenital Diseases

Kennedy Disease

Androgens

Hormones

Androgen Antagonists

Nilutamide

Hormone Antagonists

Nilutamide 150mg orally each day for 28 days per cycle. After first progression, Nilutamide 150mg orally each day in combination with Dasatinib 100mg orally each day for 28 days per cycle.

Dasatinib 100mg orally daily x 28 days per cycle. After first progression, Dasatinib 100mg orally each day in combination with Nilutamide 150mg orally each day for 28 days per cycle.

Daniel George, MD

This is a phase II multi-center study to determine the clinical impact of using a patient-specific genomic expression signature of androgen receptor (AR) activity to determine therapy for patients with castration-resistant metastatic prostate cancer (CRPC). After patient eligibility is determined, the genomic signature will be applied to fresh frozen tissue harvested from a metastatic lesion during image-guided biopsy. After assessing for androgen receptor activity, the investigators will select patients for either continued androgen manipulation with nilutamide (high AR activity) or targeted therapy with dasatinib (low AR activity). Once patients develop a first progression on either arm, patients will receive combination therapy with dasatinib and nilutamide. The primary aim is to estimate the median progression free survival in men with CRPC treated according to tumor AR activity. The investigators hypothesize that by treating men based upon AR activity, median progression free survival (PFS) will improve from a historical median of 3.0 months to 6.0 months.

Prostate cancer is the most commonly diagnosed non-cutaneous malignancy of men in the United States and remains the second leading cause of cancer-related mortality among men. Novel approaches are necessary to personalize and improve treatment. The androgen receptor (AR) plays a critical role in the normal development and function of the prostate and promotes growth in most prostate cancers. Most patients with advanced prostate cancer have cancer that will initially respond to androgen-targeting therapy (focusing on decreasing the circulating levels of testosterone which is the primary source of ligand for the AR receptor). However, castrate resistance usually develops within 18 to 24 months and the median survival of men with castration resistant prostate cancer (CRPC) ranges between 12 to 18 months. Current options are limited including: secondary hormonal manipulations, radiopharmaceuticals, and chemotherapy and only docetaxel, a taxane that targets microtubules, has been proven to prolong survival.

Importantly, it has become clear that for some patients with CRPC, the prostate tumors remain dependent on AR activity. This has been supported by studies demonstrating different genetic and metabolic mechanisms by which prostate cancer cells maintain AR activity despite low levels of circulating androgen. An assay detecting AR activity that more comprehensively reflects the variety of mechanisms by which AR activity is preserved has the potential to accurately differentiate between men who have tumors still dependent on AR activity from those that are truly independent of AR activity. The identification of patients with continued AR activity has the potential to improve response to secondary hormonal manipulations; men with tumors having low levels of AR activity are likely to require alternative approaches.

We have developed a transcriptional "signature" for AR activity with the goal of identifying the true status of AR in tumors of men with CRPC. After validating the AR signature on in vitro and human prostate samples to ensure that it accurately and reproducibly detects AR activity, we applied the AR signature to several independent datasets to determine the distribution of CRPC tumors with preserved AR activity. Interestingly, there is consistent heterogeneity with respect to predicted AR activity. While overall AR activity decreases in CRPC, there is a subgroup of patients with persistently elevated AR activity. In tumors with low AR activity, we observed that the probability of AR activity was negatively correlated with predicted SRC activity in localized prostate cancer and CRPC.

Patients with persistently high AR activity will be treated with nilutamide, an approved oral agent used in metastatic CRPC to target the AR. Patients with tumors having low AR activity will be treated with dasatinib (an oral drug known to target the SRC family kinases). As there is compelling pre-clinical evidence of interactions between the SRC pathway and AR signaling, patients failing either single agent treatment will be treated with the combination of nilutamide and dasatinib and followed again for progression.

Genomic Guided Therapy With Dasatinib or Nilutamide in Metastatic Castration-Resistant Prostate Cancer

A Phase II Trial of Genomic Guided Therapy With Dasatinib or Nilutamide in Metastatic Castration-Resistant Prostate Cancer

PFS is the interval from start of monotherapy until first disease progression or death, whichever occurred first.

Tumor response was based on Response Criteria in Solid Tumors (RECIST). Complete response (CR) is defined as disappearance of all target and non-target lesions and normalization of tumor marker level. Partial response (PR) is defined as at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD.

Tumor response is based on Response Evaluation Criteria in Solid Tumors (RECIST). Complete response (CR) is defined as disappearance of all target and non-target lesions and normalization of tumor marker level. Partial response (PR) is defined as at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD.

High Androgen Receptor (AR) activity of \>= 0.50

Nilutamide: Nilutamide 150mg orally each day for 28 days per cycle. After first progression, Nilutamide 150mg orally each day in combination with Dasatinib 100mg orally each day for 28 days per cycle.

Arm 1=High AR Nilutamide

Low Androgen Receptor (AR) activity of \< 0.50

Dasatinib: Dasatinib 100mg orally daily x 28 days per cycle. After first progression, Dasatinib 100mg orally each day in combination with Nilutamide 150mg orally each day for 28 days per cycle.

Arm 2= Low AR Dasatinib

Combination Nilutamide and Dasatinib

Total

Age, Categorical

64 consented but 7 screen failures, so 57 enrolled. 2 never assigned to rx (withdrew consent, clinically unstable), 33 assigned by AR activity (15 high AR to nilutamide, 18 low AR to dasatinib) and 22 QC technical failures (received dasatinib). 14 of 15 high AR and 17 of 18 low AR began protocol treatment. Analyses include the 31 treated patients.

Dr. Daniel George

Progression Free Survival (PFS)

14 subjects began treatment; 13 with response documentation are included in the calculation; 1 subject was omitted because response documentation was not provided.

Overall Response Rate of Men With High AR Activity

Of the 17 subjects treated, 15 had response documentation and are included in the calculation. Two were omitted (1 because response documentation was not provided; 1 ended treatment after 2 weeks for toxicity prior to repeat scans).

Overall Response Rate of Men With Low AR Activity

Monotherapy

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.

Neal Ready, M.D.

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.

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.

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

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

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

Determine the safety and tolerability of neoadjuvant dasatinib in early stage NSCLC.

Determine whether gene expression profile activation of Src pathways is correlated with anti-tumor activity of dasatinib in early stage NSCLC.

Determine the safety and tolerability of adjuvant dasatinib in early stage NSCLC.

Neoadjuvant Dasatinib

70 mg dasatinib orally twice daily for 3 weeks

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

Neal Ready, MD

Response Rate

Due to insufficient accrual, data analysis was not performed.

Safety and Tolerability of Neoadjuvant Dasatinib

Gene Expression Profile Activation of Src Pathways

Safety and Tolerability of Adjuvant Dasatinib

Symptoms and General Pathology

Skin and Connective Tissue Diseases

Neoplasm Metastasis

Breast Neoplasms

Breast Diseases

Skin Diseases

Patients who have a "good signature" for the genomic analysis. They will receive the standard chemotherapy.

genomic signature

Jean-Marc EXTRA, MD

Method: This multicentric prospective cohort is composed of patients with no metastatic breast cancer selected by tumor's genomic analysis and treated by chemotherapy with Anthracycline without Taxanes (6 cycles of FEC 100).

The patient can be included before or after the surgery and a written consent must be signed for the proteomic and genomic analysis of the tumor.

Patients who have a "good signature" for the genomic analysis will receive the standard chemotherapy.

Primary objective:

* To compare metastasis free survival at 5 years in a cohort of patients with no metastatic breast cancer, who are selected by their genomic profile of the tumor and received a standard chemotherapy containing Anthracycline, with result of retrospectives studies.

Secondary Objectives:

* Overall survival.
* Creation of a circuit (transport-extraction-genomic analysis-result) which allows the beginning of the chemotherapy within 6 weeks following the primary surgery.
* Histological and seric proteomic exploratory studies.

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
Genomic Guided Therapy With Dasatinib or Nilutamide in Metastatic Castration-Resistant Prostate Cancer	NCT00918385	Prostate Cancer	Nilutamide Dasatinib	18 Years -	Duke University
Phase II Study Evaluating The Safety And Response To Neoadjuvant Dasatinib In Early Stage Non-Small Cell Lung Cancer	NCT00564876	Carcinoma, Non-...	Dasatinib	18 Years -	Duke University
Utilization of Genomic Signature as Decision-making for Adjuvant Treatment of Breast Cancer	NCT00912080	Breast Cancer	genomic signatu...	18 Years - 70 Years	Institut Paoli-Calmettes

Spots Global Cancer Trial Database for genomic signature