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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Non Small Cell Lung Cancer

Intervention / Treatment
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* Drug: Cisplatin & Gemcitabine
* Drug: Cisplatin & Pemetrexed
* Drug: Docetaxel & Gemcitabine
* Drug: Pemetrexed & Gemcitabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Suspected or histologic/cytologic select stage IIIB or IV NSCLC, not amenable to curative treatment with surgery or XRT. Histologic/cytologic documentation of recurrence required in patients who were previously completely resected and now have metastatic disease. Fresh frozen tissue must be available to generate and apply the genomics predictor. If not obtained at the time of diagnosis, then subject must consent to another biopsy as a fresh tissue sample must yield adequate high quality RNA. Patients with symptomatic brain metastases must complete brain XRT and be neurologically stable (steroids permitted) prior to research biopsy. If patient had prior XRT therapy, fresh frozen tissue biopsy for genomics analysis must be outside XRT field. At least one, non-radiated, measurable lesion by RECIST criteria. ECOG performance status of 0 or 1. NO prior chemo, biologic or targeted therapy for any malignancy. Prior therapy with low dose methotrexate or similar medications allowed if used for non-malignant conditions. Prior XRT therapy is permitted if ≥1 week since completion of XRT (≥2 weeks for whole brain XRT). XRT must be <25% of bone marrow reserve. Age ≥18 years. No previous or concomitant malignancy in past 5 years other than surgical management for carcinoma in situ of the cervix, breast, NSCLC, basal cell or squamous cell carcinoma of the skin. No other serious medical or psychiatric illness. Signed informed consent. Required lab data within 2 weeks of enrollment: ANC/AGC ≥1500 per uL Platelets ≥100,000 per uL Total bili ≤1.5 mg/dL Creatinine ≤2 mg/dL; creatinine clearance ≥45 ml/min. SGOT/SGPT ≤3x ULN except in presence of known hepatic mets (may be up to 5x ULN) unless receive docetaxel/gemcitabine than SGOT/SGPT ≤1.5x ULN. Females of child-bearing potential (not surgically sterilized and between menarche and 1 year post menopause) must test negative for pregnancy within 7 days prior to or at the time of enrollment based on a serum pregnancy test. Both sexually active males and females of reproductive potential must agree to use a reliable method of birth control, as determine by the patient and their health care team, during study and for 3 months following the last dose of study drug. Exclusion Criteria: Treatment within the last 30 days with a drug that has not received regulatory approval for any indication at the time of study entry. Concurrent administration of any other anti-tumor therapy (see #5 inclusion for exceptions). Inability to comply with protocol or study procedures. Active infection requiring IV antibiotics, antifungal or antiviral agents, that in the opinion of the investigator would compromise the patient's ability to tolerate therapy. Untreated CNS metastases unless brain XRT completed and neurologically stable (steroids permitted). Major surgery within 2 weeks of study or other serious concomitant systemic disorders that would compromise the safety of the patient or patient's ability to complete the study. MI having occurred less than 6 months before inclusion, any known uncontrolled arrhythmia, symptomatic angina pectoris, active ischemia or cardiac failure not controlled by meds. Contraindications to corticosteroids. Inability/unwillingness to take folic acid or vitamin B12. Unwillingness to stop taking herbal supplements while on study. Presence of clinically significant third-space fluid collections (for example, ascites or pleural effusions) that cannot be controlled by drainage or other procedures prior to treatment initiation and throughout study enrollment. Inability to discontinue aspirin at a dose >1300 mg/day or other non-steroidal anti-inflammatory agents for 2 days before, the day of, and 2 days after the dose of pemetrexed (5 days for long-acting agents such as piroxicam). Female patients that are pregnant or breast-feeding.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Cisplatin Sensitive (Post-Amendment)<br>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). | Drug: Cisplatin & Gemcitabine<br>* 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<br>* Other names: Gemzar;Drug: Cisplatin & Pemetrexed<br>* 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<br>* Other names: Alimta;|
| Active Comparator: Cisplatin Resistant (Post-Amendment)<br>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). | Drug: Docetaxel & Gemcitabine<br>* 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<br>* Other names: Gemzar;Drug: Pemetrexed & Gemcitabine<br>* 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<br>* Other names: Gemzar;|
| Active Comparator: Cisplatin Sensitive (Pre-Amendment)<br>Assignment to Treatment Group based on tumor genomics analysis: Cisplatin day 1, Gemcitabine days 1 & 8 | Drug: Cisplatin & Gemcitabine<br>* 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<br>* Other names: Gemzar;|
| Active Comparator: Cisplatin Resistant (Pre-Amendment)<br>Assignment to Treatment Group based on tumor genomics analysis: Pemetrexed day 1, Gemcitabine days 1 & 8 | Drug: Pemetrexed & Gemcitabine<br>* 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<br>* Other names: Gemzar;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 1-year Progression Free Survival Rate in Chemo-naive Select Stage IIIB or Stage IV NSCLC Patients | 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. | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median Time to Progressive Disease | 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. | 1 Year | 
| Mean Change From Baseline to Follow-up Cycle in Quality of Life - Functional Assessment of Cancer Therapy-Lung (FACT-L) | 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. | Baseline, Every 21 days for a maximum of 6 cycles | 
| Drug Sensitivity Quartiles for Cisplatin and Pemetrexed | 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. | 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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genomics, genomics predictor, genomics analysis, squamous, non-squamous