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

NCT ID: NCT00509366

Last Updated: 2014-08-28

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE2
• Total Enrollment: 101 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2007-05-31
• Study Completion Date: 2011-12-31

Brief Summary

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

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.

Conditions

Non Small Cell Lung Cancer

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Cisplatin Sensitive (Post-Amendment)

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).

Group Type: ACTIVE_COMPARATOR

Cisplatin & Gemcitabine

Intervention Type: DRUG

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 & Pemetrexed

Intervention Type: DRUG

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 Resistant (Post-Amendment)

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).

Group Type: ACTIVE_COMPARATOR

Docetaxel & Gemcitabine

Intervention Type: DRUG

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

Pemetrexed & Gemcitabine

Intervention Type: DRUG

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

Cisplatin Sensitive (Pre-Amendment)

Assignment to Treatment Group based on tumor genomics analysis:

Cisplatin day 1, Gemcitabine days 1 & 8

Group Type: ACTIVE_COMPARATOR

Cisplatin & Gemcitabine

Intervention Type: DRUG

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 Resistant (Pre-Amendment)

Assignment to Treatment Group based on tumor genomics analysis:

Pemetrexed day 1, Gemcitabine days 1 & 8

Group Type: ACTIVE_COMPARATOR

Pemetrexed & Gemcitabine

Intervention Type: DRUG

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

Interventions

Cisplatin & Gemcitabine

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

Intervention Type: DRUG

Cisplatin & Pemetrexed

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

Intervention Type: DRUG

Docetaxel & Gemcitabine

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

Intervention Type: DRUG

Pemetrexed & 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

Intervention Type: DRUG

Other Intervention Names

Gemzar; Alimta; Taxotere; Gemzar; Alimta; Gemzar

Eligibility Criteria

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:

1. ANC/AGC ≥1500 per uL

2. Platelets ≥100,000 per uL

3. Total bili ≤1.5 mg/dL

4. Creatinine ≤2 mg/dL; creatinine clearance ≥45 ml/min.

5. 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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Eli Lilly and Company

INDUSTRY

Sponsor Role: collaborator

Duke University

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Gordana Vlahovic, MD, MHS

Role: PRINCIPAL_INVESTIGATOR

Duke University

Locations

Duke University Medical Center

Durham, North Carolina, United States

Maria Parham Hospital

Henderson, North Carolina, United States

Scotland HealthCare System (Scotland Memorial Hospital)

Laurinburg, North Carolina, United States

Southeastern Regional Medical Center, Gibson Cancer Center

Lumberton, North Carolina, United States

Duke Raleigh Hospital

Raleigh, North Carolina, United States

Beaufort Memorial Hospital

Beaufort, South Carolina, United States

Coastal Cancer Center

Myrtle Beach, South Carolina, United States

Community Memorial Health Center

South Hill, Virginia, United States

Countries

United States

References

Potti A, Dressman HK, Bild A, Riedel RF, Chan G, Sayer R, Cragun J, Cottrill H, Kelley MJ, Petersen R, Harpole D, Marks J, Berchuck A, Ginsburg GS, Febbo P, Lancaster J, Nevins JR. Genomic signatures to guide the use of chemotherapeutics. Nat Med. 2006 Nov;12(11):1294-300. doi: 10.1038/nm1491. Epub 2006 Oct 22.

Reference Type: BACKGROUND

PMID: 17057710 (View on PubMed)

Bild AH, Yao G, Chang JT, Wang Q, Potti A, Chasse D, Joshi MB, Harpole D, Lancaster JM, Berchuck A, Olson JA Jr, Marks JR, Dressman HK, West M, Nevins JR. Oncogenic pathway signatures in human cancers as a guide to targeted therapies. Nature. 2006 Jan 19;439(7074):353-7. doi: 10.1038/nature04296. Epub 2005 Nov 6.

Reference Type: BACKGROUND

PMID: 16273092 (View on PubMed)

Related Links

http://www.cancer.duke.edu/CTrials/index.php

Clinical Trials at Duke Comprehensive Cancer Center

Other Identifiers

Pro00004599

Identifier Type: -

Identifier Source: org_study_id