Adjuvant Cisplatin With Either Genomic-Guided Vinorelbine or Pemetrexed for Early Stage Non-Small-Cell Lung Cancer (TOP0703)

• Estimate percentage of completely resected non-squamous NSCLC tumors that can be analyzed and used to direct adjuvant chemotherapy [ Time Frame: 2 years ] [ Designated as safety issue: No ]
• Describe overall survival experience of patients treated according to their tumor genomic expression profile for sensitivity to chemotherapy [ Time Frame: 2 years ] [ Designated as safety issue: No ]
• Assess patient understanding and perceptions of participating in a clinical trial evaluating cancer genomics for adjuvant treatment of early stage lung cancer [ Time Frame: 2 years ] [ Designated as safety issue: No ]
• Compare drug sensitivity patterns of cisplatin and pemetrexed in both treatment arms [ Time Frame: 2 years ] [ Designated as safety issue: No ]

This study will assign subjects to either cisplatin/vinorelbine or cisplatin/pemetrexed chemotherapy using a genomic based expression profile to determine chemotherapy sensitivity in completely resected early stage non-squamous non-small-cell lung cancer (NSCLC). Once patient eligibility is determined, the genomic expression profile will be done on fresh frozen tumor with a diagnosis of non-squamous NSCLC resected at the time of surgery. Two-year progression free survival was chosen as an endpoint in order to assess the effectiveness of directed adjuvant chemotherapy regimens in a population of patients receiving platinum based chemotherapy for early stage non-squamous NSCLC.

The proposed study is a multi-center open label phase II study of the chemotherapy doublets cisplatin/vinorelbine and cisplatin/pemetrexed as adjuvant therapy in early stage non-squamous NSCLC.

Eligible patients will have no previous treatment for the current diagnosis of non-squamous NSCLC. The two treatment groups of patients will be determined by gene expression profile analysis of each patient's tumor: one group of vinorelbine-sensitive patients and one group of pemetrexed-sensitive patients. The genomic expression profiling that will be utilized generates a percentage for likelihood of chemotherapy sensitivity. Patients will be directed to receive the chemotherapy regimen for which the percentage of predicted sensitivity is highest. For instance, if the model predicted the likelihood of tumor sensitivity was 46% to vinorelbine and 48% to pemetrexed, then the adjuvant chemotherapy would be directed to cisplatin/pemetrexed. Patients whose tumors cannot be adequately analyzed for gene expression will be offered adjuvant therapy off protocol as deemed appropriate by their primary oncologist.

One hundred and seventeen patients with stage IB (> 4 cm), II or IIIA non-squamous NSCLC will be enrolled. The vinorelbine-sensitive tumors group will receive Vinorelbine 25 mg/m2 days 1 and 8, followed by cisplatin 75 mg/m2 day 1, every 21 days for 4 cycles. The pemetrexed-sensitive tumors group will receive pemetrexed 500 mg/m2 day 1 followed by cisplatin 75 mg/m2 day 1, every 21 days for 4 cycles. Standard pre-medication regimens will include dexamethasone, vitamin B12 and folate supplementation in the pemetrexed group. Patients in both groups will receive up to a maximum of 4 cycles of therapy.

A pilot study is appropriate in this case because currently there is not a defined clinical role for genomics technology in determining therapy for NSCLC. The two chemotherapy regimens provided to the study patients are active agents in the treatment of non-squamous NSCLC. Study treatment will consist of 4 cycles of chemotherapy.

• Drug: Vinorelbine followed by Cisplatin
  Vinorelbine 25 mg/m2 IV over 6-10 minutes on days 1 and 8, followed by Cisplatin 75 mg/m2 IV over 60 minutes on day 1 (every 21 days x 4 cycles).
  Other Names:

  • Navelbine
  • Platinol
• Drug: Pemetrexed followed by Cisplatin
  Pemetrexed 500 mg/m2 IV infusion over approximately 10 minutes on day 1, followed by Cisplatin 75 mg/m2 IV over 60 min on day 1 (every 21 days x 4 cycles)
  Other Names:

  • Alimta
  • Platinol

• Arm A-Vinorelbine
  Resected tumor will be used for genomic expression profiling. Patients with a genomic expression pattern suggestive of vinorelbine sensitivity will be given cisplatin + vinorelbine.
  Intervention: Drug: Vinorelbine followed by Cisplatin
• Arm B-Pemetrexed
  Resected tumor will be used for genomic expression profiling. Patients with a genomic expression pattern suggestive of pemetrexed sensitivity will be given cisplatin + pemetrexed.
  Intervention: Drug: Pemetrexed followed by Cisplatin

• Potti A, Mukherjee S, Petersen R, Dressman HK, Bild A, Koontz J, Kratzke R, Watson MA, Kelley M, Ginsburg GS, West M, Harpole DH Jr, Nevins JR. A genomic strategy to refine prognosis in early-stage non-small-cell lung cancer. N Engl J Med. 2006 Aug 10;355(6):570-80. Erratum in: N Engl J Med. 2007 Jan 11;356(2):201-2.
• 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. Epub 2006 Oct 22.

Inclusion Criteria:

Patients are eligible to be included in the study only if they meet all of the following criteria:

1. Patients with completely resected stage IB (> 4 cm), II, or IIIA Non-Squamous NSCLC. Patient must be enrolled and begin therapy within 4 to 12 weeks from the date of complete surgical resection.
2. Fresh tissue must be available for genomics expression profiling.
3. ECOG performance status of 0 or 1.
4. NO prior chemotherapy, radiation therapy, or biologic/targeted therapy within the last 5 years. Prior therapy with low dose methotrexate or similar medications is allowed if therapy used to treat non-malignant conditions.
5. Age ≥ 18 years.
6. No previous or concomitant malignancy in the past 5 years other than curatively-treated carcinoma in situ of the cervix, or basal cell or squamous cell carcinoma of the skin.
7. No other serious medical or psychiatric illness.
8. Signed informed consent.

9. Required laboratory data within one week of enrollment:

   • ANC or AGC ≥ 1500 per uL;
   • Platelets ≥ 100,000 per uL;
   • Total bilirubin ≤ 1.5 mg/dL;
   • Creatinine ≤ 2 mg/dL; creatinine clearance ≥ 45 mL/min;
   • SGOT/SGPT ≤ 1.5x ULN.
10. 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 determined by the patient and their health care team, during the study and for 3 months following the last dose of study drug.

Exclusion Criteria:

Patients will be excluded from the study if they meet any of the following criteria:

1. Treatment within the last 30 days with a drug that has not received regulatory approval for any indication at the time of study entry.
2. Concurrent administration of any other anti-tumor therapy (see #4 inclusion for exceptions).
3. Inability to comply with protocol or study procedures.
4. 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.
5. Major surgery (other than definitive lung cancer surgery) within two weeks of study or other serious concomitant systemic disorders that, in the opinion of the investigator, would compromise the safety of the patient or compromise the patient's ability to complete the study.
6. Myocardial infarction having occurred less than 6 months before inclusion, any known uncontrolled arrhythmia, symptomatic angina pectoris, active ischemia, or cardiac failure not controlled by medications.
7. Contraindication to corticosteroids.
8. Inability or unwillingness to take folic acid or vitamin B12 supplementation.
9. Unwillingness to stop taking herbal supplements while on study.
10. 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 study entry and throughout study enrollment as the distribution of pemetrexed in this fluid space is not fully understood.
11. Inability to discontinue administration of aspirin at a dose > 1300 mg/day or other long acting, non-steroidal anti-inflammatory agents for 2 days before, the day of, and 2 days after the dose of pemetrexed (5 days prior for long-acting agents such as piroxicam). Moderate dose ibuprofen may be continued.
12. Female patients that are pregnant or breast-feeding.