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

• ClinicalTrials.gov Identifier: NCT00545948
• Recruitment Status: Terminated
• First Posted: October 18, 2007
• Results First Posted: June 9, 2014
• Last Update Posted: July 21, 2014
• Sponsor: Duke University
• Collaborator: Eli Lilly and Company
• Information provided by (Responsible Party): Duke University

Tracking Information

• First Submitted Date: October 16, 2007
• First Posted Date: October 18, 2007
• Results First Submitted Date: May 7, 2014
• Results First Posted Date: June 9, 2014
• Last Update Posted Date: July 21, 2014
• Study Start Date: December 2007
• Actual Primary Completion Date: January 2012 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 7, 2014)

2-Year Progression-Free Survival Rate in Patients With Completely Resected Stage IB, II, or IIIA NSCLC [ Time Frame: 2 years ]

Progression-free survival time was defined as 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 two-year progression free survival rate is a percentage, representing the fraction of treated patients who, after two years, are disease free or alive.

• Original Primary Outcome Measures (submitted: October 17, 2007): Two year progression-free survival rate. [ Time Frame: Two year ]

Current Secondary Outcome Measures (submitted: June 25, 2014)

• Percentage of Patients With Completely Resected NSCLC Tumors That Can Be Analyzed and Used to Direct Adjuvant Chemotherapy [ Time Frame: 4 years ]
  The percentage of patients with completely resected NSCLC tumors who had successful genomic analysis and assigned to treatment among patients. All 31 patients enrolled in the study had completely resected tumors. These tumors included a mixture of squamous and non-squamous histologies as indicated the original protocol. However, an amendment dated January 25, 2010 limited eligibility to patients with non-squamous disease. Given that only 5 patients were accrued into the study after this amendment, results reported will consider all histologies.
• 2-Year Overall Survival in Patients Treated for NSCLC [ Time Frame: 2 years ]
  Overall survival time was defined as the time from initiation of study treatment to the date of death as a result of any cause. Time was censored at the date of the last follow-up visit for patients who were still alive. The two-year overall survival rate is a percentage, representing the fraction of treated patients who, after two years, are alive
• Patient Understanding and Perceptions of Participating in a Clinical Trial Evaluating Cancer Genomics for Adjuvant Treatment of Early Stage Lung Cancer [ Time Frame: Baseline ]
  Do to space limitations, see the Detailed Description in the study protocol for the wording of the questions used in the Patient Expectations Questionnaire.
• Compare Drug Sensitivity Patterns of Cisplatin and Pemetrexed in Both Treatment Arms [ Time Frame: 2 years ]
  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. There is lack of integrity regarding the available data due to irreproducible genomic signatures. Therefore the results of this outcome are not presented.

• Original Secondary Outcome Measures (submitted: October 17, 2007): Time to progressive disease, which is defined as the time from enrollment to the first date of disease progression.
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Adjuvant Cisplatin With Either Genomic-Guided Vinorelbine or Pemetrexed for Early Stage Non-Small-Cell Lung Cancer
• Official Title: Phase II Prospective Study Evaluating the Role of Directed Cisplatin Based Chemo With Either Vinorelbine or Pemetrexed for the Adj Tx of Early Stage NSCLC in Patients Using Genomic Expression Profiles of Chemo Sensitivity to Guide Therapy
• Brief Summary: This study assigned 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). The vinorelbine-sensitive tumors group received Vinorelbine followed by cisplatin, while the pemetrexed-sensitive tumors group received pemetrexed followed by cisplatin. The primary objective of this trial was to determine whether genomic-based adjuvant chemotherapy treatment increased the 2-year progression-free survival rate in completely resected patients with NSCLC compared to historic controls. Secondary objectives included: 1) estimation of the percentage of completely resected NSCLC tumors that can be adequately analyzed and used to direct specific adjuvant chemotherapy; 2) estimation of the proportion of patients who are assigned to treatment with vinorelbine and pemetrexed; 3) evaluation of drug sensitivity patterns of cisplatin and pemetrexed in both treatment arms; 4) description of the overall median survival experience of treated patients; and 5) assessment of patient understanding and perceptions of participating in a clinical trial evaluating cancer genomics for adjuvant treatment of early stage lung cancer.

Detailed Description

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 had no previous treatment for the current diagnosis of 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 was utilized generated a percentage for likelihood of chemotherapy sensitivity. Patients were 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 could not be adequately analyzed for gene expression were offered adjuvant therapy off protocol as deemed appropriate by their primary oncologist. Patients with either squamous or non-squamous cell histology were eligible to participate in this study as indicated in study protocols dated prior to January 25, 2010. An amendment to the protocol on January 25, 2010 indicated inclusion of only non-squamous histology. However, because of low accrual after January 25, 2010 (5 patients, including 2 screen failures), this report reflects the original study outcomes that includes both squamous and non-squamous histologies.

Thirty-one patients with stage IB (> 4 cm), II or IIIA non-squamous NSCLC were enrolled, from which 24 were assigned treatment. The vinorelbine-sensitive tumors group received 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 received pemetrexed 500 mg/m2 day 1 followed by cisplatin 75 mg/m2 day 1, every 21 days for 4 cycles. Standard pre-medication regimens included 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.

Subsequent reevaluation of the genomic signatures of chemotherapy sensitivity have shown that they were irreproducible, suggesting inaccurate patient assignments into the two treatment arms. As a result, it would be inappropriate to separately analyze outcomes for the different treatment groups. Instead, information from both arms will be combined to reflect the overall measure of two-year progression-free survival in this study. Similarly for secondary objectives, both arms will be combined to address endpoints.

To assess patient understanding and perceptions of participating in a clinical trial evaluating cancer genomics for adjuvant treatment of early stage lung cancer, patients provided responses for the following questions at baseline:

1. Did your doctor talk to you today about choosing chemotherapy treatment for lung cancer based on the genomics of your tumor?
2. How well did you understand what you doctor told you about choosing chemotherapy based on the genomics of your tumor? (circle a number between 1 and 7, where 1 = very poorly and 7 = very well)
3. Do you think the type of chemotherapy that you will get is based on the genomics of your tumor?
4. Do you think you will get better medical care for the treatment of your lung cancer if it is based on the genomics of your tumor?
5. To what extent do you think treating lung cancer based on the genomics of the tumor will lead to more successful treatment strategies? (circle a number between 1 and 7, where 1 = definitely will not lead to a more successful treatment and 7 = definitely will lead to a more successful treatment)
6. How effective do you think chemotherapy will be at stopping your cancer from coming back? (circle a number between 1 and 7, where 1 = not at all effective and 7 = completely effective)
7. To what extent is YOUR lung cancer primarily caused by genetics? (circle a number between 1 and 7, where 1 = not at all caused by genetics and 7 = completely caused by genetics)
8. To what extent to do you think your lung cancer is treatable? (circle a number between 1 and 7, where 1 = definitely not treatable and 7 = definitely treatable)
9. Did your doctor talk to you about your chance of your lung cancer coming back? (Yes - go to question 10, No - go to question 11, Do not know - go to question 11)
10. What did your doctor say was your chance of your cancer coming back? (Low Risk, Moderate or intermediate risk, High risk, Do not know)
11. What do you think is your chance of your lung cancer coming back in the next year on a scale from 1 to 7 where 1=definitely will not come back and 7=definitely will come back?
12. How worried are you that your lung cancer will come back in the next year? (circle a number between 1 and 7, where 1=not at all worried and 7=extremely worried)

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Carcinoma, Non-Small-Cell Lung

Intervention

• 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

Study Arms

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

Publications *

• 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. doi: 10.1056/NEJMoa060467. Erratum In: N Engl J Med. 2007 Jan 11;356(2):201-2.
  Retraction in: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. N Engl J Med. 2011 Mar 24;364(12):1176
• 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. Erratum In: Nat Med. 2007 Nov;13(11):1388. Nat Med. 2008 Aug;14(8):889.
  Retraction in: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. Nat Med. 2011 Jan;17(1):135

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: May 7, 2014): 31
• Original Estimated Enrollment (submitted: October 17, 2007): 117
• Actual Study Completion Date: January 2012
• Actual Primary Completion Date: January 2012 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT00545948
• Other Study ID Numbers: Pro00000657
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Duke University
• Original Responsible Party: Not Provided
• Current Study Sponsor: Duke University
• Original Study Sponsor: Same as current
• Collaborators: Eli Lilly and Company

Investigators

• Principal Investigator: Neal Ready, Ph.D., M.D.; Duke University Medical Center, Hematology/Oncology, Duke Cancer Institute

• PRS Account: Duke University
• Verification Date: June 2014