Trial on Refinement of Early Stage Lung Cancer Adjuvant Therapy
Condition: Non Small Cell Lung Cancer
MeSH terms: Lung Neoplasms; Carcinoma, Non-Small-Cell Lung
Study type: Interventional
Phase: Phase 2

Summary: 
      The purpose of this randomized phase II trial is to determine the clinical feasibility - in
      terms of patients without dose limiting toxicities or premature treatment withdrawal or death
      - of the combination of Cisplatin and Pemetrexed and of the combination of Cisplatin and
      Vinorelbine. The combination of Cisplatin / Pemetrexed is assumed to be distinctly less toxic
      than Vinorelbine / Cisplatin.
    

Detailed description: 
      Derived from recent large randomized clinical trials, there is clear evidence for adjuvant
      chemotherapy in stage IB-IIB (incidental IIIA) non-small cell lung cancer (Arriagada et al.,
      2004; Winton et al., 2005, Strauss et al., 2004, Douillard et al., 2005). The majority of
      patients in the adjuvant treatment setting received a combination of Cisplatin and
      Vinorelbine (Aragiada et al., 2004; Winton et al., 2005; Douillard et al., 2005). This
      combination improved 5 year-survival rates up to 15% (54% to 69%) (Winton et al., 2005).
      However, the combination of Cisplatin and Vinorelbine resulted in rates of grade 3/4
      neutropenia of around 75%, rates of febrile neutropenia of up to 12.5% and rates of treatment
      related death of 1-2%. Up to 77% of the patients had at least one dose reduction or omission
      and 55% required one dose delay or more, most related to neutropenia. Only about 50 % of
      patients randomized on the combination of cisplatin and vinorelbine received the intended
      dose of Vinorelbine (dose reduction mainly due to toxicity) and only 50% of patients
      completed all four cycles of chemotherapy (Winton et al., 2005, Douillard et al., 2005, Alam
      et al., 2005).

      Therefore it seems reasonable to test a less toxic regimen also in early stages after R0
      resection of the tumor, where reduced toxicities might improve the feasibility of drug
      delivery, compliance and the convenience of treatment for the patient and hence perhaps
      survival.

      Pemetrexed, a folate antimetabolite, shows clear activity in non-small cell lung cancer with
      several Phase II studies of Pemetrexed in combination with Cisplatin, Oxaliplatin, or
      Carboplatin showing efficacy similar to other standard platinum doublets, with response rates
      of 27% to 45% and median survival of 8.9 to 10.9 months (Scagliotti et al., 2005; Clarke et
      al., 2002; Rusthoven et al., 1999; Manegold et al., 2000; Shepherd et al., 2001). The
      combination of platin and Pemetrexed can be easily delivered and is well tolerated.
      Furthermore, it only results in a 25% rate of grade 3/4 neutropenia and in vitamin
      supplemented patients the incidence of febrile neutropenia was < 1%. Dose reductions occur
      only in 2-4% of the patients and dose delivery of the intended Pemetrexed and platin dose is
      excellent with dose deliveries of Pemetrexed up to 95% (Hanna et al., 2004; Vogelzang et al.,
      2003, Scagliotti et al., 2005).

      In this randomized phase II trial, the clinical feasibility of the combination of Cisplatin
      and Pemetrexed as well as of the combination of Cisplatin and Vinorelbine will be assessed.
      Treatment is considered to have clinical feasibility if dose limiting toxicity will not be
      observed, and no non-acceptance by the patient leading to premature withdrawal, and no death
      due to cancer or cancer therapy will occur.

      Patients will be randomized according to center, lobectomy vs. pneumonectomy and N0 vs. N1 to
      4 cycles (arm A) of 500 mg/m2 pemetrexed d1, and Cisplatin 75 mg/m2 d1, q d22 versus (arm B)
      25 mg/m2 Vinorelbine d1, 8, 15, 22, and Cisplatin 50 mg/m2 d1+8; q d29. Radiotherapy or
      maintenance therapy are not intended. Study drug administration will begin on d28 to d42
      after R0 resection of the tumor and within 14 days after randomization.

      In an initial study phase 36 patients (i.e. 18 in each treatment arm) will be accrued to
      confirm feasibility. In the second step, further patients will be recruited up to a total
      number of 134 (i.e. 67 cases per treatment arm). Patients will be followed-up in 3 monthly
      intervals for the first 2 years starting 30 days after end of the last cycle and in the 3rd
      year patients will be followed-up in 6 monthly intervals.
    

Intervention name(s): Pemetrexed; Cisplatin; Vinorelbine
Intervention type(s): Drug; Drug; Drug
Intervention description(s): Pemetrexed 500 mg/m2 d1 and Cisplatin 75 mg/m2 d1; q d22; Pemetrexed 500 mg/m2 d1 and Cisplatin 75 mg/m2 d1; q d22
Comparator:
Vinorelbine 25 mg/m2 d1, 8, 15, 22; q d29 Cisplatin 50 mg/m2 d1, 8; q d29; Vinorelbine 25 mg/m2 d1, 8, 15, 22; q d29
Intervention MeSH terms: Pemetrexed; Vinorelbine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Non-small cell lung cancer; adjuvant therapy; clinical feasibility rate