Bortezomib and Pemetrexed Disodium in Treating Patients With Advanced Non-Small Cell Lung Cancer or Other Solid Tumors
Condition: Lung Cancer; Unspecified Adult Solid Tumor, Protocol Specific
MeSH terms: Lung Neoplasms; Carcinoma, Non-Small-Cell Lung
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      RATIONALE: Bortezomib and pemetrexed disodium may stop the growth of tumor cells by blocking
      some of the enzymes needed for cell growth. Giving bortezomib together with pemetrexed
      disodium may kill more tumor cells.

      PURPOSE: This phase I/II trial is studying the side effects and best dose of two different
      schedules of bortezomib when given together with pemetrexed disodium and to see how well they
      work in treating patients with advanced non-small cell lung cancer or other solid tumors.
    

Detailed description: 
      OBJECTIVES:

      Primary

        -  Determine the safety, including dose-limiting toxicities, and feasibility of combining
           bortezomib with pemetrexed disodium in patients with advanced non-small cell lung cancer
           (NSCLC) or other solid tumors. (Phase I)

        -  Determine the response rate in patients with advanced NSCLC treated with this regimen.
           (Phase II)

      Secondary

        -  Compare the toxicity of 2 different schedules of bortezomib and pemetrexed disodium in
           patients with advanced solid tumors. (Phase I)

        -  Determine the maximum tolerated dose (MTD) of bortezomib when administered with
           pemetrexed disodium in 2 different treatment schedules in these patients. (Phase I)

        -  Determine, preliminarily, the efficacy of the combination of bortezomib and pemetrexed
           disodium in patients with advanced solid tumors. (Phase I)

        -  Assess the overall survival and progression-free survival of these patients. (Phase II)

        -  Evaluate the frequency and severity of toxicities associated with this regimen. (Phase
           II)

      Tertiary

        -  Perform laboratory correlative studies on tumor tissue and blood samples to investigate
           potential predictors of response. (Phase II)

      OUTLINE: This is a phase I, dose-escalation study of bortezomib followed by a phase II,
      open-label study.

        -  Phase I: Patients will be accrued, in an alternating fashion, to 1 of 2 treatment
           groups.

             -  Group I: Patients receive pemetrexed disodium IV on day 1 and bortezomib IV on days
                1, 4, 8, and 11.

             -  Group II: Patients receive pemetrexed disodium IV on day 1 and bortezomib IV on
                days 1 and 8.

      In both groups, treatment repeats every 21 days in the absence of unacceptable toxicity or
      disease progression.

      Cohorts of 3-6 patients per group receive escalating doses of bortezomib until the maximum
      tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2
      of 3 or 2 of 6 patients experience dose-limiting toxicity.

        -  Phase II: Patients receive pemetrexed disodium bortezomib (at the MTD) as in either
           group I or group II of the phase I portion of the study. Selection of the treatment
           schedule is based upon observed toxicity, safety, tolerability, efficacy, and clinical
           practicality.

      Blood is drawn at baseline and prior to courses 2 and 3 for correlative and molecular
      studies.

      Tumor tissue and blood samples from patients enrolled in the phase II portion of the study
      are examined for various biological markers. Immunohistochemistry is used to measure BCL-2
      gene, BCL-xL gene, BAX gene, and p27. Reverse transcriptase-polymerase chain reaction is used
      to assay the expression of thymidylate synthase, folsyl-polyglutamate synthase, and reduced
      folate carrier. Levels of plasminogen-activator inhibitor 1 gene, vascular endothelial growth
      factor, and osteopontin are measured by immunoenzyme techniques. The nuclear expression of
      NF-kB and p27 in blood is compared before and after study treatment by flow cytometry.

      After completion of study treatment, patients in phase I are followed for 30 days and
      patients in phase II are followed periodically.
    

Intervention name(s): bortezomib; pemetrexed disodium; gene expression analysis; mutation analysis; protein expression analysis; reverse transcriptase-polymerase chain reaction; flow cytometry; immunoenzyme technique; immunohistochemistry staining method
Intervention type(s): Drug; Drug; Genetic; Genetic; Genetic; Genetic; Other; Other; Other
Intervention MeSH terms: Pemetrexed; Bortezomib
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: recurrent non-small cell lung cancer; stage IIIB non-small cell lung cancer; stage IV non-small cell lung cancer; unspecified adult solid tumor, protocol specific