Extension Study (Extended Access) of Cyclosporine Inhalation Solution (CIS) in Lung Transplant and Hematopoietic Stem Cell Transplant Recipients for the Treatment of Bronchiolitis Obliterans
Condition: Bronchiolitis Obliterans; Constructive Bronchiolitis; Graft Versus Host Disease; Bronchiolitis, Exudative; Bronchiolitis, Proliferative; Graft-Versus-Host Disease
MeSH terms: Bronchiolitis; Bronchiolitis Obliterans; Bronchiolitis Obliterans Syndrome; Graft vs Host Disease
Intervention: Cyclosporine Inhalation Solution (CIS)
Intervention description: CIS is a sterile, clear, colorless, preservative-free solution of cyclosporine (USP) in propylene glycol developed specifically for administration by oral inhalation.
Intervention MeSH terms: Cyclosporine; Cyclosporins
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 7.0
Sex: All
Minimum age: 10 Years
Maximum age: 80 Years
Healthy volunteers: No
Keywords: Peripheral Blood Stem Cell Transplant; Inhaled Cyclosporine; Graft-Versus-Host Disease

Summary:

      Bronchiolitis Obliterans (BO) is an obstructive lung disease that can affect individuals that
      have undergone a lung or hematopoietic stem cell transplant. BO has been studied most
      extensively in lung transplant recipients, where it is considered to represent chronic lung
      rejection. It is the leading cause of death after lung transplant, with mortality rates up to
      55 percent. In hematopoietic stem cell transplantation, BO is thought to be a manifestation
      of chronic graft-vs-host disease (GVHD). Up to 45 percent of patients undergoing
      hematopoietic stem cell transplantation at the NHLBI develop a decline in pulmonary function.
      Conventional therapy for patients who develop BO consists of augmentation of systemic
      immunosuppressants. Systemic immunosuppression has limited efficacy for BO and is associated
      with deleterious consequences including increased risk of infections and decreased
      graft-versus tumor/leukemia effects.

      Recently, cyclosporine inhalation solution (CIS) in solution with propylene glycol has been
      shown to improve overall survival and chronic rejection-free survival in lung transplant
      patients. These findings suggest targeted delivery of immunosuppressive therapy to the
      diseased organ warrants further investigation as this may minimize the morbidity associated
      with systemic immunosuppression. However, there currently exists limited data regarding the
      overall efficacy of inhaled cyclosporine to treat established BO following lung
      transplantation. Furthermore, inhaled cyclosporine has not been studied in the treatment of
      BO following hematopoietic stem cell transplantation.

      Here, we propose to evaluate the long-term safety and efficacy, of inhaled CIS for the
      treatment of BO. Enrollment will be offered to subjects who have completed the end of study
      (week 18 visit) for the initial protocol (Phase II Trial of CIS in lung transplant and
      hematopoietic stem cell transplant recipients for treatment of Bronchiolitis Obliterans) and
      who have shown evidence of benefit (either an improvement or stabilization) in BO/BOS with
      CIS treatment.

      Clinical parameters, including pulmonary function tests, will be measured in addition to
      laboratory markers of the anti-inflammatory response to CIS. Adverse events associated with
      extended treatment with CIS will be recorded.

      The primary objective is to provide long-term safety and efficacy data for the use of CIS in
      hematopoietic transplant patients and lung transplant patients with established BO.

      Secondary objectives include investigation of the inflammatory pathways that lead to chronic
      BO and ascertainment of the long term anti-inflammatory effects of this CSA preparation ex
      vivo and in vivo.

      Primary endpoint is the efficacy of extended use CIS for BO/BOS. Secondary endpoints include
      the toxicity profile (adverse events), improvement in high resolution chest CT images,
      results of peripheral blood and bronchoalveolar cytokine arrays to assess secondary markers
      of inflammation, and functional capacity measurements using a six-minute walk test.
    

Eligibility criteria:

        -  INCLUSION CRITERIA:

               1. Completed the End of Study visit (week 19) on the initial protocol (Phase II
                  Trial of Cyclosporine Inhalation Solution (CIS) in Lung Transplant and
                  Hematopoietic Stem Cell Transplant Recipients for Treatment of Bronchiolitis
                  Obliterans) in the preceding 12 weeks

               2. Patients have shown evidence for a clinical benefit to CIS as evidenced by one or
                  more of the following:

          -  Improvement in pulmonary function defined by a 10 percent or more increase in the FEV1
             at week 18, confirmed with repeat PFTs at least 1 week apart.

          -  In patients with progressive disease at study entry on the initial protocol (Phase II
             Trial of Cyclosporine Inhalation Solution (CIS) in Lung Transplant and Hematopoietic
             Stem Cell Transplant Recipients for Treatment of Bronchiolitis Obliterans),
             stabilization in pulmonary function, defined as less than a 10 percent improvement in
             FEV1 or less than 10 percent decline in FEV1 at week 18, confirmed with repeat PFTs at
             least 1 week apart.

          -  In patients with stable disease (active BOS stable by FEV1 criteria) at study entry on
             the initial protocol (Phase II Trial of Cyclosporine Inhalation Solution (CIS) in Lung
             Transplant and Hematopoietic Stem Cell Transplant Recipients for Treatment of
             Bronchiolitis Obliterans), stabilization in pulmonary function, defined as less than a
             10 percent improvement in their FEV1 or less than 10 percent decline in FEV1, and a
             decrease in the dose of one or more systemic immunosuppressants by at least 20 percent
             (sustained for 3 weeks, excluding adjustments made for target drug levels). * The
             criteria for study entry on this extension protocol are not the same as the criteria
             for response on the primary protocol to allow for entry of patients on this extension
             protocol, which is deriving some clinical benefit, but have not met the full response
             criteria as defined in the primary protocol.

        EXCLUSION CRITERIA:

          1. More than a 12 week gap in study drug administration (CIS)

          2. Evidence of uncontrolled, pulmonary infection

          3. ECOG performance status greater than or equal to 3

          4. Patient pregnant or breast feeding or not willing to continue the use of an approved
             method of birth control

          5. Life expectancy less than 18 weeks

          6. History of hypersensitivity reaction to propylene glycol

          7. Documented allergy or intolerance to CIS

          8. History of untreated coronary insufficiency, severe cardiac arrhythmias, and/or
             uncontrolled hypertension.

          9. Serum creatinine greater than 2.5 mg/dl

         10. Inability to comprehend the investigational nature of the study and provide informed
             consent