Evaluation of a Single Dose of Inhaled Sargramostim in Patients With Autoimmune Pulmonary Alveolar Proteinosis
Condition: Autoimmune Pulmonary Alveolar Proteinosis
MeSH terms: Pulmonary Alveolar Proteinosis; Autoimmune Diseases
Study type: Interventional
Phase: Phase 1

Summary: 
      Autoimmune PAP is a rare lung disease affecting less than 5,000 individuals in US with no
      FDA-approved pharmacologic therapy. Results from "off-label" use in case reports and clinical
      studies completed outside of the US indicate that inhaled rhGM-CSF may be a safe and
      effective thera-py for autoimmune PAP. Preliminary clinical trials of inhaled rhGM-CSF in
      autoimmune PAP patients show promising results, 62%-96% therapeutic response rate without any
      identifiable drug-related adverse effects in at least 73 autoimmune PAP patients. However,
      the pharmacokinetics (PK), pharmacodynamics (PD), optimal dose, and treatment duration to
      maximize efficacy are unknown.

      The goal is to begin to address these knowledge gaps for inhaled sargramostim for autoimmune
      PAP patients with a pilot safety and PK/PD study (TPSC-110). TPSC-110, PharmPAP, which is a
      self-controlled open-label, phase I study to evaluate the safety, PK, and PD of inhaled
      sargra-mostim in autoimmune PAP patients. These results will impact the field by 1)
      confirming existing published data, 2) monitoring the local effects of inhaled sargramostim
      in autoimmune PAP patients, 3) potentially demonstrating a safe starting dose for a later
      trial to evaluate the therapeutic efficacy of inhaled sargramostim for autoimmune PAP.
    

Detailed description: 
      PAP is a rare syndrome of surfactant accumulation and resulting hypoxemic respiratory failure
      that occurs in a number of diseases classified pathogenically into three groups: primary PAP
      (caused by disruption of GM-CSF signaling - autoimmune PAP, hereditary PAP), secondary PAP
      (caused by reduction in alveolar macrophage numbers and/or functions), and surfactant
      dysfunction-related PAP (caused by mutations in genes required for normal surfactant
      production). In current clinical practice, PAP is diagnosed based on a lung biopsy; an
      approach that is not able to identify the etiology of the PAP. Current therapy involves the
      physical removal of surfactant by a procedure in which the lungs are repeatedly filled with
      saline and emptied - whole lung lavage, which is invasive, inefficient, and not widely
      available, especially for children. Importantly, research advances have elucidated the
      pathogenesis of diseases causing PAP in most patients and have identified new diagnostic and
      therapeutic approaches. Simple blood-based research tests can now identify the PAP-causing
      disease in about 95% of patients. Further, several promising potential disease-specific
      therapies are currently in development. Preliminary clinical trials of inhaled rhGM-CSF in
      autoimmune PAP patients show promising results, 62%-96% therapeutic response rate at two
      doses (250 and 500 mcg/day) without any identified safety concerns. At least 73 people with
      autoimmune PAP have been reported to have received inhaled sargramostim with no identified
      drug-related adverse effects. However, the PK, PD, optimal dose, and treatment duration
      needed to maximize efficacy are unknown. The short-term goal is to address knowledge gaps for
      inhaled sargramostim for autoimmune PAP patients in the following clinical study: a pilot
      safety and PK/PD study (TPSC-110). A major goal of this protocol is to evaluate the local and
      systemic safety, PK, and PD one dose of inhaled sargramostim in autoimmune PAP. The central
      hypothesis is that in patients with autoimmune PAP, aerosol inhalation of sargramostim will
      be well-tolerated and safe because the GM-CSF autoantibody will limit detection of free
      GM-CSF thereby preventing local and systemic toxicity. The specific objectives of this study
      are to: 1) evaluate the safety profile of one dose of inhaled sargramostim in patients with
      autoimmune PAP 2) estimate the PK profile of inhaled sargramostim following single dose
      administration in patients with autoimmune PAP 3) measure the PD effects of inhaled
      sargramostim following single dose administration in patients with autoimmune PAP.

      The target population is adults with autoimmune PAP who have measurable, clinically
      significant disease satisfying all of the inclusion and exclusion criteria. The study design
      will involve recruitment, screening, and enrollment of participants into a phase I,
      open-label, multi-site study. Sargramostim will be administered to autoimmune PAP patients
      via aerosol inhalation one time at a dose of 125 mcg or 250 mcg. Adverse events (AEs),
      serious AEs (SAEs), PK, and PD parameters will be evaluated (see Appendix 3 Schedule of
      Events). The experimental approach will evaluate 1) safety of inhaled sargramostim by
      documenting occurrence of treatment-emergent AEs and SAEs, 2) PK profile of GM-CSF in serum
      and BAL fluid, 3) local and systemic PD effects of inhaled GM-CSF and 4) effects of inhaled
      GM-CSF on the quality of life for participants. Anticipated results will determine the safety
      profile of inhaled sargramostim in patients with autoimmune PAP, will evaluate total and free
      GM-CSF levels in blood and lung, effects of sargramostim on blood and BAL cell counts,
      differentials, baseline- and GM-CSF-responsiveness of blood leukocytes and BAL cells, and
      biomarkers of PAP in patients with autoimmune PAP after single dose administration. These
      results will impact the field by 1) confirming existing published data, 2) monitoring local
      effects of inhaled sargramostim in autoimmune PAP patients, 3) demonstrating a safe starting
      dose to evaluate the efficacy of inhaled sargramostim for autoimmune PAP.
    

Intervention name(s): Sargramostim
Intervention type(s): Drug
Intervention description(s): Participants will receive a single administration of inhaled sargramostim (either 125 mcg or 250 mcg dose)
Other intervention name(s): Leukine; recombinant human GM-CSF
Intervention MeSH terms: Molgramostim; Sargramostim
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Basic Science