Safety and Efficacy of PMT Therapy of hPAP

Last updated: January 28, 2025
Sponsor: Children's Hospital Medical Center, Cincinnati
Overall Status: Active - Recruiting

Phase

1/2

Condition

Lung Disease

Treatment

Gene-Corrected Macrophages administered by bronchoscopic instillation

Clinical Study ID

NCT05761899
2022-0424
R33HL156888
  • Ages > 18
  • All Genders

Study Summary

The major goal of this study is to evaluate a new type of cell transplantation therapy for individuals with hereditary PAP, study a new treatment that may be useful for treatment of other diseases, and research mechanisms that drive the development and function of lung macrophages.

Eligibility Criteria

Inclusion

Inclusion Criteria:

Patients must meet all of the following conditions to be eligible for participation in this study:

  1. Male or female with a confirmed diagnosis of hPAP defined as:

  • Homozygous or compound heterozygous CSF2RA mutations - AND -

  • A normal GM-CSF autoantibody test result - AND -

  • An abnormal STAT5-PI test result - OR -

  • An abnormal GM-CSF 50% effective concentration (EC50) test result

  1. Diffuse ground glass opacification of the lungs visualized on a chest computedtomogram (CT)

  2. History of prior receipt of WLL therapy or moderate hPAP lung disease severityrequiring therapy in the opinion of the Clinical Site Investigator and/or Sponsor

  3. Able to undergo bone marrow collection by routine clinical aspiration

  4. 18 years of age or older on the date the Informed consent form (ICF) is signed

  5. Females who have been post-menopausal for >2 years or females of child-bearingpotential after a confirmed menstrual period using a highly efficient method ofcontraception (as described in Section 11.4.2) for the period from 3 months prior tothe first administration of gene-corrected macrophages until 12 months after thelast administration of gene-corrected macrophages. Females of child-bearingpotential must have a negative serum pregnancy test at Screening (Visit 1), at bonemarrow collection (Visit 2), and immediately before each administration ofgene-corrected macrophages (Visits 3, 5, 7), and must not be lactating.

  6. Males of reproductive potential must agree to use condoms for the period from the 1st administration of gene-corrected macrophages until 12 months after the last doseof gene-corrected macrophages, have a partner who is not of child-bearing potential (i.e. men or females who have been post-menopausal for >2 years), or have a femalepartner who is using adequate contraception as described in Section 11.4.2.

  7. Signed written informed consent form (ICF)

Exclusion

Exclusion Criteria:

Patients who meet any of the following conditions will not be eligible for participation in this study:

  1. History of a confirmed diagnosis of any other PAP-causing disease defined as:

  2. PAP caused by function-altering mutations in CSF2RB, adenosine triphosphate (ATP)-binding cassette subfamily A member 3 (ABCA3), SFTPB, SFTPC, ThyroidTranscription Factor 1 (TTF-1), GATA-binding factor 2 (GATA2), SLC7A7, andmethionyl-transfer RNA (tRNA) synthetase (MARS), or other genes demonstrated tocause PAP other than CSF2RA

  3. PAP associated with an abnormal GM-CSF autoantibody test

  4. PAP associated with hematologic disorders including but not limited tomyelodysplasia, aplastic anemia, leukemia, multiple myeloma, lymphoma

  5. PAP associated with non-hematologic malignancies

  6. PAP associated with immune deficiency syndromes

  7. PAP associated with chronic inflammatory syndromes

  8. PAP associated with chronic infections including but not limited to humanimmunodeficiency virus, Mycobacteria tuberculosis or other Mycobacterialspecies, or other organisms

  9. PAP associated with inhaled materials including but not limited to inorganicdusts (e.g., silica, titanium, indium, aluminum), organic dusts (e.g., sawdust,fertilizer); or gases/vapors (e.g., cleaning products, paints, andwelding-related fumes)

  10. Pulmonary fibrosis that is clinically significant in the opinion of Clinical SiteInvestigator and/or Sponsor

  11. A confirmed (i.e., repeated) positive serum anti-GM-CSF receptor antibody testand/or a confirmed positive anti-lentiviral antibody test at the time of screeningand prior to each administration of gene-corrected macrophages

  12. History of receipt of any investigational agent within 3 months of Study Visit 3

  13. History of active chronic infection (e.g., HIV, Hepatitis, others) at the time ofScreening

  14. History of significant alcohol consumption for a period of more than 3 consecutivemonths within 1 year prior to Study Visit 3, defined as more than 14 drinks/week forfemales or 21 drinks/week for males (1 drink - 5 ounces (150 ml) of wine or 12ounces (360 ml) of beer, or 1.5 ounces (45 ml) of hard liquor)

  15. History of medication or illicit drug abuse within 1 year prior to Study Visit 3,including but not limited to cocaine, heroin, or other opioids

  16. Currently or planning to become pregnant between the Screening visit and Visit 14and/or currently breast-feeding

  17. Any other medical, behavioral, or psychiatric condition that would interfere withthe completion of Study Visits or assessments in the opinion of the Clinical SiteInvestigator and/or Sponsor

Study Design

Total Participants: 3
Treatment Group(s): 1
Primary Treatment: Gene-Corrected Macrophages administered by bronchoscopic instillation
Phase: 1/2
Study Start date:
June 26, 2023
Estimated Completion Date:
October 01, 2038

Study Description

Hereditary pulmonary alveolar proteinosis (hPAP) is a rare lung disease characterized by the progressive accumulation of pulmonary surfactant in alveoli resulting in progressive hypoxemic respiratory failure, and in some patients, secondary infections and/or pulmonary fibrosis. While hPAP affects men, women, and children, most patients present as children. The lung structure appears well-preserved in many cases with pathogenesis being driven by the consequences of the filling of alveoli with surfactant sediment; however, some patients develop respiratory failure caused by pulmonary fibrosis requiring therapeutic lung transplantation.

Hereditary PAP is caused by homozygous or compound heterozygous mutations in the genes (CSF2RA or CSF2RB) encoding the GM-CSF receptor alpha or beta chains, respectively. Mutations in these genes disrupt GM-CSF receptor function, blocking GM-CSF signaling and impairing the removal of excess surfactant from alveoli by alveolar macrophages (AMs).

This study is an open-label, non-randomized, single center clinical treatment study to evaluate the feasibility of manufacturing CSF2RA gene-corrected macrophages, as well as the safety, tolerability, efficacy, and durability of CSF2RA gene correction/pulmonary macrophage transplantation (PMT) therapy in three patients with hPAP caused by recessive homozygous or compound heterozygous CSF2RA mutations. In addition to safety and tolerability, the clinical trial will evaluate outcome measures related to clinical efficacy and biologic signature of CSF2RA gene-correction/PMT therapy, as well as pharmacokinetics, pharmacodynamics, and the mechanism of action.

The clinical trial design includes a 2-month observation period, a Baseline visit, 5-month treatment period, and Short-, Medium-, and Long-Term follow-up periods of 1, 4, and 10 years, respectively. Each patient will serve as their own self-control and receive a split-dose comprising three administrations of autologous, bone marrow cluster of differentiation 34+ (CD34+) cell-derived, lentiviral CSF2RA gene-corrected macrophages at a minimum of 2-month intervals, delivered by direct bronchoscopic instillation of cells into individual lung segments (5.8x105 cells/segment); an increasing number of cells at each administration will be achieved by sequentially increasing the number of segments treated. Current standard medical care (whole lung lavage and supplemental oxygen) will be continuously available to all enrolled patients.

Assessments will include safety (adverse events and serious adverse events), tolerability (short-term, treatment-emergent pulmonary symptoms), efficacy (beneficial effects on clinical, physiological, and radiological manifestations of hPAP), durability (persistence of beneficial effects), and mechanism of action (persistence, CSF2RA-expression, and function of alveolar macrophages (AMs)).

Expected results will inform the feasibility, safety, tolerability, efficacy, durability, and mechanism of action of gene transfer/PMT as therapy of hPAP. These results will impact the field because it departs markedly from the current inefficient, highly invasive method of physically removing surfactant by whole lung lavage (WLL) and instead uses a novel approach to restore AM function. This study is expected to establish the feasibility of a novel, specific therapy for children with hPAP and a new type of cell transplantation therapy (PMT) that may be useful for other diseases.

Connect with a study center

  • Cincinnati Children's Hospital Medical Center

    Cincinnati, Ohio 45229
    United States

    Active - Recruiting

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