A Proposal to Test the Efficacy and Tolerability of Bortezomib in Pulmonary Chronic GVHD
Condition: Bronchiolitis Obliterans
MeSH terms: Bronchiolitis; Bronchiolitis Obliterans; Bronchiolitis Obliterans Syndrome
Intervention: Bortezomib
Intervention description: Each patient will receive 2 cycles of Bortezomib. For each cycle Bortezomib wil be given once a week, 1.3mg/m2 for 4 weeks with 2 weeks between each cycle.
Intervention MeSH terms: Bortezomib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 17.0
Sex: All
Healthy volunteers: No
Keywords: Bortezomib GVHD Bronchiolitis Obliterans

Summary:

      Approximately 10,000 allogeneic hematopoietic stem cell transplants (HSCT) are performed
      annually in the US for various indications. Bronchiolitis obliterans (BO) is the most common
      late noninfectious complication following allogeneic hematopoietic stem cell transplant.
      Prognosis of BO in the allogeneic HSCT setting is dismal and there are no therapies proven to
      be consistently effective. The exact incidence is not clear but may be as high as 30%2 . Risk
      factors include new or ongoing chronic graft versus host disease (cGVHD), age, antecedent
      obstructive airways disease and viral infections1. BO is characterized physiologically by
      progressive irreversible airflow obstruction and pathologically by luminal occlusion of the
      distal airways due to progressive scarring3. The pathogenesis is not completely understood
      but the cytokine transforming growth factor-beta 1 (TGF-b1), important for both tissue repair
      and fibrosis, is thought to play a pivotal role. Bortezomib, an FDA approved proteasomal
      inhibitor inhibits TGF-b1 signaling in vitro and protects against lung injury/fibrosis in
      bleomycin mouse model as well as in a mouse model for skin fibrosis. This is consistent with
      other data in the literature that proteasomal inhibition can prevent the development of
      fibrosis. Thus the investigators propose to test the safety, tolerability and efficacy of
      bortezomib in chronic pulmonary GVHD (BO).
    

Eligibility criteria:

        Inclusion Criteria:

          -  Voluntary written informed consent before performance of any study-related procedure
             not part of normal medical care, with the understanding that consent may be withdrawn
             by the subject at any time without prejudice to future medical care.

          -  Female subject is either post-menopausal or surgically sterilized or willing to use an
             acceptable method of birth control (i.e., a hormonal contraceptive, intra-uterine
             device, diaphragm with spermicide, condom with spermicide, or abstinence) for the
             duration of the study.

          -  Male subject agrees to use an acceptable method for contraception for the duration of
             the study.

          -  Day >100 after allogeneic hematopoietic stem cell transplantation

          -  Underlying cancer in remission

          -  Decrease in FEV1 of ≥12% from the pre-transplant baseline (FEV1/FVC ratio <0.8)

          -  No evidence of acute infection

          -  ANC >1000

          -  Platelets >50,000

          -  Age 18-70

          -  ECOG performance Status 0-2.

        Exclusion Criteria:

          -  Patient has a platelet count of less than 50,000 within 14 days before enrollment.

          -  Patient has an absolute neutrophil count of less 1000 within 14 days before
             enrollment.

          -  Patient has a calculated or measured creatinine clearance of < 20 ml/minute within 14
             days before enrollment.

          -  Patient has Grade 2 peripheral neuropathy within 14 days before enrollment.

          -  Myocardial infarction within 6 months prior to enrollment or has New York Heart
             Association (NYHA) Class III or IV heart failure (see section 8.4), uncontrolled
             angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence
             of acute ischemia or active conduction system abnormalities. Prior to study entry, any
             ECG abnormality at Screening has to be documented by the investigator as not medically
             relevant.

          -  Patient has hypersensitivity to bortezomib, boron or mannitol.

          -  Female subject is pregnant or breast-feeding. Confirmation that the subject is not
             pregnant must be established by a negative serum b-human chorionic gonadotropin
             (b-hCG) pregnancy test result obtained during screening. Pregnancy testing is not
             required for post-menopausal or surgically sterilized women.

          -  Patient has received other investigational drugs with 14 days before enrollment

          -  Serious medical or psychiatric illness likely to interfere with participation in this
             clinical study.

          -  Inability of give consent