A Proposal to Test the Efficacy and Tolerability of Bortezomib in Pulmonary Chronic GVHD
| Status: | Active, not recruiting |
|---|---|
| Conditions: | Bronchitis, Pulmonary, Hematology |
| Therapuetic Areas: | Hematology, Pulmonary / Respiratory Diseases |
| Healthy: | No |
| Age Range: | Any |
| Updated: | 1/13/2018 |
| Start Date: | July 2010 |
| End Date: | June 2020 |
A Phase 2 Proposal to Test the Efficacy and Tolerability of Bortezomib in Pulmonary Chronic GVHD
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).
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).
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
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