Clinical trial NCT01163786: A Proposal to Test the Efficacy and Tolerability of Bortezomib in Pulmonary Chronic GVHD
Official title: A Phase 2 Proposal to Test the Efficacy and Tolerability of Bortezomib in Pulmonary Chronic GVHD
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Bronchiolitis Obliterans
Keywords: Bortezomib GVHD Bronchiolitis Obliterans
Lead sponsor: Northwestern University
Sponsor class: OTHER
Collaborators: name: Robert H. Lurie Cancer Center
First posted: 2010-07-16
Enrollment: 17
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief 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performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care.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

Primary outcomes:
measure: Change in Pulmonary Function as Measured by Forced Expiratory Volume in 1 Second (FEV1) Decline
timeFrame: Mean time to diagnosis (from transplant to p-CGVHD ) of 3.36 years (+/- 1.88 years) and up to 18 weeks after baseline
Secondary outcomes:
measure: Exercise Tolerance- 6 Minute Walk
timeFrame: Up to 18 weeks from baseline
measure: Short Form (SF)-36 Health Survey
timeFrame: up to 18 weeks
Other outcomes:
Locations:
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
Study officials:
affiliation: Northwestern University
name: Manu Jain, MD, MS
role: PRINCIPAL_INVESTIGATOR
affiliation: Northwestern University
name: Jayesh Mehta, MD
role: PRINCIPAL_INVESTIGATOR
References: