A Proposal to Test the Efficacy and Tolerability of Bortezomib in Pulmonary Chronic GVHD

Phase 2

Terminated

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).

Recruitment & Eligibility

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performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care.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

Arm && Interventions

Group	Intervention	Description
Bortezomib	Bortezomib	Patients will Receive 2 4week cycles of Bortezomib. Each cycle will consist of weekly bortezomib with a 2 week interval between cycles.

Primary Outcome Measures

Name	Time	Method
Change in Pulmonary Function as Measured by Forced Expiratory Volume in 1 Second (FEV1) Decline	Mean time to diagnosis (from transplant to p-CGVHD ) of 3.36 years (+/- 1.88 years) and up to 18 weeks after baseline	FEV1 will be measured by spirometry assessments at baseline (pre-transplant baseline - prior to pulmonary chronic graft-versus-host disease (p-CGVHD)) during treatment (10 weeks) and at follow up visit 9 (at 12 weeks) and at follow up visit 10 (at 18 weeks) with patients having spirometry tested up to 6 times from screening to the end of the study. FEV1 is reported as slopes computed by dividing difference in FEV1 by time in months.

Secondary Outcome Measures

Name	Time	Method
Exercise Tolerance- 6 Minute Walk	Up to 18 weeks from baseline	Patients will have an exercise tolerance assessment defined as a 6 minute walk completed at cycle 1 (week 1) and cycle 2 (week 5) of treatment and visit 9 (12 weeks) and visit 10 (18 weeks).
Short Form (SF)-36 Health Survey	up to 18 weeks	This is a quality of life questionnaire which yields scores for 8 domains (physical functioning, role-physical, bodily pain, general health, vitality, social functioning, role-emotional and mental health). This questionnaire will be completed by patients on Visit 1 (week 1), Visit 5 (week 5), Visit 8 (week 8), Visit 9 (12 weeks), and Visit 10 (18 weeks). Questionnaires were scored per the scoring rules for the RAND 36-Item Health Survey (version 1.0) A high score defines a more favorable health state. In addition, each item is scored on a 0 to 100 range so that the lowest and highest possible scores are 0 and 100, respectively. Scores represent the percentage of total possible score achieved. Items that are left blank (missing data) are not taken into account when calculating the scale scores. Hence, scale scores represent the average for all items in the scale that the respondent answered.