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

NCT01163786 | Terminated Phase 2 Results DMC

• 2 other identifiers: NU 09H7STU00022160
• Study Type: interventional
• Target: 17
• Locations: 1 country
• Sites: 1

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).

Conditions

Bronchiolitis Obliterans

Keywords

Bortezomib GVHD Bronchiolitis Obliterans

Outcome Measures

Primary Outcomes (1)

• Change in Pulmonary Function as Measured by Forced Expiratory Volume in 1 Second (FEV1) Decline

  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.

  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 (2)

• Exercise Tolerance- 6 Minute Walk

  Up to 18 weeks from baseline

• Short Form (SF)-36 Health Survey

  up to 18 weeks

Study Arms (1)

Bortezomib

EXPERIMENTAL

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

Drug: Bortezomib

Interventions

Bortezomib DRUG

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.

Also known as: Velcade

Bortezomib

Eligibility Criteria

• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Northwestern University: lead
• Robert H. Lurie Cancer Center: collaborator

Study Sites (1)

Northwestern University

Chicago, Illinois, 60611, United States

Location

MeSH Terms

Conditions

Bronchiolitis Obliterans

Interventions

Bortezomib

Condition Hierarchy (Ancestors)

Bronchiolitis; Bronchitis; Bronchial Diseases; Respiratory Tract Diseases; Lung Diseases, Obstructive; Lung Diseases

Intervention Hierarchy (Ancestors)

Boronic Acids; Acids, Noncarboxylic; Acids; Inorganic Chemicals; Boron Compounds; Organic Chemicals; Pyrazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Limitations and Caveats

The study was closed before the accrual goal of 20 evaluable patients was reached due to slow accrual.

Results Point of Contact

• Title: Clinical Trials at Northwestern University
• Organization: Northwestern University

cancertrials@northwestern.edu

312-695-6180

Study Officials

• Manu Jain, MD, MS

  Northwestern University

  PRINCIPAL INVESTIGATOR

• Jayesh Mehta, MD

  Northwestern University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 7, 2010
• First Posted: July 16, 2010
• Study Start: October 7, 2010
• Primary Completion: September 9, 2015
• Study Completion: September 9, 2015
• Last Updated: April 10, 2020
• Results First Posted: April 10, 2020

Record last verified: 2020-04

Locations

US (1)