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NCT01163786

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

Terminated Phase 2 Results posted Last updated 10 April 2020
What this trial tests

Phase 2 trial testing Bortezomib in Bronchiolitis Obliterans in 17 participants. Terminated before completion.

Timeline
7 October 2010
Primary endpoint
9 September 2015
9 September 2015

Quick facts

Lead sponsorNorthwestern University
PhasePhase 2
StatusTerminated
Study typeINTERVENTIONAL
Allocationna
Designsingle group
Maskingnone
Primary purposetreatment
Enrollment17
Start date7 October 2010
Primary completion9 September 2015
Estimated completion9 September 2015
Sites1 location across United States

Drugs / interventions tested

Conditions studied

Sponsor

Northwestern University

Who can join

Eligibility, any sex, with Bronchiolitis Obliterans. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

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

Prior to diagnosis of p-CGVHD
GroupValue95% CI
Bortezomib-1.06-5.36 – -0.33
During Treatment with Bortezomib
GroupValue95% CI
Bortezomib-0.25-9.42 – 3.52
Exercise Tolerance- 6 Minute Walk Secondary · 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).

Cycle 1 (Visit 1): Started 6 Minute walk
GroupValue95% CI
Bortezomib13
Cycle 1 (Visit 1): Stopped before 6 minutes
GroupValue95% CI
Bortezomib3
Cycle 1(Visit 1):Declined walk
GroupValue95% CI
Bortezomib0
Cycle 2 (Visit 5) : Started 6 Minute walk
GroupValue95% CI
Bortezomib3
Cycle 2 (Visit 5) : Stopped before 6 minutes
GroupValue95% CI
Bortezomib0
Cycle 2(Visit 5):Declined walk
GroupValue95% CI
Bortezomib0
Follow up/Visit 9: Started 6 Minute walk
GroupValue95% CI
Bortezomib6
Follow up/Visit 9 : Stopped before 6 minutes
GroupValue95% CI
Bortezomib1
Short Form (SF)-36 Health Survey Secondary · 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

Pt #01 Physical Functioning : Visit 1
GroupValue95% CI
Bortezomib30
Pt #01 Physical Functioning : Visit 5
GroupValue95% CI
Bortezomib55
Pt #01 Physical Functioning : Visit 8
GroupValue95% CI
BortezomibNA
Pt #01 Physical Functioning : Visit 9
GroupValue95% CI
BortezomibNA
Pt #01 Physical Functioning : Visit 10
GroupValue95% CI
BortezomibNA
Pt #01 Role-physical : Visit 1
GroupValue95% CI
Bortezomib0
Pt #01 Role-physical : Visit 5
GroupValue95% CI
Bortezomib25
Pt #01 Role-physical : Visit 8
GroupValue95% CI
BortezomibNA

Adverse events — posted to ClinicalTrials.gov

Time frame: Adverse events were collected for each patient during treatment and in follow up for up to 18 weeks.. Reporting threshold: 0%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Bortezomib
Serious: 3/17 (18%)
Deaths: 0/17

Serious adverse events (4 terms)

ReactionSystemBortezomib
Myocardial InfarctionCardiac disorders
DehydrationGastrointestinal disorders
Varicella aoster virus/systemic inflammatory responseInfections and infestations
HypoxiaRespiratory, thoracic and mediastinal disorders
Other adverse events (62 terms — click to expand)

ReactionSystemBortezomib
Glucose, serum-high (hyperglycemia)Metabolism and nutrition disorders
Fatigue (asthenia, lethargy, malaise)General disorders
Neuropathy: sensoryNervous system disorders
CoughRespiratory, thoracic and mediastinal disorders
LymphopeniaBlood and lymphatic system disorders
DiarrheaGastrointestinal disorders
NauseaGastrointestinal disorders
Sodium, serum-low (hyponatremia)Metabolism and nutrition disorders
PlateletsBlood and lymphatic system disorders
Edema: limbBlood and lymphatic system disorders
CreatinineMetabolism and nutrition disorders
Fever (in the absence of neutropenia, where neutropenia is defined as ANC <1.0 x 10e9/L)General disorders
Weight lossGeneral disorders
ConstipationGastrointestinal disorders
AST, SGOT(serum glutamic oxaloacetic transaminase)Metabolism and nutrition disorders
Calcium, serum-low (hypocalcemia)Metabolism and nutrition disorders
Magnesium, serum-low (hypomagnesemia)Metabolism and nutrition disorders
Dry eye syndromeEye disorders
Dyspnea (shortness of breath)Respiratory, thoracic and mediastinal disorders
Flu-like syndromeGeneral disorders
HemoglobinBlood and lymphatic system disorders
InsomniaGeneral disorders
AnorexiaGastrointestinal disorders
Infection - pulmonary/upper respiratory - upper airway NOSInfections and infestations
Albumin, serum-low (hypoalbuminemia)Metabolism and nutrition disorders
Phosphate, serum-low (hypophosphatemia)Metabolism and nutrition disorders
Potassium, serum-low (hypokalemia)Metabolism and nutrition disorders
Ocular/Visual - Other (Specify, Meibomitis)Eye disorders
Vision-blurred visionEye disorders
HypoxiaRespiratory, thoracic and mediastinal disorders
Neutrophils/granulocytes (ANC/AGC)Blood and lymphatic system disorders
Sweating (diaphoresis)General disorders
Weight gainGeneral disorders
Bruising (in absence of Grade 3 or 4 thrombocytopenia)Skin and subcutaneous tissue disorders
Dermatology/Skin - Other (Specify: skin lesion with some oozing)Skin and subcutaneous tissue disorders
Dry skinSkin and subcutaneous tissue disorders
HyperpigmentationSkin and subcutaneous tissue disorders
Pruritus/itchingSkin and subcutaneous tissue disorders
Rash/desquamationSkin and subcutaneous tissue disorders
Dry mouth/salivary gland (xerostomia)Gastrointestinal disorders

Most-reported serious reactions: Myocardial Infarction, Dehydration, Varicella aoster virus/systemic inflammatory response, Hypoxia.

Data from ClinicalTrials.gov NCT01163786 adverse events section.

Sponsor's own description

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).

Publications & conference data

2 peer-reviewed publications reference this trial (live from Europe PMC):

  1. Dendritic cells and regulation of graft-versus-host disease and graft-versus-leukemia activity.
    Stenger EO, Turnquist HR, Mapara MY, Thomson AW. · · 2012 · cited 89× · PMID 22403259 · DOI 10.1182/blood-2011-11-364091
  2. New and emerging therapies for acute and chronic graft <i>versus</i> host disease.
    Hill L, Alousi A, Kebriaei P, Mehta R, et al · · 2018 · cited 81× · PMID 29317998 · DOI 10.1177/2040620717741860

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