Clinical trial NCT03805477: Nintedanib in Patients With Bronchiolitis Obliterans Syndrome Following Hematopoietic Stem Cell Transplantation
Official title: Nintedanib in Patients With Bronchiolitis Obliterans Syndrome Following Hematopoietic Stem Cell Transplantation (HSCT)- a Multicentre Phase II Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Bronchiolitis Obliterans Syndrome (BOS)
Bronchiolitis Obliterans (BO)
Keywords: allogeneic hematopoietic cell transplantation.
chronic graft-versus-host disease (cGvHD)
Nintedanib
fibrotic lung disease
Lead sponsor: University Hospital, Basel, Switzerland
Sponsor class: OTHER
First posted: 2019-01-15
Enrollment: 20
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This study investigates the safety and tolerability of Nintedanib in patients with bronchiolitis obliterans syndrome (BOS) following allogeneic hematopoietic cell transplantation. All study patients with BOS will be treated with the study drug Nintedanib (300 mg/day) as an add-on therapy to their basic immunosuppressive treatment over a 12-months treatment period.

Detailed description: Allogeneic hematopoietic stem cell transplantation (HCT) is an established treatment option for several malignant and non-malignant disorders. An important limitation of long-term survival after HCT is chronic graft-versus-host disease (cGvHD). The manifestation of cGvHD in the lungs, bronchiolitis obliterans (BO - if proven by lung biopsy) or bronchiolitis obliterans syndrome (BOS - clinical diagnosis), has a reported incidence between 5 and 20%. Despite different treatment approaches, prognosis of BO remains poor, with an overall 3-year mortality of up to 65%. Nintedanib is an orally available indolinone derivate that competitively binds to the vascular endothelial growth factor (VEGF) receptors, fibroblast growth factor (FGF) receptors, and platelet derived growth factor (PDGF) receptors. The anti-fibrotic activities of Nintedanib may impact the progressive course of fibrotic lung diseases like BO. This study investigates the safety and tolerability of Nintedanib in patients with bronchiolitis obliterans syndrome following allogeneic hematopoietic cell transplantation.

Eligibility criteria: Inclusion Criteria:

* Time interval from transplant \</= 5 years at the time of inclusion
* BOS as defined per the National Institute of Health (NIH) criteria:

  1. FEV1/vital capacity \< 0.7 or the fifth percentile of predicted.
  2. FEV1 \< 75% of predicted with ≥ 10% decline over less than 2 years.
  3. Absence of infection in the respiratory tract, documented with investigations directed by clinical symptoms, such as chest radiographs, computed tomographic (CT) scans, or microbiologic cultures (sinus aspiration, upper respiratory tract viral screen, sputum culture, and broncho-alveolar lavage).
  4. One of the 2 supporting features of BOS: 1. Evidence of air trapping by expiratory CT or small airway thickening or bronchiectasis by high-resolution chest CT, or 2. Evidence of air trapping by PFTs: residual volume \> 120% of predicted or residual volume/total lung capacity elevated outside the 90% confidence interval and prior or current diagnosis of cGvHD per NIH criteria or histologically proven BO
* Diagnosis of BOS within 6 months before enrollment or prior diagnosis of BOS with an absolute decline of the percentage of predicted forced expiratory volume in 1 second (FEV1) by \>/= 10% within the past 12 months before inclusion

Exclusion Criteria

* Known intolerance to Nintedanib or any of its component
* Pregnancy or nursing
* Serum ALT \> 5 x upper limit of normal (ULN) unless explained entirely by liver GvHD or total bilirubin \> 3x ULN unless explained entirely by liver GvHD
* Any acute pulmonary infection with viruses, bacteria or fungi within four weeks before study inclusion
* Chronic oxygen therapy; non-invasive ventilation
* Inability to give informed consent or to perform repeated pulmonary function tests (PFT)
* Life expectancy \< 1 year at the time of enrolment as suggested by the treating physician
* Hematologic malignancy in hematologic relapse
* Symptomatic angina pectoris
* Therapeutic anticoagulation (primary or secondary prophylactic platelet anti-aggregation allowed)
* Recent abdominal surgery or untreated gastric ulcer

Primary outcomes:
measure: adverse event rate leading to interruption/ discontinuation of study treatment
timeFrame: from screening to month 12 after screening
Secondary outcomes:
measure: change of the percent of predicted forced expiratory volume in 1 second (FEV1)
timeFrame: Pulmonary function tests will be performed at screening, after 1, 2, 3, 6, 9, 12 and after 13 months
measure: change in forced vital capacity (FVC)
timeFrame: Pulmonary function tests will be performed at screening, after 1, 2, 3, 6, 9, 12 and after 13 months
measure: change in total lung capacity (TLC)
timeFrame: Pulmonary function tests will be performed at screening, after 1, 2, 3, 6, 9, 12 and after 13 months
measure: Change in diffusion capacity of the lung for carbon monoxide (DLCO)
timeFrame: Pulmonary function tests will be performed at screening, after 1, 2, 3, 6, 9, 12 and after 13 months
measure: Change in exhaled nitric oxide (eNO)
timeFrame: Pulmonary function tests will be performed at screening, after 1, 2, 3, 6, 9, 12 and after 13 months
measure: Nitrogen (N2)-washout
timeFrame: Pulmonary function tests will be performed at screening, after 1, 2, 3, 6, 9, 12 and after 13 months
measure: changes in in 6 minutes walking distance (6-MWD)
timeFrame: 6-MWD will be performed at screening, after 6, after 12 months
measure: cumulative steroid doses
timeFrame: assessed at screening, after 1, 2, 3, 6, 9, 12, and after 13 months
measure: occurrence of GvHD in other organs
timeFrame: assessed at screening, after 1, 2, 3, 6, 9, 12, and after 13 months
measure: disease-free survival of underlying hematologic disease
timeFrame: assessed at screening, after 1, 2, 3, 6, 9, 12, and after 13 months
measure: changes in St. George's Respiratory Questionnaire (SGRQ)
timeFrame: assessed at screening, after 1, 2, 3, 6, 9, 12, and after 13 months
measure: changes in NIH GvHD grading score
timeFrame: assessed at screening, after 1, 2, 3, 6, 9, 12, and after 13 months
measure: changes in Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) questionnaire
timeFrame: assessed at screening, after 1, 2, 3, 6, 9, 12, and after 13 months
measure: overall survival
timeFrame: assessed at screening, after 1, 2, 3, 6, 9, 12, and after 13 months
Other outcomes:
Locations:
city: Riyadh
country: Saudi Arabia
facility: King Faisal Specialist Hospital & Research Centre
city: Basel
country: Switzerland
facility: Clinic of Hematology, University Hospital Basel
city: Basel
country: Switzerland
facility: Clinic of Respiratory Medicine, University Hospital Basel
Study officials:
affiliation: Clinic of Respiratory Medicine, University Hospital Basel
name: Katrin Hostettler Haack, PD Dr. med
role: PRINCIPAL_INVESTIGATOR
References: