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

Overview

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.

Interventions

• Drug Nintedanib
  Nintedanib 150 mg Kps bid (oral); in order to manage adverse events, the dose of Nintedanib may be reduced from 150 mg twice daily to 100 mg twice daily

Primary outcome measures

• adverse event rate leading to interruption/ discontinuation of study treatment [Time frame: from screening to month 12 after screening]

Secondary outcome measures (12)

• change of the percent of predicted forced expiratory volume in 1 second (FEV1) [Time frame: Pulmonary function tests will be performed at screening, after 1, 2, 3, 6, 9, 12 and after 13 months]
• change in forced vital capacity (FVC) [Time frame: Pulmonary function tests will be performed at screening, after 1, 2, 3, 6, 9, 12 and after 13 months]
• change in total lung capacity (TLC) [Time frame: Pulmonary function tests will be performed at screening, after 1, 2, 3, 6, 9, 12 and after 13 months]
• Change in diffusion capacity of the lung for carbon monoxide (DLCO) [Time frame: Pulmonary function tests will be performed at screening, after 1, 2, 3, 6, 9, 12 and after 13 months]
• Change in exhaled nitric oxide (eNO) [Time frame: Pulmonary function tests will be performed at screening, after 1, 2, 3, 6, 9, 12 and after 13 months]
• Nitrogen (N2)-washout [Time frame: Pulmonary function tests will be performed at screening, after 1, 2, 3, 6, 9, 12 and after 13 months]
• changes in in 6 minutes walking distance (6-MWD) [Time frame: 6-MWD will be performed at screening, after 6, after 12 months]
• cumulative steroid doses [Time frame: assessed at screening, after 1, 2, 3, 6, 9, 12, and after 13 months]
• occurrence of GvHD in other organs [Time frame: assessed at screening, after 1, 2, 3, 6, 9, 12, and after 13 months]
• disease-free survival of underlying hematologic disease [Time frame: assessed at screening, after 1, 2, 3, 6, 9, 12, and after 13 months]
• changes in St. George's Respiratory Questionnaire (SGRQ) [Time frame: assessed at screening, after 1, 2, 3, 6, 9, 12, and after 13 months]
• changes in NIH GvHD grading score [Time frame: assessed at screening, after 1, 2, 3, 6, 9, 12, and after 13 months]

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:

• FEV1/vital capacity < 0.7 or the fifth percentile of predicted.
• FEV1 < 75% of predicted with ≥ 10% decline over less than 2 years.
• 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).
• 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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

Switzerland · 2 centers

• Clinic of Hematology, University Hospital Basel — Basel
• Clinic of Respiratory Medicine, University Hospital Basel — Basel

Saudi Arabia · 1 center

• King Faisal Specialist Hospital & Research Centre — Riyadh

Identifiers

NCT: NCT03805477 · 2018-00837; me17Hostettler

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗