Alvelestat (MPH966), an Oral Neutrophil Elastase Inhibitor, in Bronchiolitis Obliterans Syndrome After Allogeneic Hematopoietic Stem Cell Transplantation

Background:

• Chronic graft-versus-host disease (cGVHD) is the leading cause of non-relapse morbidity and mortality in persons after allogeneic hematopoietic stem cell transplantation (SCT).
• Bronchiolitis obliterans syndrome (BOS) is a complication of cGVHD associated with a high morbidity and mortality, and treatment options are limited.
• Neutrophil elastase (NE) is a protease released by neutrophils in the setting of inflammation, and has been implicated in the pathogenesis of BOS.
• Alvelestat (MPH966) (Formerly known as AZD9668) is a potent and selective inhibitor of NE that has demonstrated evidence of target inhibition and a good safety profile in patients with inflammatory lung diseases, but has not been evaluated in BOS.

Objectives:

Phase 1b:

To determine the optimal biologic dose (OBD) based on maximal NE inhibition measured in blood, and to determine the safety of alvelestat (MPH966) in patients with BOS after SCT

Phase 2:

To determine the clinical efficacy of alvelestat (MPH966) at the OBD in patients with BOS after SCT, based on the proportion of patients with stable or improved forced expiratory volume in 1 second (FEV1) on pulmonary function testing

Eligibility:

Inclusion criteria:

• Age >=18 years
• BOS after SCT and moderate to severe cGVHD as defined by the NIH consensus criteria
• Within 5 years from the time of diagnosis (Phase 2 only)
• Karnofsky performance status >= 60%
• If on systemic cGVHD therapy, must be receiving stable or tapering doses in the preceding 4 weeks
• Patients will be required to have received prior treatment with a regimen consisting of inhaled steroids and montelukast +/- azithromycin for at least 3 months prior to enrollment, unless there is evidence of progression or unsatisfactory response while on this regimen prior to 3 months of treatment, as deemed by the treating or referring physician.
• Patients who are on azithromycin, an antibiotic used in the treatment of BOS, will need to discontinue for at least 2 weeks prior to enrollment

Exclusion criteria:

• FEV1 < 30% (based on absolute percent predicted using USA-ITS-NIH equation) on pulmonary function testing
• Prior use of neutrophil elastase inhibitors
• Progressive malignancy
• Uncontrolled infection or any major organ dysfunction as defined by the protocol

Design:

Phase 1b:

• This is a Phase 1b trial to determine the OBD and safety of alvelestat (MPH966) in patients with BOS after SCT.
• This trial will use an intra-patient dose escalation schedule. The starting dose will be 60mg twice daily for 2 weeks, and the dose will be increased by 60mg with each escalation every 2 weeks until a maximum dose of 240mg twice daily is reached for a total treatment period of 8 weeks. After completion of the dose escalation phase, patients will have the option to continue the dose at which maximal NE inhibition and safety are demonstrated for up to 6 additional months.
• The co-primary endpoint of OBD will be defined as the dose level at which the maximal NE inhibition occurs, and at which no more than 1/3 of patients experience a DLT. NE activity will be measured in the blood at baseline and with each dose escalation, and will be compared between dose levels to determine the OBD.
• The co-primary endpoint of safety will be determined by monitoring adverse events and dose limiting toxicities (DLT) as defined by the protocol. Further dose escalation will cease in a patient who experiences a DLT. In addition, no subsequent patients will be treated at or beyond the dose in which 1/3 of patients have experienced a DLT.
• A total of 10 patients will be enrolled in the Phase 1b trial.

Phase 2:

• This is a Phase 2 trial to determine the efficacy of alvelestat (MPH966) at the OBD in patients with BOS after SCT, as measured by stabilization or improvement of FEV1 (based on absolute percent predicted) after 6 months of treatment.
• Patients will receive alvelestat (MPH966) using an intra-patient dose escalation schedule. The starting dose will be 60 mg twice daily for 2 weeks, and the dose will be increased by 60 mg twice daily with each dose escalation every 2 weeks until a maximum dose of 240 mg twice daily is reached for a total treatment period of 18 weeks (total of 6 cycles). There is an optional continuation phase for 24 more weeks (cycles 7-12) with each cycle being 28 days and pulmonary function testing with measurement of FEV1 will be performed to determine the primary endpoint.
• Response assessments will occur every 3 months with primary efficacy endpoint evaluated at 6 months. Patients with stable or responding disease will have the option to continue therapy for another 6 months.
• As an early stopping rule for futility, if 0-2 of the first 8 patients enrolled have responded, then no further patients will be accrued. A total of 20 patients may be needed for evaluation in phase II.

In order to allow for a small number of inevaluable patients, the accrual ceiling will be set at 34 patients across both phases.