AZD9668, 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.

- 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 AZD9668 in patients with BOS after SCT

Phase 2:

To determine the clinical efficacy of AZD9668 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 greater than or equal to 18 years

- BOS after SCT and moderate to severe cGVHD as defined by the NIH consensus criteria

- Within 2 years from the time of diagnosis (Phase 2 only)

- Karnofsky performance status greater than or equal to 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 azithromycin for at
least 3 months prior to enrollment, unless there is evidence of progression or
unsatisfactory response while on azithromycin 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 AZD9668 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 AZD9668 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 AZD9668 at the OBD determined in the Phase 1b trial, 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. While up to10 patients may be
required for the Phase 1b portion of the trial and 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.

- INCLUSION CRITERIA:

- Patients must have undergone hematopoietic stem cell transplantation and have moderate
to severe chronic GVHD as defined by the NIH consensus criteria.

- Patients must have BOS as defined by the NIH consensus criteria (2014 updated
criteria). To meet the criteria for BOS, all of the following must be present, in
addition to at least one distinctive manifestation of cGVHD:

- FEV1/vital capacity <0.7 or the fifth percentile of predicted

- FEV1 <75% of predicted with greater than or equal to 10% decline over less than 2
years. FEV1 should not correct to >75% with albuterol, and the absolute decline
for the corrected values should still remain at greater than or equal to 10% from
pre-translplant

- Absence of infection in the respiratory tract

- 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 CT, or

2. Evidence of air trapping by PFTs: residual volume >120% predicted or
residual volume/total lung capacity elevated outside the 90% confidence
interval.

If a patient carries the diagnosis of cGVHD by virtue of organ involvement elsewhere, then
only the first 3 criteria above are necessary.

- For the Phase 1b study, patients may have had the diagnosis of BOS for any period of
time. For the Phase 2 study, patients must be within 2 years from the time of
diagnosis. Patients may be at any time interval after SCT as long as the criteria for
chronic GVHD and BOS are met.

- If patients are taking systemic therapy for cGVHD at the time of enrollment, they must
be receiving stable or tapering doses within the previous 4 weeks. Patients are not
required to have completed a course of steroids prior to enrollment.

- Age greater than or equal to18 years.

- Karnofsky greater than or equal to 60%

- Patients must have normal organ and marrow function as defined below:

- leukocytes greater than or equal to 3,000/mcL

- absolute neutrophil count greater than or equal to 1,000/mcL

- platelets greater than or equal to 50,000/mcL

- total bilirubin less than or equal to 3 X institutional upper limit of normal,
unless there is a known history of Gilbert s disease

- AST(SGOT)/ALT(SGPT) less than or equal to 2 X institutional upper limit of normal

- -serum creatinine less than or equal to 1.5 mg/dL or creatinine clearance greater
than or equal to 60 mL/min as estimated by the Cockcroft-Gault equation

- Patients will be required to have received prior treatment with azithromycin for at
least 3 months prior to enrollment, unless there is evidence of progression or
unsatisfactory response while on azithromycin prior to 3 months of treatment, as
deemed by the treating or referring physician. Patients who are on azithromycin will
need to discontinue for at least 2 weeks prior to enrollment

- Agree to adhere to methods of contraception and other fertility control measures:

The effects of AZD9668 on the developing human fetus are unknown. For this reason, women of
child-bearing potential and men must agree to use adequate contraception (hormonal or
barrier method of birth control; abstinence) prior to study entry and for the duration of
study therapy. Contraception should be used up until 1 week of discontinuing study
medication. Should a woman become pregnant or suspect she is pregnant while she is
participating in this study, or if a man s partner becomes pregnant or suspects she is
pregnant while he is participating in this study, she or he should inform their treating
physician immediately.

-Ability of subject to understand and the willingness to sign a written informed consent
document.

EXCLUSION CRITERIA:

- FEV1 <30% (based on absolute percent predicted using USA-ITS-NIH equation) on
pulmonary function testing

- Patients with clinically relevant abnormal ECG findings, including abnormal QTc>500 ms
on screening ECG (Note: If a patient has a QTc interval >500 ms on screening ECG, the
screening ECG may be repeated twice [at least 24 hours apart] for a total of 3 ECGs).

- Patients who are receiving any other investigational agents

- Recurrent or progressive malignancy requiring anticancer treatment

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, acute kidney injury, or psychiatric illness/social situations within the
previous 4 weeks that would limit compliance with study requirements.

- Pregnant women are excluded from this study because the teratogenic effects of AZD9668
are unknown. Because there is an unknown but potential risk for adverse events in
nursing infants secondary to treatment of the mother with AZD9668, breastfeeding
should be discontinued if the mother is treated with this agent.

- Prior use of neutrophil elastase inhibitors