Study of MEK Inhibitor Selumetinib in Combination With Azacitidine in Patients With Higher Risk Chronic Myeloid Neoplasia

This is a phase I, open-label, dose-escalation study to determine the MTD of selumetinib when
combined with the standard dose of azacitidine. For the purposes of DLT assessment, subjects
will be stratified into 2 cohorts- cohort A will include subjects with MDS and MDS/MPN;
cohort B will include subjects with myelofibrosis. Dose escalation will proceed independently
in each of these cohorts. Determination of MTD will thus also proceed independently within
each cohort. Three dose levels of selumetinib are planned for evaluation. Dose escalation
will follow a 3+3 study design. Patients will be enrolled sequentially and stratified
according to disease type as outlined above. An increased dose level will only open to
accrual once at least 3 patients have been treated at the lower dose, followed for the
defined DLT observation period (28 days, see section 2.8 below), and the lower dose level has
been deemed safe.

The 3+3 dose escalation algorithm will proceed as follows:

1. If 0/3 patients develop a DLT at a dose level, escalate to the next dose level.

2. If 1/3 patients develops a DLT at a dose level, enroll 3 additional patients at that
dose level.

1. At that dose level, if 1/6 patients develops a DLT, escalate to the next dose
level.

2. If ≥2/6 patients develop a DLT, that dose level will be determined to be too toxic.

3. If 2-3/3 patients develop a DLT at a dose level, that dose level will be determined to
be too toxic.

4. Six patients will be treated at the MTD.

1. If the study progresses to dose level 3 with 0/3 patients experiencing a DLT, an
additional 3 patients will be enrolled at that dose level to gain additional
information regarding toxicity.

2. If a dose level is determined to be too toxic and the next lower dose level only
included 3 patients, an additional 3 patients will be treated at the lower dose
level to confirm tolerability.

5. If no patients have a DLT reported at dose level 3, that will be defined as the MTD and
the dose will not be escalated above that level.

Inclusion Criteria:

All of the following criteria must be met:

- Age greater than or equal to 18 years of age

- Histologic confirmation of one of the following:

a. MDS fulfilling all the criteria below: i. International Prognostic Scoring System
(IPSS) intermediate-2 or high risk MDS; or Revised International Prognostic Scoring
System (IPSS-R) intermediate, high, or very high risk MDS ii. - relapsed/refractory
disease iii. Requiring therapy based on the presence of one or more cytopenias (Hb <10
g/dL and/or red cell transfusion dependence, platelets- <50,000/μL, or ANC <1,000/ μL)
or excess blasts (≥5% in the peripheral blood or bone marrow).

b. MDS/MPN as defined by the WHO criteria, including CMML, atypical CML, and
MDS/MPN-Unclassifiable fulfilling the criteria listed below i. relapsed/refractory
disease ii. Requiring therapy based on the presence of one or more cytopenias (Hb <10
g/dL and/or red cell transfusion dependence, platelets <50,000/μL, or ANC <1,000/ μL),
excess blasts (≥5% in the peripheral blood or bone marrow), or palpable splenomegaly
iii. or previously untreated subsets (e.g atypical CML, MDS/MPN unclassifiable)
requiring therapy as defined above and in whom no approved therapies exist.

c. Myelofibrosis, including primary myelofibrosis, post-polycythemia vera
myelofibrosis, or post-essential thrombocythemia myelofibrosis fulfilling the criteria
listed below: i. Intermediate-2 or high risk disease according to the Dynamic
International Prognostic Scoring System (DIPSS) classification ii. refractory or
intolerant to JAK inhibitor therapy, or deemed - ineligible for ruxolitinib therapy
due to pre- existing cytopenias (thrombocytopenia <50,000/uL, anemia hemoglobin <9g/dL
or red cell transfusion dependence).Requiring further therapy based on the presence of
one or more cytopenias (Hb <10 g/dL and/or red cell transfusion dependence, platelets
<50,000/μL, or ANC <1,000/μL), excess blasts (≥5% in the peripheral blood or bone
marrow), or palpable splenomegaly

- No history of prior exposure to a MEK inhibitor

- ECOG performance status of ≤ 2

- Adequate renal function, defined as serum creatinine ≤ 1.5 x ULN or creatinine
clearance >30 mL/min based on the Cockroft-Gault equation: (140 − Age) x (weight in
kg) x (0.85 if female) / 72 x serum creatinine

- Adequate liver function, defined as conjugated bilirubin ≤ 2 x ULN as well as
aspartate transaminase (AST) and alanine aminotransaminase (ALT) ≤ 3 x ULN

- Patients must be at least 2 weeks from major surgery, radiation therapy, participation
in other investigational trials and must have recovered from clinically significant
toxicities of these prior treatments

- Female patients of childbearing potential must have a negative serum pregnancy test
within 2 weeks prior to enrollment

- Female and male patients must use an effective contraceptive method during the study
and for at least 6 months thereafter

- Ability to understand and willingness to sign a written informed consent document

Exclusion Criteria:

Patients are excluded if any one of the following is present:

- Receipt of any anti-cancer therapy within 14 days prior to study entry, with the
exception of hydroxyurea. If clinically indicated in order to keep WBC <30,000/uL,
hydroxyurea may be continued through the first cycle.

- Concurrent active malignancy, with the exception of early stage basal cell or squamous
cell skin cancer

- Active cardiac conditions, including any of the following:

1. Uncontrolled hypertension (BP >150/95 mmHg despite medical therapy)

2. Acute coronary syndrome within 6 months prior to starting treatment

3. Uncontrolled angina despite medical therapy

4. Symptomatic heart failure (NYHA class II-IV despite medical therapy)

5. Baseline LV EF <50% measured by either echocardiography or MUGA scan

6. Severe valvular heart disease

7. Atrial fibrillation with ventricular rate >100 bpm on EKG at rest.

- Ophthalmologic conditions, including any of the following:

1. Current or past history of central serous retinopathy

2. Current or past history of retinal vein occlusion

3. Intraocular pressure (IOP) >21 mmHg or uncontrolled glaucoma

- Any uncontrolled concurrent illness that, in the judgment of the investigators or
treating physician, may put the patient at undo risk including but not limited to
active infection, symptomatic cardiac or pulmonary disease, ventricular arrhythmia, or
psychiatric illness.

- Pregnant or lactating patients