A Phase II Study of SGI-110 in Philadelphia-Negative Myeloproliferative Neoplasms

The active metabolite of SGI-110 (2'-deoxy-5-azacytidylyl-(3'→5')-2'-deoxyguanosine sodium
salt), a dinucleotide, is decitabine, an FDA-approved agent for the treatment of
myelodysplastic syndromes. SGI-110 is resistant to modification by cytidine deaminase, a
common pathway of decitabine metabolism and deactivation[1]. The molecular weight of SGI-110
and decitabine are 580 Da and 228 Da, respectively. Therefore, the molar equivalent dose of 1
mg of decitabine is approximately 2.5 mg of SGI-110. SGI-110's activity was demonstrated with
the same preclinical pharmacodynamic assays used to demonstrate decitabine's efficacy e.g.,
re-expression of p15, p16, and MLH1 and induction of fetal hemoglobin, in vivo. In xenograft
studies, SGI-110 demonstrates promising preclinical activity in both hematologic and solid
tumors.

In vitro evidence suggests that SGI-110 has a longer half-life than decitabine in the
presence of cytidine deaminase. These promising observations suggest that SGI-110 may have
improved pharmaceutical properties and biological activities that could extend decitabine's
current clinical utility. SGI-110 has shown to be better tolerated in mice than decitabine
and is as effective in vivo in inducing p16 expression, reducing DNA methylation at the p16
promoter region, and retarding EJ6 human bladder cancer tumor growth in athymic mice[2].

SGI-110 has been developed for subcutaneous administration. SGI-110 is pharmacologically
active both in vitro and in vivo in a variety of tumor cells and murine xenograft models when
administered subcutaneously. Treatment is well tolerated via the subcutaneous route in murine
xenografts. When administered subcutaneously to non-human primates, SGI-110 releases
decitabine slowly compared to other species, possibly prolonging the effect over longer
periods. SGI-110 has been developed as a non-aqueous formulation to ensure formulation
stability.

SGI-110 has been studied in a first-in-human, single-agent study (SGI-110-01).5 This study
was a Phase 1/2, dose escalation, multicenter study of two subcutaneous regimens of SGI-110
in subjects with intermediate or high-risk myelodysplastic syndromes (MDS) or acute myeloid
leukemia (AML). This study had two parts, a Dose Escalation Segment and a Dose Expansion
Segment. The study evaluated the biological activity, preliminary safety, and efficacy of
SGI-110 with two dosing schedules in intermediate to high risk MDS or relapsed or refractory
AML subjects, while the Dose Expansion Segment further evaluated safety and efficacy at the
recommended dose. The study was based on a 3 + 3 design within each regimen. Eligible
subjects were randomized to receive 1 of 2 dosing regimens of SGI-110 with the following
starting doses: Regimen 1: 3 mg/m2/day subcutaneously on Days 1-5 of a 28-day course, Regimen
2: 6 mg/m2 subcutaneously Weekly x 3 on Days 1, 8, 15 of a 28-day course. The minimum dose
achieving maximal biological activity or biologically effective dose (BED) for the daily
regimen was reached at 60 mg/m2 daily on Days 1-5.

Study disease: MPN

Philadelphia chromosome negative Myeloproliferative Neoplasms (PHN-MPN) comprise a group of
myeloid neoplasms with varying clinical, morphologic and laboratory features and a wide range
of survival. According to 2008 World Health Organization (WHO) classification, the MDS/MPN
overlap syndromes include chronic myelomonocytic leukemia (CMML), atypical chronic myeloid
leukemia (aCML), juvenile myelomonocytic leukemia(JMML) and
myelodysplastic/myeloproliferative neoplasm unclassifiable (MDS/MPN-U). In a recent
retrospective study from MD Anderson Cancer Center, the median survival of patients with a
diagnosis of MDS/MPN unclassifiable was 12.4 months[3] .There is no effective therapy for
PHN-MPN and this represents an unmet medical need.

The MDS/MPN overlap syndromes can present with a wide range of hematological and clinical
manifestations and individual patients may exhibit a combination of features characteristic
of both MDS and MPN. For example, while transfusion-dependent anemia is generally present,
other hematological laboratory abnormalities can range from leukopenia to leukocytosis and
from thrombocytopenia to thrombocytosis. Unlike with MDS, significant splenomegaly is often
present in patients with PHN-MPN. Also, patients may have a constellation of constitutional
findings, including fatigue, weight loss, anorexia, night sweats and other unpleasant
symptoms that lead generally to poor quality of life. Thus, while improving overall survival
is a critical goal of therapy, effective therapy for this group of patients will include also
agents that can be demonstrated to improve as many of the disease-related clinical issues as
possible.

Overall Study Design

This is a single arm, open-label study of SGI-110 in patients with MPN. SGI-110 will be
administered subcutaneously at a dose of 60 mg/m2 on days 1-5, repeated every 28 days.
Toxicity will be evaluated using the NCI Common Terminology Criteria for Adverse Events
Active Version 4. The frequency of toxicities per organ system will be tabulated using
descriptive statistics. All patients who receive any amount of the study drug will be
evaluable for toxicity.

Screening and pre-treatment criteria Screening Procedures Screening procedures and tests will
be performed within 14 days before treatment administration with the exception of informed
consent, bone marrow biopsy which may be performed within 28 days of the first dose of study
drug.

- Provision of written informed consent. The ICF must be signed and dated by the subjects
before collection of any samples or performance of any study-specific evaluations.

- Complete medical history, including demographics (date of birth, sex, race). A disease
history, including the date of initial diagnosis and list of prior treatments and
responses to these treatments, also will be recorded. Concurrent medical signs and
symptoms must be documented to establish baseline conditions.

- Record concomitant medications.

- Record all study-procedure related AEs from the time of informed consent and then
treatment-emergent AEs after the start of study drug administration (Course 1, Day 1)
through 30 days after the last dose of study drug.

- Investigator's confirmation of eligibility. Perform all necessary procedures and
evaluations to document that the subject meets each eligibility criterion.

- Complete physical exam including weight and examination

- Vital signs include resting systolic/diastolic blood pressure, resting heart rate,
resting respiration rate, body temperature and pulse oximetry. Assess after the subject
has rested in the sitting position for at least three minutes.

- ECOG performance status.

- 12-lead ECG (rhythm, atrial rate, ventricular rate, PR interval, QRS duration, and
QT/QTc (QtcF), morphology and overall interpretation).

- Height.

- Sample collection for clinical laboratory tests (hematology, chemistry and urinalysis).

- Serum or urine pregnancy test: for female subjects of child-bearing potential only.
Results must be negative for the subject to be eligible for enrollment into the study.

Agent Administration

• SGI-110 administered at dose level of 60 mg/m2 SC daily on Days 1-5 of a 28-day cycle.
However, treatment delays are allowed per section 6.3.1 SGI-110 is administered by SC
injection preferably in the abdominal area. The total amount (in mg) of SGI-110 to be
administered will be determined based on the body surface area (BSA). In calculating the BSA,
actual heights and weights should be used. There will be no adjustments to "ideal" body
weight. The institutional standard for calculating BSA is acceptable. Dose adjustment should
be made for a +/- 10% weight change at the beginning of each cycle The site(s) of SGI-110 SC
injections will be captured on the dosing CRF. Investigators are prohibited from supplying
SGI-110 to any subjects not properly enrolled in this study or to any physicians or
scientists except those designated as sub-investigators on Food and Drug Administration (FDA)
Form 1572. The investigator must ensure that subjects receive SGI-110 only from personnel who
fully understand the procedures for administering the study treatment.

Duration of Therapy

Duration of therapy will depend on individual response, evidence of disease progression and
tolerance. In the absence of treatment delays due to adverse events, treatment may continue
until one of the following criteria applies:

- Disease progression to acute leukemia unless, in the opinion of the principal
investigator, the subject is experiencing clinical benefit from SGI-110 despite
laboratory evidence of progression to acute leukemia.

- Intercurrent illness that prevents further administration of treatment,

- Unacceptable adverse event(s)

- Participant demonstrates an inability or unwillingness to comply with the medication
regimen and/or documentation requirements

- Participant decides to withdraw from the study

- General or specific changes in the participant's condition render the participant
unacceptable for further treatment in the opinion of the treating investigator.

Duration of Follow Up

Participants will be followed monthly for six months after removal from study or until death,
whichever occurs first. Participants removed from study for unacceptable adverse events will
be followed until resolution or stabilization of the adverse event. Post-study case report
forms will capture information including subsequent treatments, response to subsequent
therapy, and survival.

Anticipated Toxicities

Adverse Event List(s) for SGI-110

The most common AEs suspected by the investigators in Study SGI-110-01 to be related to the
drug and observed to date in the MDS/AML population are: injection site pain, fatigue,
nausea, thrombocytopenia, anemia and diarrhea. Based on the mechanism of action of the drug
and its active form decitabine, myelosuppression (neutropenia, thrombocytopenia, and anemia)
and the related consequences such as infection (e.g. pneumonia), sepsis, and bleeding are the
most likely risks for the drug. Mucositis has also been reported.

Pain and burning at the injection site has been reported that are related to dose and volume
of injection as well as the speed of injection. Care must be taken to avoid intradermal
injection. Ice packs will be applied prior to injection of SGI-110 and the drug will be
injected slowly, over 30-60 seconds. If the injection site events are reported at subsequent
injections despite slow injection and the use of ice packs, pre-treatment with topical or
systemic analgesics can be considered.

Inclusion Criteria:

3.1.1 Participants must have confirmed diagnosis of Philadelphia chromosome negative MPN
neoplasm based on WHO classification (reference) including Chronic Neutrophilic Leukemia
(CNL), atypical Chronic Myeloid Leukemia (aCML), Chronic Myelomonocytic Leukemia (CMML),
MPN/MDS overlap syndromes, accelerated phase myelofibrosis and MPN unclassifiable.

3.1.2 Age minimum of 18 years. Because no dosing or adverse event data are currently
available on the use of SGI-110 in participants <18 years of age, children are excluded
from this study but may be eligible for future pediatric trials.

3.1.3 ECOG performance status <3

3.1.4 Participants must have normal organ function as defined below:

- Total bilirubin < or = 1.5 X institutional upper limit of normal unless attributable
to underlying disease, hemolysis or documented Gilbert's syndrome

- AST (SGOT)/ALT (SGPT) < 2.5 X institutional upper limit of normal unless attributable
to underlying disease

- Creatinine < 1.5add < or = 1.5X institutional upper limit of normal or creatinine
clearance add using Cockcroft Gault > 50 mL/min/1.73 m2 for subjects with creatinine
levels above institutional normal.

- LVEF < 40 % is allowed as long as there is no NY class III/IV heart failure or
uncontrolled arrhythmias.

3.1.5 The effects of SGI-110 on the developing human fetus are unknown. For this reason and
because oncological agents are known to be teratogenic, 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 participation.
Should a woman become pregnant or suspect she is pregnant while participating in this
study, she should inform her treating physician immediately.

3.1.6 Ability to understand and the willingness to sign a written informed consent
document.

Exclusion Criteria:

3.2.1 Participants who have had any chemotherapy (investigational or FDA approved)
(hydroxyurea is permitted) or radiotherapy within 2 weeks prior to study entry or those who
have not recovered from adverse events due to agents administered more than 2 weeks
earlier.

3.2.2 Participants may not be treated with any other investigational agents while on this
study unless approved by the principal investigator AND the sponsors of BOTH
investigational agents.

3.2.3 History of allergic reactions attributed to compounds of similar chemical or biologic
composition to decitabine or SGI-110.

3.2.4 Uncontrolled intercurrent illness including, but not limited to, infection,
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or
psychiatric illness/social situations that would limit compliance with study requirements.

Pregnant women are excluded from this study because SGI-110 is a hypomethylating agent with
the potential for teratogenic or abortifacient effects. Because there is an unknown but
potential risk of adverse events in nursing infants secondary to treatment of the mother
with SGI-110, breastfeeding should be discontinued.

3.2.5 Individuals with a history of a different malignancy are ineligible except for the
following circumstances. Individuals with a history of other malignancies are eligible if
they have been disease-free for at least 3 years and are deemed by the investigator to be
at low risk for recurrence of that malignancy. Individuals with the following cancers are
eligible if diagnosed and treated within the past 3 years: cervical cancer in situ, and
basal cell or squamous cell carcinoma of the skin.