Study of IRX5183 in Relapsed and Refractory Acute Myeloid Leukemia and High Risk Myelodysplastic Syndrome

This research is being done to learn about the safety and effectiveness of an investigational
drug, IRX5183, in treating acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS).
IRX5183 is a derivative of Vitamin A. IRX5183 is a drug that is designed to cause cancer
cells to mature and then die. It is thought that it will stop the uncontrolled growth of
leukemia cells.

These are 2 parts to this study. The purpose of the first part is to test the safety of
IRX5183 at different dose levels. The investigators want to find out what effects, good
and/or bad, it has on AML or MDS. Once the investigators figure out the best and safest dose
of IRX5183, the investigators will enter the second part of the study using this dose. The
purpose of the second part is to see if IRX5183 is effective as a treatment for AML or MDS.
To date, IRX5183 has been used in about 25 people.

The first part of the study is called a "Phase I" study. Phase I studies use drugs starting
at low doses and slowly increase the amounts of the study drugs that are given to people
until the side effects of the drugs are too high to give more. This means that not all people
in the study will get the same dose of IRX5183. Doses at the beginning of the study will be
lower than doses at the end of the study. Because of the design of the study, some people may
get doses that are too low to have an effect, and other people will probably get doses that
cause side effects.

People with AML, MDS, or CMML that has 1) not responded to standard therapy or 2) has
returned after a previous response may join.

Inclusion Criteria:

1. Patients must be able to understand and voluntarily sign an informed consent form.

2. Age ≥ 18 years at the time of signing the informed consent form.

3. Able to adhere to the study visit schedule and other protocol requirements.

4. Pathologically confirmed disease with A or B as follows:

A) AML patients who either have:

- Relapsed or refractory disease after receiving one or more courses of induction
chemotherapy, hypomethylating agent therapy, or bone marrow transplant or

- de novo AML but not deemed to be a candidate for conventional therapy based on
age, co-morbidities, or patient preference

B) MDS, CMML, or MDS/myeloproliferative neoplasm (MPN) with high risk features as
defined below who have relapsed after initial response or are refractory (failure to
achieve a complete remission (CR), partial remission (PR), or hematologic improvement
(HI)) after receiving at least 4 cycles of hypomethylating agents 5-azacitidine or
decitabine ± other therapies ± bone marrow transplant OR with de novo MDS but have
refused to receive hypomethylating therapy:

- Intermediate (INT)-2 or high International Prognostic Scoring System (IPSS) score
OR high or very high revised IPSS (IPSS-R) or

- Secondary MDS (defined as MDS developing in a patient with an antecedent
hematologic disorder or any patient with prior chemotherapy or radiation
exposure) or

- INT-1 IPSS or intermediate IPSS-R MDS with excess blasts (≥5% blasts in bone
marrow) or transfusion-dependency or

- MDS progressing to oligoblastic AML with 21-30% bone marrow blasts or

- CMML or MDS/MPN with ≥ 5% marrow blasts, transfusion-dependency, abnormal
karyotype, or proliferative features (white blood cell count ≥13,000/µL,
splenomegaly on physical examination, or extramedullary disease)

5. Eastern Cooperative Oncology Group performance status of ≤ 2 at study entry or
Karnofsky > 60%.

6. Laboratory test results within these ranges:

Creatinine level of 3 mg/dL or lower, total bilirubin ≤ 3 mg/dL unless due to
Gilbert's syndrome, hemolysis, or ineffective hematopoiesis, aspartate
aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 x upper limit of normal,
white blood count (WBC) ≤ 10,000/µL

7. Patients must not have received any other treatment for their disease, including
hematopoietic growth factors, aside from hydroxyurea for count control, within three
weeks of beginning the trial, and should have recovered from all toxicities of prior
therapy (to grade 0 or 1).

8. Patients requiring hydroxyurea to bring WBC below 10,000/µL prior to study enrollment
will require a 48-hour washout prior to starting the study drug.

9. Women of childbearing potential must have a negative serum or urine pregnancy test
within 72 hours prior to start of IRX5183.

10. Patients must have no clinical evidence of central nervous system (CNS) or pulmonary
leukostasis, disseminated intravascular coagulation, or CNS leukemia.

Exclusion Criteria:

1. Any serious medical condition or uncontrolled intercurrent illness including, but not
limited to, ongoing or active infection, symptomatic congestive heart failure,
unstable angina pectoris, cardiac arrhythmia, laboratory abnormality, or psychiatric
illness/social situations that would limit compliance with study requirements or
prevent the subject from signing the informed consent form.

2. Any condition, including the presence of laboratory abnormalities, which places the
subject at unacceptable risk if he/she were to participate in the study or confounds
the ability to interpret data from the study.

3. Use of any other experimental drug or therapy within 21 days of baseline.

4. Known hypersensitivity or history of allergic reactions attributed to compounds of
similar chemical or biologic composition to IRX5183.

5. Prior use of other retinoid therapies in the 3 months prior to enrollment in the
study.

6. Patients with other active cancers receiving anti-cancer agents, with exceptions being
hormonal therapy for breast or prostate cancer and skin cancers treated with local
therapies only.

7. Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for
nitrosoureas or mitomycin C) prior to entering the study or those who have not
recovered from adverse events due to agents administered more than 4 weeks earlier
(e.g. alopecia, hypothyroid, neuropathy, etc.).

8. Pregnant women are excluded from this study because of potential for teratogenic or
abortifacient effects. Because there is an unknown but potential risk for adverse
events in nursing infants secondary to treatment of the mother with IRX5183,
breastfeeding should be discontinued if the mother is treated with IRX5183.