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

Phase I/II Study of IRX5183 in Relapsed and Refractory Acute Myeloid Leukemia (AML) and High Risk Myelodysplastic Syndrome (MDS)

The purpose of this study is to evaluate the use of IRX5183 in 1) patients with relapsed and/or refractory AML and 2) patients with high-risk MDS or chronic myelomonocytic leukemia (CMML).

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.