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RARalpha Agonist IRX5183 in Treating Patients with Relapsed or Refractory Acute Myeloid Leukemia and High Risk Myelodysplastic Syndrome

Trial Status: Complete

This phase I / II trial studies the best dose and side effects of RARalpha agonist IRX5183 and how well it works in treating patients with acute myeloid leukemia and high risk myelodysplastic syndrome that has come back or does not respond to treatment. RARalpha agonist IRX5183 causes cancer cells to mature and die, and may stop the uncontrolled growth of leukemia cells.

Inclusion Criteria

  • Patients must be able to understand and voluntarily sign an informed consent form
  • Able to adhere to the study visit schedule and other protocol requirements
  • Pathologically confirmed disease as follows: * 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 * MDS, chronic myelomonocytic leukemia (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 response [CR], partial response [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 International Prognostic Scoring System (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 R-IPSS MDS with excess blasts (>= 5% blasts in bone marrow [BM]) or transfusion-dependency or ** MDS progressing to oligoblastic AML with 21-30% BM blasts or ** CMML or MDS/MPN with >= 5% marrow blasts, transfusion-dependency, abnormal karyotype, or proliferative features (white blood cell count >= 13,000/uL, splenomegaly on physical examination, or extramedullary disease)
  • Eastern Cooperative Oncology Group (ECOG) performance status of =< 2 at study entry or Karnofsky >= 60%
  • 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) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x upper limit of normal (ULN)
  • White blood cells (WBC) =< 10,000/uL
  • 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)
  • Patients requiring hydroxyurea to bring WBC below 10,000/uL prior to study enrollment will require a 48-hour washout prior to starting the study drug
  • Women of childbearing potential must have a negative serum or urine pregnancy test within 72 hours prior to start of IRX5183
  • Patients must have no clinical evidence of central nervous system (CNS) or pulmonary leukostasis, disseminated intravascular coagulation, or CNS leukemia

Exclusion Criteria

  • 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
  • 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
  • Use of any other experimental drug or therapy within 21 days of baseline
  • Known hypersensitivity or history of allergic reactions attributed to compounds of similar chemical or biologic composition to IRX5183
  • Prior use of other retinoid therapies in the 3 months prior to enrollment in the study
  • 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
  • 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.)
  • Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with IRX5183


Johns Hopkins University / Sidney Kimmel Cancer Center
Contact: B. Douglas Smith
Phone: 410-614-5068


I. To evaluate the safety and toxicity of RARalpha agonist IRX5183 (IRX5183) in patients with relapsed/refractory (R/R)-acute myeloid leukemia (AML) and high-risk (HR)-myelodysplastic syndrome (MDS) and determine the recommended phase 2 dose (RP2D).

II. To obtain preliminary efficacy data of IRX5183 in patients with R/R-AML and HR-MDS after at least 2 cycles of therapy at the RP2D.


I. To determine pharmacokinetic (PK) parameters of IRX5183 and assess bioactivity through pharmacodynamics (PD) studies.

II. To measure clinical activity of IRX5183 as defined by best International Working Group (IWG) response at any time, time to response, improvement in transfusion requirements, cytopenias, quality of life assessments, event-free survival (EFS), and overall survival (OS) and to determine the toxicity profile of IRX5183 at the optimal dose.

OUTLINE: This is a dose-escalation study.

INDUCTION THERAPY: Patients receive RARalpha agonist IRX5183 orally (PO) once daily (QD) on days 1-28. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity.

CONSOLIDATION/MAINTENANCE THERAPY: After 5-14 days of induction therapy, patients who achieve complete remission (CR), partial remission (PR), hematologic improvement (HI), or stable disease (SD) receive RARalpha agonist IRX5183 QD on days 1-28. Treatment repeats every 28 days for up to 4 courses in the absence of disease progression or unacceptable toxicity.

EXTENDED MAINTENANCE THERAPY: Patients who achieve SD but not CR, receive RARalpha agonist IRX5183 QD on days 1-28. Courses repeats every 28 days for up to 1 year in the absence of disease progression or unacceptable toxicity. Patients who achieve CR undergo observation biweekly for 1 month and monthly for at least 6 months.

After completion of study treatment, patients are followed up for monthly for 6 months, then every 3 months for up to 2 years.

Trial Phase Phase I/II

Trial Type Treatment

Lead Organization
Johns Hopkins University / Sidney Kimmel Cancer Center

Principal Investigator
B. Douglas Smith

  • Primary ID J15219
  • Secondary IDs NCI-2017-00282, CRMS-62978, IRB00083855
  • ID NCT02749708