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

NCT02749708 | Terminated Phase 1 DMC FDA Drug

• 2 other identifiers: J15219IRB00083855
• Study Type: interventional
• Target: 13
• Locations: 1 country
• Sites: 1

Brief Summary

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).

Conditions

Acute Myeloid Leukemia (AML); Myelodysplastic Syndrome (MDS); Chronic Myelomonocytic Leukemia (CMML)

Keywords

IRX5183; relapsed/refractory AML; high-risk MDS

Outcome Measures

Primary Outcomes (2)

• Evaluate safety and tolerability of IRX5183 in phase I using National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0, to determine dose limiting toxicities (DLTs) and the recommended phase 2 dose (RP2D).

  We will determine DLTs at specified dose levels to determine the RP2D.

  2 years

• Determine the best overall response rate (ORR) per International Working Group (IWG) criteria with the RP2D after at least 2 therapy cycles.

  The primary endpoint of phase II is best ORR per IWG criteria after at least 2 cycles of therapy. If enough patients achieve an objective response, enrollment will continue to a second stage, per a Simon's 2 stage design.

  2 years

Secondary Outcomes (9)

• Measure trough plasma levels of IRX5183 on day 1 and day 14.

  4 years

• Measure peak plasma/bone marrow levels of IRX5183 on day 1 and day 14.

  4 years

• Determine flow markers of differentiation in the peripheral blood and/or bone marrow.

  4 years

• Determine changes in cytogenetics in the peripheral blood and bone marrow before and after treatment with IRX5183.

  4 years

• Determine the time to first and best response, per IWG criteria.

  4 years

Study Arms (2)

Dose level 1

EXPERIMENTAL

IRX5183 50 mg daily

Drug: IRX5183

Dose level 2

EXPERIMENTAL

IRX5183 75 mg daily

Drug: IRX5183

Interventions

IRX5183 DRUG

IRX5183 will be administered orally daily on days 1-28 of each cycle for 2 cycles of induction. In the phase I part of the study, there will be 3 dose levels (dose level 1 \[DL1\] with 50 mg, DL2 with 75 mg, and DL3 with 100 mg), with 1 additional dose level to be only used if excessive toxicity noted at the DL1. There will be no intra-patient dose escalation. A phase II portion of the study was originally planned, but the study was terminated prior to phase II enrollment.

Dose level 1; Dose level 2

Eligibility Criteria

• Age: 18 Years - 100 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients must be able to understand and voluntarily sign an informed consent form.
• Age ≥ 18 years at the time of signing the informed consent form.
• Able to adhere to the study visit schedule and other protocol requirements.
• 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)
• Eastern Cooperative Oncology Group performance status of ≤ 2 at study entry or Karnofsky \> 60%.
• Laboratory test results within these ranges:

You may not qualify if:

• 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 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.

Sponsors & Collaborators

• Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins: lead
• Io Therapeutics: collaborator

Study Sites (1)

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Baltimore, Maryland, 21231, United States

Location

Related Publications (1)

• Ambinder AJ, Norsworthy K, Hernandez D, Palau L, Paun B, Duffield A, Chandraratna R, Sanders M, Varadhan R, Jones RJ, Douglas Smith B, Ghiaur G. A Phase 1 Study of IRX195183, a RARalpha-Selective CYP26 Resistant Retinoid, in Patients With Relapsed or Refractory AML. Front Oncol. 2020 Oct 23;10:587062. doi: 10.3389/fonc.2020.587062. eCollection 2020.

  PMID: 33194741 DERIVED

MeSH Terms

Conditions

Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Leukemia, Myelomonocytic, Chronic

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Bone Marrow Diseases; Myelodysplastic-Myeloproliferative Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• Douglas Smith, MD

  Johns Hopkins University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 5, 2016
• First Posted: April 25, 2016
• Study Start: January 30, 2017
• Primary Completion: August 14, 2018
• Study Completion: August 14, 2018
• Last Updated: April 22, 2019

Record last verified: 2019-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)