Study of R289 in Patients With Lower-risk Myelodysplastic Syndromes (LR MDS)

Phase 1

Recruiting

• Conditions: Low Risk Myelodysplastic Syndromes
• Interventions: Drug: R906289 Monosodium (R289 Na)

• Registration Number: NCT05308264
• Lead Sponsor: Rigel Pharmaceuticals

Brief Summary

Phase 1b Study of R289 in Patients with Lower-risk Myelodysplastic Syndromes (LR MDS)

Detailed Description

An open-label, Phase 1b study of R289, an IRAK 1/4 Inhibitor, to determine tolerability and preliminary efficacy in patients with LR MDS who are relapsed/refractory/resistant, intolerant, or have inadequate response to prior therapies such as erythropoietin (EPO), luspatercept, or hypomethylating agents (HMAs) for MDS.

Study Timeline

• Study First Submitted: 2022-03-02
• Study First Submitted QC: 2022-03-25
• Study First Posted: 2022-04-04
• Study Start: 2022-09-12
• Status Verified: 2025-03
• Last Update Submitted: 2025-04-09
• Last Update Posted: 2025-04-15
• Primary Completion: 2026-08
• Study Completion: 2026-12

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 86

Inclusion Criteria

• Patient must be ≥ 18 years of age at the time of signing the informed consent.

• Must have definitive diagnosis of MDS with very low, low, or intermediate-1 risk (International Prognostic Scoring System (IPSS)-R ≤ 3.5) and ≤5% bone marrow myeloblasts.

• Must be relapsed, refractory/resistant, intolerant, or have inadequate response to therapies with known clinical benefits for MDS, such as EPOs, luspatercept, and HMAs(i.e., azacytidine or decitabine). Patients with del (5q) must have failed prior lenalidomide therapy.

• Symptomatic anemia untransfused with hemoglobin < 9.0 g/dL and no RBC transfusion within 16 of registration or

• RBC transfusion dependent defined as receiving ≥ 2 units of packed red blood cells (PRBCs) within 8 weeks in the preceding 16 weeks for a hemoglobin <9.0 g/dL.

• Exploratory Phase 1B Cohort:

  1. Transfusion-dependent LR-MDS who are refractory or intolerant to, or are ineligible for ESAs.
  2. No prior therapy with any approved or investigational therapies for MDS
  3. No del 5q cytogenetic abnormality
  4. RBC transfusion dependent defined as receiving ≥ 2 units of PRBCs within 8 weeks in the preceding 16 weeks for a hemoglobin <9.0 g/dL

• All participants must have documented marrow iron stores. If marrow iron stain is not available, the transferrin saturation must be >20% or a serum ferritin > 100ng/100mL

• Must have Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2 at screening.

• Must have adequate organ function, defined as:

  1. Hepatic function:

     • aspartate amino transferase (AST) and alanine aminotransferase (ALT) ≤ 1.5 × upper limit of normal (ULN)
     • total bilirubin ≤ 1.5 × ULN

  2. Renal function defined as creatinine clearance > 60 mL/min (using Cockcroft-Gault), or blood creatine < 1.5 mg/dL

Exclusion Criteria

• Prior treatment for MDS (i.e., TPOs, EPOs, luspatercept, HMAs) concluded < 4 weeks prior to study treatment

• Clinically significant anemia resulting from iron, B12 or folate deficiencies, autoimmune or hereditary hemolysis, or GI bleeding.

• MDS secondary to treatment with radiotherapy, chemotherapy, and/or immunotherapy for malignant or autoimmune diseases.

• Diagnosis of chronic myelomonocytic leukemia.

• History of uncontrolled seizures.

• Uncontrolled bacterial or viral infection (i.e., documented HIV, hepatitis B or hepatitis C).

• History of an active malignancy within the past 2 years prior to study entry, with the exception of:

  1. Adequately treated in situ carcinoma of the cervix uteri
  2. Adequately treated basal cell carcinoma or localized squamous cell carcinoma of the skin, or
  3. Low grade, early-stage prostate cancer (Gleason score 6 or below, stage 1 or 2) with no requirement for therapy at any time prior to the study, or previously resected.

• History of or active, clinically significant, cardiovascular, respiratory, GI, renal, hepatic, neurological, psychiatric, musculoskeletal, genitourinary, dermatological, or other disorder that, in the Investigator's opinion, could affect the conduct of the study or the absorption, metabolism or excretion of the study treatment.

• Prior history of autologous or allogeneic stem cell transplantation

• Marked baseline prolongation of QT/QTc interval (e.g., repeated demonstration of a QTc interval > 480 milliseconds [msec]) (Common Terminology Criteria for Adverse Events [CTCAE] Grade 1) using Fridericia's QT correction formula.

• History of additional risk factors for TdP (e.g., symptomatic heart failure with left ventricular ejection fraction [LVEF] <40%, hypokalemia, family history of Long QT Syndrome).

• Receiving any other concurrent chemotherapy, radiotherapy, or immunotherapy (within 2 weeks of initiating study treatment), or the toxicity of the relevant prior treatment has not been resolved yet.

• Use of concomitant medications that prolong the QT/QTc interval during study treatment

• Use of concomitant medications that are strong CYP3A or CYP2B6 inhibitors or inducers during study treatment

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Experimental	R906289 Monosodium (R289 Na)	Dose Level 1: 250mg PO qd Dose Level 2: 500mg PO qd Dose Level 3: 750 mg PO qd Dose Level 4: 250 mg PO bid Dose Level 5: 500 mg PO AM/250 mg PO PM Dose Level 6: 500 mg PO bid

Primary Outcome Measures

Name	Time	Method
Safety and Tolerability	2 Year	* Incidence of adverse events (AEs); * Incidence of discontinuation or interruptions of R289 due to AEs; * Incidence of dose limiting toxicities (DLTs)

Secondary Outcome Measures

Name	Time	Method
Outcome Measure: Preliminary Efficacy	24 Weeks for Primary Efficacy; 8 Weeks for Characterized PK	Measure Description Primary Efficacy: Proportion of patients achieving red blood cell transfusions independence by ≥ 8 weeks, ≥ 16 weeks, and ≥ 24 weeks Proportion of patients with overall response per IWG 2006 Proportion of patients with hematologic improvement per IWG 2018 Time Frame: 24 Weeks Measure Description Characterized PK Maximum plasma concentration (Cmax) Time Frame: 8 Weeks
Characterize pharmacokinetics (PK)	8 Weeks	Maximum plasma concentration (Cmax)

Trial Locations

Locations (10)

Oncology Clinical Research Referral Office; 🇺🇸 Hackensack, New Jersey, United States

University of California, Los Angeles; 🇺🇸 Los Angeles, California, United States

University of California, Irvine; 🇺🇸 Orange, California, United States

Mount Sinai Medical Center; 🇺🇸 Miami Beach, Florida, United States

University of Miami; 🇺🇸 Miami, Florida, United States

Rutgers Cancer Institute of New Jersey; 🇺🇸 New Brunswick, New Jersey, United States

Ichan School of Medicine at Mount Sinai; 🇺🇸 New York, New York, United States

Cleveland Clinic; 🇺🇸 Cleveland, Ohio, United States

University of Texas, Southwestern; 🇺🇸 Dallas, Texas, United States

MD Anderson Cancer Center; 🇺🇸 Houston, Texas, United States