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

An Open-label, Phase 1b Study of R289, an IRAK1/4 Inhibitor, in Participants With Lower-risk Myelodysplastic Syndromes (LR MDS) Who Are Refractory/Resistant to Prior Therapies

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

Study Overview

• Status: Recruiting
• Conditions: Low Risk Myelodysplastic Syndromes
• Intervention / Treatment: Drug: R906289 Monosodium (R289 Na)

Detailed Description

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

• Study Type: Interventional
• Enrollment (Estimated): 34
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Elizabeth Franklin; Phone Number: (650) 624-1100; Email: clinicaltrials@rigel.com
• Study Contact Backup: Name: Donna Chow; Phone Number: (650) 624-1100; Email: clinicaltrials@rigel.com

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90095
      • Recruiting
      • University of California, Los Angeles
    • Orange, California, United States, 92868
      • Recruiting
      • University of California, Irvine
  • Florida
    • Miami, Florida, United States, 33136
      • Recruiting
      • University of Miami
    • Miami Beach, Florida, United States, 33140
      • Recruiting
      • Mount Sinai Medical Center
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • Recruiting
      • Hackensack University Medical Center
    • New Brunswick, New Jersey, United States, 09083
      • Withdrawn
      • Rutgers Cancer Institute of New Jersey
  • New York
    • New York, New York, United States, 10029
      • Recruiting
      • Ichan School of Medicine at Mount Sinai
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Recruiting
      • Cleveland Clinic
  • Texas
    • Dallas, Texas, United States, 75390
      • Recruiting
      • University of Texas, Southwestern
    • Houston, Texas, United States, 77030
      • Recruiting
      • MD Anderson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Participant 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 TPOs, EPOs, luspatercept, and HMAs(i.e., azacytidine or decitabine). Participants with del (5q) must have failed prior lenalidomide therapy.

• Must be blood transfusion dependent and meet at least one of the disease-related criteria for RBC transfusion, or platelet count within 8 weeks prior to initial administration of study treatment:

  1. Symptomatic anemia untransfused with hemoglobin < 9.0 g/dL within 8 weeks of registration or red blood cell (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.
  2. Clinically relevant thrombocytopenia (platelet counts of <100 × 109/L in at least 2 blood counts prior to study treatment and transfusion dependence).

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) or 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. Any other malignancy with a life expectancy of more than 2 years
• 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 bone marrow 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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Experimental; Dose Level 1: 250mg PO qd Dose Level 2: 500mg PO qd Dose Level 3: 750 mg PO qd and 1000 mg PO qd	Drug: R906289 Monosodium (R289 Na); Drug: R906289 Monosodium (R289 Na) R906289 Monosodium (250mg PO qd,500 mg PO qd, 750 mg PO qd, 1000 mg PO qd); Other Names: R906289 Monosodium

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety and Tolerability	Incidence of adverse events (AEs); Incidence of discontinuation or interruptions of R289 due to AEs; Incidence of dose limiting toxicities (DLTs)	2 Year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Characterize pharmacokinetics (PK)	Maximum plasma concentration (Cmax)	8 Weeks
Participants with red blood cell transfusion independence by Week 24	Proportion of participants who achieve ≥ 50% reduction in number of red blood transfusion compared to baseline and ≥ 24 weeks.	24 Weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Characterize pharmacodynamic (PD)	Change from baseline biomarker expression levels in plasma and bone marrow (including but not limited to, C-reactive protein [CRP] and tumor necrosis factor [TNF]-a)	1 year

Collaborators and Investigators

• Sponsor: Rigel Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): September 12, 2022
• Primary Completion (Estimated): May 1, 2025
• Study Completion (Estimated): May 1, 2025

Study Registration Dates

• First Submitted: March 2, 2022
• First Submitted That Met QC Criteria: March 25, 2022
• First Posted (Actual): April 4, 2022

Study Record Updates

• Last Update Posted (Estimated): October 10, 2023
• Last Update Submitted That Met QC Criteria: October 6, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: MDS; Myelodysplastic Syndromes; Hematology Oncology; LR MDS; Hem/ Onc
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Disease; Bone Marrow Diseases; Hematologic Diseases; Precancerous Conditions; Syndrome; Myelodysplastic Syndromes; Preleukemia
• Other Study ID Numbers: C-906289-002

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No