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

• ClinicalTrials.gov Identifier: NCT05308264
• Recruitment Status: Recruiting
• First Posted: April 4, 2022
• Last Update Posted: March 15, 2023
• Sponsor: Rigel Pharmaceuticals
• Information provided by (Responsible Party): Rigel Pharmaceuticals

Study Description

Brief Summary:

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

Condition or disease	Intervention/treatment	Phase
Low Risk Myelodysplastic Syndromes	Drug: R906289 Monosodium (R289 Na)	Phase 1; Phase 2

Detailed Description:

The study will be an open-label, Phase 1b study of R289 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), thrombopoietin (TPO), luspatercept, or hypomethylating agents (HMAs) for MDS.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 22 participants
• Allocation: N/A
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-label, Phase 1b Study of R289, an IRAK1/4 Inhibitor, in Patients With Lower-risk Myelodysplastic Syndromes (LR MDS) Who Are Refractory/Resistant to Prior Therapies
• Actual Study Start Date: September 12, 2022
• Estimated Primary Completion Date: April 2024
• Estimated Study Completion Date: May 2024

Arms and Interventions

Arm	Intervention/treatment
Experimental: Experimental; Dose Level 1: 250mg PO qd Dose Level 2: 500mg PO qd	Drug: R906289 Monosodium (R289 Na); Drug: R906289 Monosodium (R289 Na) R906289 Monosodium (250mg PO qd or 500 mg PO qd); Other Name: R906289 Monosodium

Outcome Measures

Primary Outcome Measures :

1. Safety and Tolerability [ Time Frame: 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 :

1. Subjects with red blood cell transfusion independence by Week 24 [ Time Frame: 24 Weeks ]
   Proportion of subjects who achieve ≥ 50% reduction in number of red blood transfusion compared to baseline and ≥ 24 weeks.
2. Characterize pharmacokinetics (PK) [ Time Frame: 8 Weeks ]
   Maximum plasma concentration (Cmax)

Other Outcome Measures:

1. Characterize pharmacodynamic (PD) [ Time Frame: 1 year ]
   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)

Eligibility Criteria

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

Criteria

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

• Must 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 subjects must have documented marrow iron stain. 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., heart failure, 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

Contacts and Locations

Contacts

Contact: Elizabeth Franklin; (650) 624-1100; clinicaltrials@rigel.com

Contact: Donna Chow; (650) 624-1100; clinicaltrials@rigel.com

Locations

United States, California

University of California, Los Angeles; Recruiting

Los Angeles, California, United States, 90095

University of California, Irvine; Recruiting

Orange, California, United States, 92868

United States, Florida

Mount Sinai Medical Center; Recruiting

Miami Beach, Florida, United States, 33140

University of Miami; Recruiting

Miami, Florida, United States, 33136

United States, New Jersey

Hackensack University Medical Center; Recruiting

Hackensack, New Jersey, United States, 07601

Rutgers Cancer Institute of New Jersey; Recruiting

New Brunswick, New Jersey, United States, 09083

United States, New York

Ichan School of Medicine at Mount Sinai; Recruiting

New York, New York, United States, 10029

United States, Texas

University of Texas, Southwestern; Recruiting

Dallas, Texas, United States, 75390

MD Anderson Cancer Center; Recruiting

Houston, Texas, United States, 77030

Sponsors and Collaborators

Rigel Pharmaceuticals

More Information

• Responsible Party: Rigel Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT05308264
• Other Study ID Numbers: C-906289-002
• First Posted: April 4, 2022
• Last Update Posted: March 15, 2023
• Last Verified: March 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Rigel Pharmaceuticals:

MDS; LR MDS; Myelodysplastic Syndromes; Hematology Oncology; Hem/ Onc

Additional relevant MeSH terms:

Preleukemia; Myelodysplastic Syndromes; Syndrome; Disease; Pathologic Processes; Bone Marrow Diseases; Hematologic Diseases; Precancerous Conditions; Neoplasms