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

Sponsor

Rigel Pharmaceuticals (Industry)

Overall Status

Not yet recruiting

CT.gov ID

NCT05308264

Collaborator

(none)

Enrollment

Arm

Anticipated Duration (Months)

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Low Risk Myelodysplastic Syndromes	Drug: R906289 Monosodium (R289 Na)	Phase 1/Phase 2

Study Design

Study Type:

Interventional

Anticipated Enrollment :

22 participants

Allocation:

N/A

Intervention Model:

Single Group 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

Anticipated Study Start Date :

Aug 1, 2022

Anticipated Primary Completion Date :

Apr 1, 2024

Anticipated Study Completion Date :

May 1, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Dose Escalation Experimental: Dose Expansion Phase	Drug: R906289 Monosodium (R289 Na) 250 mg tablet

Arm

Intervention/Treatment

Experimental: Dose Escalation

Experimental: Dose Expansion Phase

Drug: R906289 Monosodium (R289 Na)

250 mg tablet

Outcome Measures

Primary Outcome Measures

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)

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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, platelet count, or absolute neutrophil (ANC) within 8 weeks prior to initial administration of study treatment:

Symptomatic anemia untransfused with hemoglobin < 9.0 g/dL within 8 weeks of registration or red blood cell (RBC) transfusion dependent defined as receiving > 3 units of packed red blood cells (PRBCs) in the preceding 16 weeks for a hemoglobin <9.0 g/dL.
Clinically relevant thrombocytopenia (platelet counts of <100 × 109/L in at least 2 blood counts prior to study treatment and transfusion dependence).
Absolute neutrophil count (ANC) of < 1.0 × 109/L in at least 2 blood counts prior to randomization.

Must have Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2 at screening.
Must have Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2 at screening.
Must have adequate organ function, defined as:

Hepatic function:

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

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

Adequately treated in situ carcinoma of the cervix uteri
Adequately treated basal cell carcinoma or localized squamous cell carcinoma of the skin, or
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).
Treatment with cytotoxic chemotherapeutic agents or experimental agents for the treatment of MDS within 8 weeks of study treatment.
Receiving any other concurrent chemotherapy, radiotherapy, or immunotherapy (within 8 weeks of initiating study treatment).
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