Clinical trial NCT05308264: Study of R289 in Patients With Lower-risk Myelodysplastic Syndromes (LR MDS)
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 Relapsed/Refractory/Resistant to Prior Therapies
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Low Risk Myelodysplastic Syndromes
Keywords: MDS
LR MDS
Myelodysplastic Syndromes
Hematology Oncology
Hem/ Onc
Lead sponsor: Rigel Pharmaceuticals
Sponsor class: INDUSTRY
First posted: 2022-04-04
Enrollment: 86
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.

Eligibility 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 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

Primary outcomes:
measure: Safety and Tolerability
timeFrame: 2 Year
Secondary outcomes:
measure: Outcome Measure: Preliminary Efficacy
timeFrame: 24 Weeks for Primary Efficacy; 8 Weeks for Characterized PK
measure: Characterize pharmacokinetics (PK)
timeFrame: 8 Weeks
Other outcomes:
measure: Characterize pharmacodynamic (PD)
timeFrame: 1 year
Locations:
city: Los Angeles
country: United States
facility: University of California, Los Angeles
state: California
city: Orange
country: United States
facility: University of California, Irvine
state: California
city: Miami Beach
country: United States
facility: Mount Sinai Medical Center
state: Florida
city: Miami
country: United States
facility: University of Miami
state: Florida
city: Hackensack
country: United States
facility: Oncology Clinical Research Referral Office
state: New Jersey
city: New Brunswick
country: United States
facility: Rutgers Cancer Institute of New Jersey
state: New Jersey
city: New York
country: United States
facility: Ichan School of Medicine at Mount Sinai
state: New York
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Dallas
country: United States
facility: University of Texas, Southwestern
state: Texas
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
Study officials:
References: