DR-18 to Prevent or Treat Acute Myeloid Leukemia or Myelodysplastic Syndrome Relapse After Hematopoietic Cell Transplantation, the DR. DREAM Trial

Decoy-Resistant Interleukin-18 (DR-18) for Relapse, Pre-emptive Treatment or Prophylaxis After Allogeneic Hematopoietic Cell Transplantation in Patients With Acute Myeloid Leukemia and Myelodysplastic Syndrome (DR. DREAM)

This phase I trial tests the safety, side effects and best dose of decoy-resistant interleukin-18 (DR-18) and how well it works in treating patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) that has come back after a period of improvement (relapsed) or that remains despite treatment (persistent) after hematopoietic cell transplantation (HCT). HCT is the only curative therapy for most forms of AML and MDS. However, relapse occurs in a third of patients and is the most common cause of death after HCT. DR-18, a variant of the human cytokine interleukin-18, binds to IL-18 binding probein (IL-18BP) and overcomes the inhibitory effect of the IL-18BP on IL-18, which may boost the body's immune system and may interfere with the ability of tumor cells to grow and spread. Giving DR-18 may be safe, tolerable and/or effective in treating patient with relapsed or persistent AML or MDS after HCT.

Study Overview

• Status: Recruiting
• Conditions: Acute Myeloid Leukemia; Myelodysplastic Syndrome; Recurrent Acute Myeloid Leukemia; Recurrent Myelodysplastic Syndrome
• Intervention / Treatment: Procedure: Biospecimen Collection; Procedure: Bone Marrow Aspiration; Biological: Decoy-resistant interleukin-18

Detailed Description

OUTLINE: This is a dose-escalation study.

INDUCTION: Patients receive DR-18 subcutaneously (SC) once weekly on approximately days 0, 7, 14, and 21.

MAINTENANCE: After induction treatment, following a two-week pause (GROUP 1 - Treatment) or following discontinuation of prophylactic systemic immunosuppression post-transplant (GROUP 2 - Prophylaxis) patients without grade 3-4 acute GVHD, grade 2 acute GVHD requiring ongoing systemic immunosuppression, or moderate/severe chronic GVHD may receive DR-18 SC approximately for 4 additional weeks.

Additionally, patients undergo blood and bone marrow sample collection throughout the study.

After completion of study treatment, patients are followed weekly for 4 weeks, monthly through 6 months and at 12 months.

• Study Type: Interventional
• Enrollment (Estimated): 40
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Elizabeth Krakow; Phone Number: 206-667-3410; Email: efkrakow@fredhutch.org

Study Locations

• United States
  • Washington
    • Seattle, Washington, United States, 98109
      • Recruiting
      • Fred Hutch/University of Washington Cancer Consortium
      • Contact: Elizabeth Krakow; Phone Number: 206-667-3410; Email: efkrakow@fredhutch.org
      • Principal Investigator: Elizabeth Krakow

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• ≥ 18 years of age (no upper age limit)
• The most recent HCT was from a 10/10 human leukocyte antigen (HLA)-matched related or unrelated donor (assessed at HLA-A, B, C, DR, DQ)
• Evidence of blood count recovery at any time post-HCT defined as absolute neutrophil count (ANC) ≥ 0.5 x 10^9/L for ≥ 3 consecutive days and platelets ≥ 30 x 10^9/L (independent of granulocyte colony-stimulating factor [G-CSF] or platelet transfusions for 5 days). (Blood count recovery may not be sustained.)
• Absent, stable or reducing immune suppression in the preceding 4 weeks without GvHD flares
• Karnofsky performance status (KPS) ≥ 80%
• Agrees to use a suitable method of contraception during study treatment and for 4 months after the last dose of DR-18
• Capable of providing informed consent

• GROUP 1: Documented persistent or recurrent measurable residual AML or MDS after HCT, defined as bone marrow blasts < 5% by morphology (unless suspected to be regenerative) and malignant bone marrow blasts < 5% by flow cytometry.

  • Note: MRD (< 5% malignant blasts) must be detected with flow cytometry testing at University of Washington Medical Center (UWMC)/Fred Hutchinson Cancer Center (Fred Hutch) clinical laboratory
• GROUP 1: Absence of circulating malignant blasts detected by the complete blood count (CBC)
• GROUP 1: Absence of extramedullary disease
• GROUP 1: Post-HCT restaging never detected overt relapse or disease persistence, defined as ≥ 5% (non-regenerative) blasts by morphology or flow cytometry, or circulating malignant blasts on CBC, or extramedullary disease
• GROUP 1: At least 60 days have elapsed since the HCT donor cell infusion (HCT day 0). (There is no upper limit to the time elapsed since HCT.)
• GROUP 1: No Food and Drug Administration (FDA)-approved targeted therapy for the participant's AML or MDS is available, or if such therapy is available, that class of drugs previously failed for the participant or the participant was intolerant of the therapy
• GROUP 2: HCT is with post-transplant cyclophosphamide or other form of in vivo or ex-vivo T cell depletion
• GROUP 2: Informed consent was signed pre-HCT or latest day 28 post-HCT. (Treatment may start as early as 30 days post-HCT.)
• GROUP 2-ONLY IF AML BY WORLD HEALTH ORGANIZATION (WHO) OR INTERNATIONAL CONSENSUS CLASSIFICATION (ICC) 2022 CRITERIA: Pre-HCT bone marrow shows residual leukemia by flow cytometry (MRD or overt disease with ≥ 5% blasts)
• GROUP 2-ONLY IF AML BY WHO OR ICC 2022 CRITERIA: The participant had at least 1 course of intensive induction chemotherapy or 2 cycles of hypomethylating therapy with venetoclax or 4 cycles of hypomethylating therapy prior to HCT

• GROUP 2-ONLY IF MDS BY WHO OR ICC 2022 CRITERIA: Any one of the following high-risk features was detected in the pre-HCT disease course:

  • International Prognostic Scoring System-MDS (IPSS-M) score "very high" risk
  • TP53 pathogenic or likely pathogenic mutation with variant allele frequency (VAF) ≥ 50%
  • TP53 pathogenic or likely pathogenic mutation with VAF < 50% and complex cytogenetics or 5q or 7q cytogenetic abnormalities
  • Biallelic TP53 mutations
  • The patient had at least 1 course of intensive induction chemotherapy or 2 cycles of hypomethylating therapy with venetoclax or 4 cycles of hypomethylating therapy and the pre-HCT bone marrow evaluation still shows > 5% malignant blasts by flow cytometry

Exclusion Criteria:

• Cellular immunotherapy or new targeted therapy in the 4 weeks prior to the first DR-18 injection
• History of grade 3 or 4 acute GvHD after the most recent HCT
• History of moderate or severe chronic GvHD after the most recent HCT
• Active acute or chronic GvHD or other immunologic phenomenon (e.g., immune cytopenias, cryptogenic immunologic pneumonia) in last month requiring systemic therapy (Hydrocortisone or prednisone for adrenal insufficiency at ≤ 10 mg/day prednisone-equivalent is permitted.)
• Active moderate-severe thrombotic microangiopathy (TMA) as evidenced by any of the following: > 10 schistocytes per high-power field, or required anti-C5 or other anti-complement therapy for TMA in the prior 4 weeks, any of the following manifestations if attributed to TMA in the prior 4 weeks: hypertension, worsening or new renal insufficiency, ≥ 2+ proteinuria, hematochezia, seizure, transient or ongoing neurologic deficits
• Renal insufficiency: Estimated glomerular filtration rate (eGFR) (calculated per the performing laboratory's standard formula) or measured 24 hour (hr.) creatinine clearance < 30 mL/min
• Hemodialysis in the prior 4 weeks
• Major cardiac event requiring evaluation in the emergency room (ER) or hospitalization in the past 4 weeks
• New York Heart Association (NYHA) class II or higher congestive heart failure (CHF) in the past 4 weeks
• Uncontrolled cardiac arrhythmias, including atrial fibrillation
• Left ventricular ejection fraction (LVEF) < 35%. LVEF may be established with echocardiogram or MUGA scan, and left ejection fraction must be ≥ 35%
• Liver dysfunction: aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 5 x upper limit of normal (ULN) or bilirubin > 3 x ULN

• Active uncontrolled infection. Note: Examples of controlled infections:

  • Bacterial infection may be still requiring antibiotics at the time of enrollment, but clinical signs and symptoms of the infection should be improving. If the participant had bloodstream infection, negative blood cultures off antibiotics must be documented prior to initiating DR-18 treatment. For urinary tract infection, a repeat urine culture must be sterile prior to initiating DR-18. Radiographic improvement of bacterial pneumonia may lag behind clinical improvement so is not mandatory prior to DR-18 initiation
  • Fungal infection may be still requiring antifungal medication at the time of enrollment, but evidence of clinical response to antifungal medication (such as regression of lesions on chest CT) must be available at the time of enrollment
  • Asymptomatic shedding of respiratory viruses after cessation of antiviral therapy, or if not specifically treated with antiviral therapy, is permitted
  • Cytomegalovirus (CMV) viremia or organ infection meeting institutional criteria for CMV treatment with antiviral therapy such as ganciclovir, valganciclovir or foscarnet must be on maintenance phase of treatment or must have completed treatment and must not be in the induction treatment phase at the time of enrollment. Low-level CMV viremia not meeting institutional criteria for antiviral therapy is permitted, including low-level viremia in patients receiving CMV prophylaxis with letermovir
• Any of the following: Pulmonary dysfunction requiring supplemental oxygen, even intermittently, in the past 2 weeks; corrected diffusion capacity of the lung for carbon monoxide (DLCO) or forced expiratory volume in 1 second (FEV1) < 60% predicted; bronchiolitis obliterans syndrome; prior diagnosis of idiopathic pulmonary fibrosis; prior diagnosis of drug-induced pneumonitis; cryptogenic organizing pneumonia under active treatment
• Seizure in the past 4 weeks or significant underlying neurologic disease: Study participants must not have significant active underlying neurologic disease, such as Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, epilepsy, prior symptomatic ischemic or hemorrhagic stroke, or transient ischemic attack, unless approved by principal investigator (PI). Peripheral neuropathy related to diabetes or prior chemotherapy is acceptable
• Other medical, social, or psychiatric factor that interferes with medical appropriateness and/or ability to comply with study, as determined by the PI
• Known allergic reactions to any of the components of study treatments
• Concurrent use of other investigational anti-cancer agents
• Peripheral blood T cell chimerism < 40%
• Pregnant or breastfeeding

Study Plan

How is the study designed?

Design Details

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

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment (DR-18); INDUCTION: Patients receive DR-18 SC once weekly on approximately days 0, 7, 14, and 21. MAINTENANCE: Two weeks after induction treatment, patients without grade 3-4 acute GVHD, grade 2 acute GVHD requiring ongoing systemic immunosuppression, or moderate/severe chronic GVHD may receive DR-18 SC once weekly on approximately days 35, 42, 49 and 56. Additionally, patients undergo blood and bone marrow sample collection throughout the study.

Procedure: Biospecimen Collection; Undergo blood sample collection; Other Names: Biological Sample Collection; Biospecimen Collected; Specimen Collection; Procedure: Bone Marrow Aspiration; Undergo bone marrow aspiration; Biological: Decoy-resistant interleukin-18; Given SC; Other Names: Engineered IL-18 Variant ST-067; Engineered Interleukin-18 Variant ST-067; ST 067; ST-067; ST067; DR-18

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Occurrence of dose-limiting toxicities (DLTs)	DLTs will be defined as the dosing scheme associated with a true DLT rate of ≤ 25%. DLTs will be recorded using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v)5.0.	Up to 6 weeks after first dose of DR-18, or 2 weeks after the last induction dose of DR-18, whichever is later
Number of subjects who complete a minimum of 2 doses within 4 consecutive weeks of DR-18		At the end of week 4

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Composite complete response (CR)	Composite CR will be assessed according to European LeukemiaNet 2022 criteria.	At 1 month after the first dose of DR-18
Overall survival (OS)	OS will be assessed with the Kaplan-Meier method.	At 6 months and at 12 months after first dose of DR-18
Incidence of grade 2 and grade 3-4 acute graft versus host disease (GVHD)	Cumulative incidence estimates will be obtained for outcomes with competing risks.	From first DR-18 injection up to 6 months after the last injection
Incidence of moderate to severe chronic GVHD	Cumulative incidence estimates will be obtained for outcomes with competing risks.	At 6 months after the first DR-18 injection
Incidence of grade 1-4 cytokine release syndrome (CRS)	Incidence of grade 1-4 CRS will be graded using the American Society for Transplantation and Cellular Therapy Cytokine Release Syndrome grading system.	Up to 4 weeks after the last dose of DR-18
Incidence of neutropenia	Neutropenia will be defined as absolute neutrophil count (ANC) < 500/uL for > 14 days not attributed to disease progression or other cause, assessable in subjects with ANC ≥ 500/uL and no granulocyte colony-stimulating factor receipt in the prior 100 days at time of first DR-18 injection.	Up to 4 weeks after the last dose of DR-18
Incidence of thrombocytopenia	Thrombocytopenia will be defined as platelets < 20 K/uL for > 14 days not attributed to disease progression or other cause, assessable in subjects with platelets ≥ 20 K/uL and no platelet transfusion in the prior 7 days at time of first DR-18 injection.	Up to 4 weeks after the last dose of DR-18
Incidence of other grade 3-5 adverse events (AEs)	AEs will be recorded using NCI CTCAE v5.0.	Up to 4 weeks after the last DR-18 injection
Partial response (PR)	PR will be defined as 25% reduction in blasts in subjects with morphologic disease pre-DR-18 treatment. Response will be assessed according to European LeukemiaNet 2022 criteria.	At 1 month after first dose of DR-18
Overall response rate (ORR)	ORR will be defined as composite CR + PR in subjects with morphologic disease pre-DR-18 treatment. ORR will be determined using European LeukemiaNet 2022 response criteria.	At 1 month after the first dose of DR-18
Minimal residual disease (MRD) negativity		At 1 month after the first dose of DR-18
Sustained MRD negativity		At 3, 6, and 12 months after the first dose of DR-18

Collaborators and Investigators

• Sponsor: Fred Hutchinson Cancer Center
• Collaborators: Simcha Therapeutics
• Investigators: Principal Investigator: Elizabeth Krakow, Fred Hutch/University of Washington Cancer Consortium

Study record dates

Study Major Dates

• Study Start (Actual): September 23, 2024
• Primary Completion (Estimated): October 1, 2027
• Study Completion (Estimated): October 1, 2028

Study Registration Dates

• First Submitted: July 1, 2024
• First Submitted That Met QC Criteria: July 1, 2024
• First Posted (Actual): July 9, 2024

Study Record Updates

• Last Update Posted (Actual): June 26, 2026
• Last Update Submitted That Met QC Criteria: June 24, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Histologic Type; Hematologic Diseases; Leukemia, Myeloid; Bone Marrow Diseases; Leukemia; Hemic and Lymphatic Diseases; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Investigative Techniques; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Specimen Handling
• Other Study ID Numbers: RG1124197; NCI-2024-04811 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); FH20254 (Other Identifier: Fred Hutch/University of Washington Cancer Consortium)

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