Using DR-18 to treat relapsed or persistent acute myeloid leukemia or myelodysplastic syndrome after stem cell transplantation

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

This study is testing a new treatment called DR-18 to see if it can help people with relapsed or persistent acute myeloid leukemia or myelodysplastic syndrome feel better after having a stem cell transplant.

Quick facts

• Phase: Phase 1
• Study type: Interventional
• Enrollment: 20 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: Fred Hutchinson Cancer Center (Academic / other)
• Drugs / interventions: chemotherapy, immunotherapy, prednisone
• Locations: 1 site (Seattle, Washington)
• Trial ID: NCT06492707 on ClinicalTrials.gov

What this trial studies

This phase I trial evaluates the safety, side effects, and optimal dosing of decoy-resistant interleukin-18 (DR-18) in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) that has relapsed or persisted after hematopoietic cell transplantation (HCT). The study involves administering DR-18 subcutaneously on a weekly basis during an induction phase, followed by a maintenance phase for eligible patients. Throughout the trial, blood and bone marrow samples will be collected to monitor the treatment's effects and patient responses. The goal is to determine if DR-18 can enhance the immune response against tumor cells and improve patient outcomes.

Who should consider this trial

Good fit: Ideal candidates are adults aged 18 and older with documented persistent or recurrent AML or MDS after HCT who have no available FDA-approved targeted therapies.

Not a fit: Patients with a history of severe acute or chronic graft-versus-host disease (GvHD) or those requiring systemic therapy for immunologic conditions may not benefit from this study.

Why it matters

Potential benefit: If successful, this treatment could provide a new therapeutic option for patients with relapsed or persistent AML or MDS after HCT.

How similar studies have performed: While this approach is novel, similar studies targeting immune modulation in hematologic malignancies have shown promise, indicating potential for success.

Eligibility criteria

Inclusion Criteria:

* ≥ 18 years of age (no upper age limit)
* Documented persistent or recurrent AML or MDS after HCT (including measurable residual disease \[MRD\] or overt leukemia). Nota bene (NB): 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
* No Food and Drug Administration (FDA)-approved targeted therapy for the subject's AML or MDS is available, or if such therapy is available, that class of drugs previously failed for the subject or the subject was intolerant of the therapy
* No history of grade 3 or 4 acute GvHD after the most recent HCT
* No history of moderate or severe chronic GvHD after the most recent HCT
* No 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.)
* Stable or reducing immune suppression in the preceding 4 weeks without GvHD flares
* 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.)
* No cellular immunotherapy or new targeted therapy in the 4 weeks prior to enrollment
* Karnofsky performance status (KPS) ≥ 80%
* Not pregnant/breastfeeding
* Agrees to use a suitable method of contraception for 4 months after the last dose of DR-18
* Capable of providing informed consent
* 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.)

Exclusion Criteria:

* 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. NB: 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 subject 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%

Where this trial is running

Seattle, Washington

• Fred Hutch/University of Washington Cancer Consortium — Seattle, Washington, United States (Recruiting)

Study contacts

• Principal investigator: Elizabeth Krakow — Fred Hutch/University of Washington Cancer Consortium
• Study coordinator: Elizabeth Krakow

Conditions Acute Myeloid Leukemia; Myelodysplastic Syndrome; Recurrent Acute Myeloid Leukemia; Recurrent Myelodysplastic Syndrome