Clinical trial NCT06529731: Interferon-γ (IFN-γ) With Donor Leukocyte Infusion to Treat Relapsed Acute Myeloid Leukemia and Myelodysplastic Syndromes Post Allogeneic Hematopoietic Stem Cell Transplantation
Official title: A Phase 2 Trial of Interferon-γ (IFN-γ) in Combination With Donor Leukocyte Infusion (DLI) to Treat Relapsed Acute Myeloid Leukemia (AML) and Myelodysplastic Syndromes (MDS) After Allogeneic Hematopoietic Stem Cell Transplantation (alloSCT)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Acute Myeloid Leukemia
Myelodysplastic Syndromes
Keywords: interferon-γ (IFN-γ)
donor leukocyte infusion (DLI)
allogeneic hematopoietic stem cell transplantation (alloSCT)
Lead sponsor: University of Pittsburgh
Sponsor class: OTHER
Collaborators: name: Evans MDS Discovery Research Grant
name: Amgen
name: FDA Office of Orphan Products Development
First posted: 2024-07-31
Enrollment: 45
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This phase 2 study aims to confirm the efficacy seen in the prior phase 1 trial, and further contribute to this effort through the collection of leukemia cells pre- and post- in vivo IFN-γ therapy. As in the previously conducted phase 1 trial, this trial will test whether leukemia blasts were responsive to IFN-γ in vitro and in vivo, with single-cell RNA sequencing (scRNAseq) conducted to understand the transcriptomic changes induced by IFN-γ in leukemia cell subsets, including those with stem cell characteristics.

Detailed description: This novel regimen has the potential to fill a large unmet need for this high-risk population of patients who have few, if any, effective therapeutic options. If this trial confirms the clinical efficacy of IFN-γ/DLI, it will establish a new standard of care for post-transplant AML/MDS relapse. It would also provide a rationale to explore other indications for IFN-γ in the context of an alloSCT, including 1) IFN-γ/DLI for relapsed disease after haploidentical alloSCT; 2) pre-emptive post-alloSCT treatment of patients transplanted with measurable residual disease (MRD) or with poor-risk AML/MDS such as with TP53 mutations; and 3) prevention of relapse in patients who can only tolerate reduced-intensity conditioning regimens which in most studies results in higher rates of post-alloSCT AML/MDS relapse than when intensive conditioning regimens are employed. Together, this work would allow more patients with AML/MDS to be referred for and ultimately benefit from an alloSCT.

Eligibility criteria: Inclusion Criteria:

* Recipients of an alloSCT for AML or MDS from an HLA-matched donor
* AML/MDS relapsed post-alloSCT with measurable residual disease defined by at least 5% of more myeloblasts based on bone marrow biopsy morphology by pathologist review. Abnormal myeloblasts cannot not exceed 30% overall
* Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0-2
* A DLI is available, or the donor is available and agrees to undergo apheresis to collect lymphocytes for infusion
* If salvage therapy for post-alloSCT relapse was received, the therapy is limited to 1 cycle of the following:

  1. For hypomethylating agents, venetoclax, and targeted therapies (e.g., tyrosine kinase inhibitors, IDH1/IDH2 inhibitors, or FLT3 inhibitors), the last dose must be \> 2 week prior to the initiation of IFN-γ
  2. For cytotoxic chemotherapy agents, the last dose must be \>2 weeks prior to start of treatment for the present study
  3. For investigational agents, the last dose must be ≥ 4 weeks or 5 half-lives (whichever is longer) prior to the start of treatment for the present study
* Provision of signed and dated informed consent form
* Stated willingness to comply with all study procedures and availability for the duration of the study
* For female subject, who is \< 55 years old without hysterectomy, oophorectomy or documented menopause, willingness to use two forms of contraception including one form of highly effective contraception (i.e., long-acting reversible contraception, oral contraceptive pills) for the duration of the study
* For male subject, willingness to use highly effective contraception methods including male condoms by male subject and one form of highly effective contraception by his female partner (i.e., long-acting reversible contraception, oral contraceptive pills) for the duration of the study

Exclusion Criteria:

* Primary engraftment failure after alloSCT
* Grade 3 or 4 aGVHD per Mount Sinai Acute GVHD International Consortium (MAGIC) at the time of planned enrollment
* History of grade 4 aGVHD per the MAGIC criteria
* Moderate or severe cGVHD per NIH Consensus Criteria at time of planned enrollment
* Any systemic immunosuppressive medications taken within 2 weeks before the enrollment
* Grade 3 or higher non-hematologic toxicity related to any prior therapy at the time of enrollment
* A contraindication to receive IFN-γ including a known hypersensitivity to IFN-γ, E. coli derived products or any other component of the product
* Positive pregnancy test or currently breastfeeding on Day 1 of study treatment
* Active cardiac arrhythmia not controlled by medical management or current NYHA class II or higher congestive heart failure within 2 months of enrollment unless it was due to a tachyarrhythmia which is under control at the time of enrollment
* Active ischemic heart disease not controlled with medications within 2 months of enrollment
* Acute or chronic pulmonary disease requiring continuous oxygen treatment
* Seizure disorder not controlled by medications within 2 months of enrollment
* AST or ALT \> 5x ULN or total bilirubin \>3x ULN at time of enrollment
* Renal function eGFR \<30 mL/min at time of enrollment using modified Cockcroft-Gault formula
* Body surface area ≤ 1.5 m2 or ≥ 2.5 m2 so as to minimize variation in IFN-γ exposure based on differences in body surface area

Primary outcomes:
measure: Event-free survival (EFS)
timeFrame: At 1 year
Secondary outcomes:
measure: Event-free survival (EFS) - Landmark 1-year
timeFrame: Up to 1 year
measure: Minimal residual disease (MRD)
timeFrame: At 6 months
measure: Complete Remission (CR)
timeFrame: At 6 months
measure: Complete remission with partial hematologic recovery (CRh)
timeFrame: At 6 months
measure: Complete remission with incomplete count recovery (CRi)
timeFrame: At 6 months
measure: Overall survival
timeFrame: Up to 1 year
measure: Rate of donor chimerism
timeFrame: At 6 months
measure: Rate of transfusion independence
timeFrame: At 1 year
measure: Frequency and severity of adverse events (AEs)
timeFrame: Up to 6 months
measure: Frequency of new onset grade 3 or 4 acute graft-versus-host disease (aGVHD)
timeFrame: Up to 12 months
measure: Frequency of new onset moderate or severe chronic GVDH (cGVHD)
timeFrame: Up to 12 months
Other outcomes:
Locations:
city: Pittsburgh
country: United States
facility: UPMC Hillman Cancer Center
state: Pennsylvania
city: Seattle
country: United States
facility: Fred Hutchinson Cancer Center
state: Washington
Study officials:
affiliation: UPMC Hillman Cancer Center
name: Sawa M Ito, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: