Interferon-γ (IFN-γ) With Donor Leukocyte Infusion to Treat Relapsed Acute Myeloid Leukemia and Myelodysplastic Syndromes Post Allogeneic Hematopoietic Stem Cell Transplantation

Официальное название

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)

Обзор

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.

Подробное описание

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.

Вмешательства

• Препарат Interferon gamma-1b
  ACTIMMUNE/Interferon gamma-1b is a single-chain polypeptide containing 140 amino acids that is produced by fermentation of a genetically engineered Escherichia coli bacterium containing the DNA which encodes for the recombinant protein. Interferon gamma-1b is part of a drug regimen used to treat Chronic Granulomatous Disease, or CGD. CGD is a genetic disorder, usually diagnosed in childhood, that affects some cells of the immune system and the body's ability to fight infections effectively.
• Биопрепарат Donor Leukocyte Infusion (DLI)
  Donor lymphocyte infusion is a procedure that transfers healthy white blood cells (lymphocytes) from a bone marrow or stem cell donor to a recipient's blood. An infusion of healthy lymphocytes helps the recipient's immune system get rid of remaining cancer cells if they have a relapse after a bone marrow or stem cell transplant for blood cancer.

Первичные конечные точки

• Event-free survival (EFS) [Срок оценки: At 1 year]

Вторичные конечные точки (11)

• Event-free survival (EFS) - Landmark 1-year [Срок оценки: Up to 1 year]
• Minimal residual disease (MRD) [Срок оценки: At 6 months]
• Complete Remission (CR) [Срок оценки: At 6 months]
• Complete remission with partial hematologic recovery (CRh) [Срок оценки: At 6 months]
• Complete remission with incomplete count recovery (CRi) [Срок оценки: At 6 months]
• Overall survival [Срок оценки: Up to 1 year]
• Rate of donor chimerism [Срок оценки: At 6 months]
• Rate of transfusion independence [Срок оценки: At 1 year]
• Frequency and severity of adverse events (AEs) [Срок оценки: Up to 6 months]
• Frequency of new onset grade 3 or 4 acute graft-versus-host disease (aGVHD) [Срок оценки: Up to 12 months]
• Frequency of new onset moderate or severe chronic GVDH (cGVHD) [Срок оценки: Up to 12 months]

Критерии участия

Критерии включения

• Age ≥ 18 years
• Recipients of an alloSCT for AML or MDS from a minimally 8/8 HLA-matched donor (Cohort 1: HLA -matched alloSCT recipients) or recipients of a haploidentical donor SCT for AML or MDS from a minimally 4/8 HLA-matched donor (Cohort 2: Haplo-SCT recipients)
• AML/MDS relapsed post-alloSCT with measurable residual disease defined by either of the following criteria:

• At least 5% or more myeloblasts based on bone marrow biopsy morphology by pathologist review. Abnormal myeloblasts cannot not exceed 30% overall 36
• At least 0.1% of abnormal myeloblasts with a leukemia-associated immunophenotype (LAIP) by multiparameter flow cytometry. The abnormal cells with LAIP should not exceed 30% of nucleated cells.
• Recurrent or persistent cytogenetic abnormalities detectable by FISH or karyotype analysis.
• For patients with mutant NPM1, at least 1,000 mutant transcript copies per 106 ABL or equivalent housekeeping transcripts in bone marrow by qPCR or dPCR
• 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 line of the following:

• 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
• For cytotoxic chemotherapy agents, the last dose must be >2 weeks prior to start of treatment for the present study
• 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

Критерии исключения

• Primary engraftment failure after alloSCT
• Evidence of mixed phenotype leukemia with lymphoid differentiation (Cohort 1: HLA -matched alloSCT recipients)
• 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 37
• 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 CrCl <30 mL/min at time of enrollment using modified Cockcroft-Gault formula
• Detection of HLA loss of heterozygosity (LOH) in relapsed malignant cells. Specifically, there has been a loss of the mismatched set of HLA alleles encoded on chromosome 6 (ie uniparental disomy of chromosome 6), within 30 days prior to enrollment (Cohort 2: Haplo-SCT recipients)

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Не применимо

Модель

Одна группа

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

США · 3 центра

• Washington University — St Louis
• UPMC Hillman Cancer Center — Pittsburgh
• Fred Hutchinson Cancer Center — Seattle

Идентификаторы

NCT: NCT06529731 · HCC 23-160 · 1R01FD008187-01

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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