IFN-γ to Treat Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS) That Has Relapsed After Allogeneic Hematopoietic Stem Cell Transplantation

Sponsor

Sawa Ito, MD (Other)

Overall Status

Recruiting

CT.gov ID

NCT04628338

Collaborator

Horizon Pharma USA, Inc. (Industry)

Enrollment

Location

Arm

20.8

Anticipated Duration (Months)

0.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This study proposes a safe dosing regimen IFN-γ that is sufficient to stimulate IFN-γ receptors on malignant blasts in patients who developed relapsed acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) after alloSCT with no active or history of III-IV acute graft-versus-host disease (GVHD). It is hypothesized that IFN-γ will promote graft-vs-leukemia (GVL) in patients with AML/MDS that has relapsed after alloSCT.

Condition or Disease	Intervention/Treatment	Phase
Myelodysplastic Syndromes Myeloid Leukemia Allogeneic Stem Cell Transplantation	Drug: IFN-γ (interferon gamma-1b) injection	Early Phase 1

Detailed Description

Allogeneic hematopoietic stem cell transplantation (alloSCT) can cure patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). However, relapsed AML/MDS is the most significant single cause of treatment failure, and the majority of relapsed patients ultimately succumb. Alloreactive T cells in the donor graft can kill residual leukemia cells, mediating the graft-vs-leukemia (GVL) effect. Consistent with this, recipients of T cell-depleted grafts have higher rates of relapse. GVL is more potent against chronic leukemias than acute myeloblastic diseases, and the higher incidence of relapse in patients with AML/MDS reflects a failure in GVL.

The central goal of this pilot trial will be to explore whether IFN-γ in this setting is safe and whether it has the desired biological activities on malignant blasts in vivo. IFN-γ will be tested in relapsed patients as monotherapy and in conjunction with donor leukocyte infusions (DLI). The clinical and biological information from this study is essential to design a phase II trial with a therapeutic endpoint.

Treatment will be initiated at 100mcg (almost equal to the dose of 50 mcg/m2 for an adult) three times a week, with the potential to deescalate the frequency of injection for unacceptable toxicity. To explore whether this dosing regimen is sufficient to activate myeloblasts, pre- and post-treatment bone marrow specimens will be harvested to analyze for IFN-γ action (upregulation of HLA class I; HLA class II, ICAM-1 and phosphorylation of STAT1). The primary safety concern is the development of GVHD, which is routinely monitored for all alloSCT patients.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

6 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Pilot Study of IFN-γ to Treat Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS) That Has Relapsed After Allogeneic Hematopoietic Stem Cell Transplantation

Actual Study Start Date :

Mar 8, 2021

Anticipated Primary Completion Date :

Dec 1, 2022

Anticipated Study Completion Date :

Dec 1, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: IFN-γ 100mcg IFN-γ subcutaneously three times per week (Weeks 0-7), once per week (Weeks 8-12) (or per protocol guidance based on tolerability, response, or DLI infusions)	Drug: IFN-γ (interferon gamma-1b) injection Dosage form: 100 mcg (2 million International Units) per 0.5 mL solution, administered subcutaneously Dose regimen: three times weekly (Weeks 0-7), once weekly (Weeks 8-12) Other Names: ACTIMMUNE®

Arm

Intervention/Treatment

Experimental: IFN-γ

100mcg IFN-γ subcutaneously three times per week (Weeks 0-7), once per week (Weeks 8-12) (or per protocol guidance based on tolerability, response, or DLI infusions)

Drug: IFN-γ (interferon gamma-1b) injection

Dosage form: 100 mcg (2 million International Units) per 0.5 mL solution, administered subcutaneously Dose regimen: three times weekly (Weeks 0-7), once weekly (Weeks 8-12)

Other Names:

ACTIMMUNE®

Outcome Measures

Primary Outcome Measures

Upregulation HLA l (HLA-ABC) [Up to 6 months]
Upregulation of HLA l (HLA-ABC) in bone marrow malignant blasts post-IFN-γ treatment, measured by the change in mean florescent intensity by flow cytometry.
Upregulation of HLA ll (HLA-DR/DQ) [Up to 6 months]
Upregulation of HLA ll (HLA-DR/DQ) in bone marrow malignant blasts post-IFN-γ treatment, measured by the change in mean florescent intensity by flow cytometry.
Upregulation of ICAM-1 [Up to 6 months]
Upregulation of ICAM-1 in bone marrow malignant blasts post-IFN-γ treatment, measured by the change in mean florescent intensity by flow cytometry as a percentage of positive cells.
Adverse events related to IFN-γ [Up to 6 months]
Adverse events of IFN-γ in relapsed patients after alloSCT per CTCAE v5.0.
Generation of phosphorylated-STAT1 [Up to 6 months]
Generation of phosphorylated-STAT1 in bone marrow malignant blasts post-IFN-γ treatment, measured by the change in mean florescent intensity by flow cytometry as a percentage of positive cells.

Secondary Outcome Measures

Malignant Blast Burden [Up to 6 months]
Change in malignant blasts number after IFN-γ therapy and subsequent donor lymphocyte infusion.
Incidence of GVHD [Up to 6 months]
Incidence of Graft Versus Host Disease (GVHD) progression or de novo GVHD after INF-g therapy and subsequent donor lymphocyte infusion.
Incidence of de novo GVHD [Up to 6 months]
Incidence of graft-versus-host disease (GVHD) progression after IFN-γ therapy and subsequent DLI.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Recipients of allogeneic stem cell transplantation for acute myeloid leukemia or myelodysplastic syndrome from a human leukocyte antigen (HLA) matched donor
Relapsed of primary disease with 5% to 20% of blasts in the bone marrow by flow cytometry in the bone marrow with an clear leukemia-associated immunophenotype (If the patient received therapy to treat the relapse, he or she must have 5-20% residual blasts prior to enrollment on this study)
Performance status KPS score >60% (ECOG 0-2)
No increases in systemic immunosuppression in the prior four weeks other than to maintain therapeutic levels
No systemic corticosteroid with a dose higher than 0.5mg/kg/day prednisone or equivalent
No history of grade IV acute GVHD
No new systemic immunosuppressive medications in the prior two weeks initiated due to GVHD
Willingness to have bone marrow and peripheral blood collected as per the study protocol
Must be able to give informed consent
Age 18 or older

Exclusion Criteria:

Contraindication to receive IFN-γ including known hypersensitivity to interferon-gamma, E. coli derived products or any component of the product
Subjects with a positive pregnancy test or who are breastfeeding
For men or women of childing bearing potential (age < 50 without hysterectomy or oophorectomy or documented menopause), unwilling to use effective contraception for the duration of the study.
Primary engraftment failure
Active cardiac arrhythmias not controlled by medical management or current NYHA class II or higher congestive heart failure
Active ischemic heart disease not well controlled with medications
A seizure disorder not well controlled by medications
Estimated GFR <30 mL/min
AST/SGOT or ALT/SPOT > 5 x ULN
Total bilirubin > 3 x ULN
Chemotherapy (other than hypomethylating and/or venetoclax therapy) within the prior 4 weeks
Body surface area at or less than 1.5 m2, or greater than 2.5 m2 so as to minimize the variation in IFN-γ exposure based on differences in BSA.
Patients less than 18 years old.
Pregnant or breastfeeding patients.