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

Primary Purpose

Myelodysplastic Syndromes, Myeloid Leukemia, Allogeneic Stem Cell Transplantation

Status

Recruiting

Phase

Early Phase 1

Locations

United States

Study Type

Interventional

Intervention

IFN-γ (interferon gamma-1b) injection

About this trial

This is an interventional treatment trial for Myelodysplastic Syndromes focused on measuring allogeneic hematopoietic stem cell transplantation, acute myeloid leukemia, myelodysplastic syndrome, graft versus host disease, AML, MDS, alloSCT, GVHD, interferon-gamma-1b, Actimmune, IFN-g, donor lymphocyte infusion

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept 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.

Sites / Locations

UPMC Hillman Cancer CenterRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

IFN-γ

Arm Description

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)

Outcomes

Primary Outcome Measures

Upregulation HLA l (HLA-ABC)

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)

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

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

Adverse events of IFN-γ in relapsed patients after alloSCT per CTCAE v5.0.

Generation of phosphorylated-STAT1

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

Change in malignant blasts number after IFN-γ therapy and subsequent donor lymphocyte infusion.

Incidence of GVHD

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

Incidence of graft-versus-host disease (GVHD) progression after IFN-γ therapy and subsequent DLI.

Full Information

NCT ID

NCT04628338

First Posted

October 29, 2020

Last Updated

August 9, 2023

Sponsor

Sawa Ito, MD

Collaborators

Horizon Pharma USA, Inc.

1. Study Identification

Unique Protocol Identification Number

NCT04628338

Brief Title

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

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

Study Type

Interventional

2. Study Status

Record Verification Date

August 2023

Overall Recruitment Status

Recruiting

Study Start Date

March 8, 2021 (Actual)

Primary Completion Date

October 31, 2023 (Anticipated)

Study Completion Date

October 31, 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor-Investigator

Name of the Sponsor

Sawa Ito, MD

Collaborators

Horizon Pharma USA, Inc.

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Data Monitoring Committee

Yes

5. 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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Myelodysplastic Syndromes, Myeloid Leukemia, Allogeneic Stem Cell Transplantation

Keywords

allogeneic hematopoietic stem cell transplantation, acute myeloid leukemia, myelodysplastic syndrome, graft versus host disease, AML, MDS, alloSCT, GVHD, interferon-gamma-1b, Actimmune, IFN-g, donor lymphocyte infusion

7. Study Design

Primary Purpose

Treatment

Study Phase

Early Phase 1

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

6 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

IFN-γ

Arm Type

Experimental

Arm Description

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)

Intervention Type

Drug

Intervention Name(s)

IFN-γ (interferon gamma-1b) injection

Other Intervention Name(s)

ACTIMMUNE®

Intervention Description

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)

Primary Outcome Measure Information:

Title

Upregulation HLA l (HLA-ABC)

Description

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.

Time Frame

Up to 6 months

Title

Upregulation of HLA ll (HLA-DR/DQ)

Description

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.

Time Frame

Up to 6 months

Title

Upregulation of ICAM-1

Description

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.

Time Frame

Up to 6 months

Title

Adverse events related to IFN-γ

Description

Adverse events of IFN-γ in relapsed patients after alloSCT per CTCAE v5.0.

Time Frame

Up to 6 months

Title

Generation of phosphorylated-STAT1

Description

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.

Time Frame

Up to 6 months

Secondary Outcome Measure Information:

Title

Malignant Blast Burden

Description

Change in malignant blasts number after IFN-γ therapy and subsequent donor lymphocyte infusion.

Time Frame

Up to 6 months

Title

Incidence of GVHD

Description

Incidence of Graft Versus Host Disease (GVHD) progression or de novo GVHD after INF-g therapy and subsequent donor lymphocyte infusion.

Time Frame

Up to 6 months

Title

Incidence of de novo GVHD

Description

Incidence of graft-versus-host disease (GVHD) progression after IFN-γ therapy and subsequent DLI.

Time Frame

Up to 6 months

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

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.

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Linda Fukas, RN, BSN

Phone

412-623-6037

fukaslj@upmc.edu

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Sawa Ito, MD; PhD

Organizational Affiliation

University of Pittsburgh

Official's Role

Principal Investigator

Facility Information:

Facility Name

UPMC Hillman Cancer Center

City

Pittsburgh

State/Province

Pennsylvania

ZIP/Postal Code

15232

Country

United States

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Linda Fukas, RN, BSN

Phone

412-623-6037

fukaslj@upmc.edu

First Name & Middle Initial & Last Name & Degree

Sawa Ito, MD; PhD

First Name & Middle Initial & Last Name & Degree

Warren Shlomchik, MD

12. IPD Sharing Statement

Plan to Share IPD

Learn more about this trial

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

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