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

• ClinicalTrials.gov Identifier: NCT04628338
• Recruitment Status: Recruiting
• First Posted: November 13, 2020
• Last Update Posted: December 2, 2021
• Sponsor: Sawa Ito, MD
• Collaborator: Horizon Pharma USA, Inc.
• Information provided by (Responsible Party): Sawa Ito, MD, University of Pittsburgh

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 (Clinical Trial)
• Estimated 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: March 8, 2021
• Estimated Primary Completion Date: July 2022
• Estimated Study Completion Date: July 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 Name: ACTIMMUNE®

Outcome Measures

Primary Outcome Measures :

1. Upregulation HLA l (HLA-ABC) [ Time Frame: 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.
2. Upregulation of HLA ll (HLA-DR/DQ) [ Time Frame: 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.
3. Upregulation of ICAM-1 [ Time Frame: 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.
4. Adverse events related to IFN-γ [ Time Frame: Up to 6 months ]
   Adverse events of IFN-γ in relapsed patients after alloSCT per CTCAE v5.0.
5. Generation of phosphorylated-STAT1 [ Time Frame: 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 :

1. Malignant Blast Burden [ Time Frame: Up to 6 months ]
   Change in malignant blasts number after IFN-γ therapy and subsequent donor lymphocyte infusion.
2. Incidence of GVHD [ Time Frame: 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.
3. Incidence of de novo GVHD [ Time Frame: Up to 6 months ]
   Incidence of graft-versus-host disease (GVHD) progression after IFN-γ therapy and subsequent DLI.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Contacts

Contact: Linda Fukas, RN, BSN; 412-623-6037; fukaslj@upmc.edu

Locations

United States, Pennsylvania

UPMC Hillman Cancer Center; Recruiting

Pittsburgh, Pennsylvania, United States, 15232

Contact: Linda Fukas, RN, BSN 412-623-6037 fukaslj@upmc.edu

Principal Investigator: Sawa Ito, MD; PhD

Sub-Investigator: Warren Shlomchik, MD

Sponsors and Collaborators

Sawa Ito, MD

Horizon Pharma USA, Inc.

Investigators

• Principal Investigator: Sawa Ito, MD; PhD; University of Pittsburgh

More Information

• Responsible Party: Sawa Ito, MD, Assistant Professor, University of Pittsburgh
• ClinicalTrials.gov Identifier: NCT04628338
• Other Study ID Numbers: HCC 20-092
• First Posted: November 13, 2020
• Last Update Posted: December 2, 2021
• Last Verified: November 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

Keywords provided by Sawa Ito, MD, University of Pittsburgh:

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

Additional relevant MeSH terms:

Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Preleukemia; Myelodysplastic Syndromes; Syndrome; Disease; Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Bone Marrow Diseases; Hematologic Diseases; Precancerous Conditions; Interferons; Interferon-gamma; Antineoplastic Agents; Antiviral Agents; Anti-Infective Agents