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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

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ClinicalTrials.gov Identifier: NCT04628338
Recruitment Status : Recruiting
First Posted : November 13, 2020
Last Update Posted : August 5, 2022
Sponsor:
Collaborator:
Horizon Pharma USA, Inc.
Information provided by (Responsible Party):
Sawa Ito, MD, University of Pittsburgh

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.

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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 : December 2022
Estimated Study Completion Date : December 2022


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®




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.



Information from the National Library of Medicine

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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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04628338


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

Locations
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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
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Principal Investigator: Sawa Ito, MD; PhD University of Pittsburgh
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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    Key Record Dates
Last Update Posted: August 5, 2022
Last Verified: August 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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:
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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