Description:
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.
Title
- 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
Clinical Trial IDs
- ORG STUDY ID:
HCC 20-092
- NCT ID:
NCT04628338
Conditions
- Myelodysplastic Syndromes
- Myeloid Leukemia
- Allogeneic Stem Cell Transplantation
Interventions
Drug | Synonyms | Arms |
---|
IFN-γ (interferon gamma-1b) injection | ACTIMMUNE® | IFN-γ |
Purpose
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.
Trial Arms
Name | Type | Description | Interventions |
---|
IFN-γ | Experimental | 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) | - IFN-γ (interferon gamma-1b) injection
|
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.
Maximum Eligible Age: | N/A |
Minimum Eligible Age: | 18 Years |
Eligible Gender: | All |
Healthy Volunteers: | No |
Primary Outcome Measures
Measure: | Upregulation HLA l (HLA-ABC) |
Time Frame: | Up to 6 months |
Safety Issue: | |
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. |
Secondary Outcome Measures
Measure: | Malignant Blast Burden |
Time Frame: | Up to 6 months |
Safety Issue: | |
Description: | Change in malignant blasts number after IFN-γ therapy and subsequent donor lymphocyte infusion. |
Measure: | Incidence of GVHD |
Time Frame: | Up to 6 months |
Safety Issue: | |
Description: | Incidence of Graft Versus Host Disease (GVHD) progression or de novo GVHD after INF-g therapy and subsequent donor lymphocyte infusion. |
Measure: | Incidence of de novo GVHD |
Time Frame: | Up to 6 months |
Safety Issue: | |
Description: | Incidence of graft-versus-host disease (GVHD) progression after IFN-γ therapy and subsequent DLI. |
Details
Phase: | Early Phase 1 |
Primary Purpose: | Interventional |
Overall Status: | Recruiting |
Lead Sponsor: | University of Pittsburgh |
Trial 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
Last Updated
April 14, 2021