Acute Myeloid Leukemia, Myelodysplastic Syndromes
Conditions
Keywords
interferon-γ (IFN-γ), donor leukocyte infusion (DLI), allogeneic hematopoietic stem cell transplantation (alloSCT)
Brief summary
This phase 2 study aims to confirm the efficacy observed in the prior phase 1 trial in Cohort 1 and to evaluate the safety of IFN-γ in combination with DLI in Cohort 2, the haploidentical donor alloSCT recipient cohort. The study will further contribute to this effort through the collection of leukemia cells pre- and post-in vivo IFN-γ therapy. As in the previously conducted phase 1 trial, this trial will assess whether leukemia blasts are responsive to IFN-γ in vitro and in vivo. Single-cell RNA sequencing (scRNAseq) will be performed to evaluate transcriptomic changes induced by IFN-γ in leukemia cell subsets, including those with stem cell characteristics.
Detailed description
This novel regimen has the potential to address a significant unmet need for this high-risk population of patients who have few, if any, effective therapeutic options. In Cohort 1, if this trial confirms the clinical efficacy of IFN-γ/DLI in patients with relapsed AML/MDS after HLA-matched alloSCT, it may establish a new therapeutic approach for post-transplant AML/MDS relapse. Cohort 2 will further evaluate the safety and potential efficacy of IFN-γ/DLI in patients with relapsed AML/MDS after haploidentical alloSCT, where treatment options are also limited and the risk of GVHD requires careful assessment. Together, these cohorts would provide a rationale to explore additional indications for IFN-γ in the context of alloSCT, including 1) IFN-γ/DLI for relapsed disease after haploidentical alloSCT; 2) pre-emptive post-alloSCT treatment of patients transplanted with measurable residual disease (MRD) or with poor-risk AML/MDS, such as disease with TP53 mutations; and 3) prevention of relapse in patients who can only tolerate reduced-intensity conditioning regimens, which in most studies are associated with higher rates of post-alloSCT AML/MDS relapse than intensive conditioning regimens. Collectively, this work may allow more patients with AML/MDS to be referred for and ultimately benefit from alloSCT.
Interventions
DRUGInterferon gamma-1b
ACTIMMUNE/Interferon gamma-1b is a single-chain polypeptide containing 140 amino acids that is produced by fermentation of a genetically engineered Escherichia coli bacterium containing the DNA which encodes for the recombinant protein. Interferon gamma-1b is part of a drug regimen used to treat Chronic Granulomatous Disease, or CGD. CGD is a genetic disorder, usually diagnosed in childhood, that affects some cells of the immune system and the body's ability to fight infections effectively.
BIOLOGICALDonor Leukocyte Infusion (DLI)
Donor lymphocyte infusion is a procedure that transfers healthy white blood cells (lymphocytes) from a bone marrow or stem cell donor to a recipient's blood. An infusion of healthy lymphocytes helps the recipient's immune system get rid of remaining cancer cells if they have a relapse after a bone marrow or stem cell transplant for blood cancer.
Sponsors
Sawa Ito, MD
Evans MDS Discovery Research Grant
Amgen
FDA Office of Orphan Products Development
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Age ≥ 18 years 2. Recipients of an alloSCT for AML or MDS from a minimally 8/8 HLA-matched donor (Cohort 1: HLA -matched alloSCT recipients) or recipients of a haploidentical donor SCT for AML or MDS from a minimally 4/8 HLA-matched donor (Cohort 2: Haplo-SCT recipients) 3. AML/MDS relapsed post-alloSCT with measurable residual disease defined by either of the following criteria: 1. At least 5% or more myeloblasts based on bone marrow biopsy morphology by pathologist review. Abnormal myeloblasts cannot not exceed 30% overall 36 2. At least 0.1% of abnormal myeloblasts with a leukemia-associated immunophenotype (LAIP) by multiparameter flow cytometry. The abnormal cells with LAIP should not exceed 30% of nucleated cells. 3. Recurrent or persistent cytogenetic abnormalities detectable by FISH or karyotype analysis. 4. For patients with mutant NPM1, at least 1,000 mutant transcript copies per 106 ABL or equivalent housekeeping transcripts in bone marrow by qPCR or dPCR 4. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0-2 5. A DLI is available, or the donor is available and agrees to undergo apheresis to collect lymphocytes for infusion 6. If salvage therapy for post-alloSCT relapse was received, the therapy is limited to 1 line of the following: 1. For hypomethylating agents, venetoclax, and targeted therapies (e.g., tyrosine kinase inhibitors, IDH1/IDH2 inhibitors, or FLT3 inhibitors), the last dose must be \> 2 week prior to the initiation of IFN-γ 2. For cytotoxic chemotherapy agents, the last dose must be \>2 weeks prior to start of treatment for the present study 3. For investigational agents, the last dose must be ≥ 4 weeks or 5 half-lives (whichever is longer) prior to the start of treatment for the present study 7. Provision of signed and dated informed consent form 8. Stated willingness to comply with all study procedures and availability for the duration of the study 9. For female subject, who is \< 55 years old without hysterectomy, oophorectomy or documented menopause, willingness to use two forms of contraception including one form of highly effective contraception (i.e., long-acting reversible contraception, oral contraceptive pills) for the duration of the study 10. For male subject, willingness to use highly effective contraception methods including male condoms by male subject and one form of highly effective contraception by his female partner (i.e., long-acting reversible contraception, oral contraceptive pills) for the duration of the study
Exclusion criteria
1. Primary engraftment failure after alloSCT 2. Evidence of mixed phenotype leukemia with lymphoid differentiation (Cohort 1: HLA -matched alloSCT recipients) 3. Grade 3 or 4 aGVHD per Mount Sinai Acute GVHD International Consortium (MAGIC) at the time of planned enrollment 4. History of grade 4 aGVHD per the MAGIC criteria 5. Moderate or severe cGVHD per NIH Consensus Criteria at time of planned enrollment 6. Any systemic immunosuppressive medications taken within 2 weeks before the enrollment 7. Grade 3 or higher non-hematologic toxicity related to any prior therapy at the time of enrollment 8. A contraindication to receive IFN-γ including a known hypersensitivity to IFN-γ, E. coli derived products or any other component of the product 9. Positive pregnancy test or currently breastfeeding on Day 1 of study treatment 37 10. Active cardiac arrhythmia not controlled by medical management or current NYHA class II or higher congestive heart failure within 2 months of enrollment unless it was due to a tachyarrhythmia which is under control at the time of enrollment 11. Active ischemic heart disease not controlled with medications within 2 months of enrollment 12. Acute or chronic pulmonary disease requiring continuous oxygen treatment 13. Seizure disorder not controlled by medications within 2 months of enrollment 14. AST or ALT \> 5x ULN or total bilirubin \>3x ULN at time of enrollment 15. Renal function CrCl \<30 mL/min at time of enrollment using modified Cockcroft-Gault formula 16. Detection of HLA loss of heterozygosity (LOH) in relapsed malignant cells. Specifically, there has been a loss of the mismatched set of HLA alleles encoded on chromosome 6 (ie uniparental disomy of chromosome 6), within 30 days prior to enrollment (Cohort 2: Haplo-SCT recipients)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Event-free survival (EFS) | At 1 year | Cohort 1: Occurrence of treatment failure, hematologic relapse from a CR (complete remission)/CRh/Cri), or death observed from start of IFN-γ treatment. Patients alive at 1 year after start of treatment will be censored on the date of last contact. |
| Incidence of steroid- and ruxolitinib- refractory GVHD within 12 weeks after the first dose of IFN-γ | 12 Weeks | Cohort 2: Lack of improvement after 7 days of methylprednisolone 2 mg/kg, AND, either of the following 1. Progression of graft-vs-host disease (GVHD) compared with baseline after 10 days of ruxolitinib, based either on an objective increase in stage/grade or new organ involvement Or 2. Lack of improvement in GVHD (PR or better) compared with baseline after at least 14 days of ruxolitinib. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Event-free survival (EFS) - Landmark 1-year | Up to 1 year | Time from start of IFN-γ treatment until event of death, date of treatment failure, or hematologic relapse from a CR/CRh/Cri. CR is defined by blasts less than 5% by morphology defined by bone marrow blasts less than 5%; absence of circulating blasts; absence of extramedullary disease; absolute neutrophil count (ANC) at or greater than 1,000/mL; platelet count at or greater than 100,000/mL CRh is defined by ANC at or greater than 500/mL and platelet count at or greater than 50,000/mL otherwise all other CR criteria met. CRi is defined by all CR criteria except for residual neutropenia less than 1,000/mL or thrombocytopenia less than 100,000/mL Treatment failure is not achieving either CR, CRh or CRi by 6 months. Patients evaluable for response without CR, CRh or CRi by 6 months and patients who die before 6 months without response assessments are considered an event at day 1 of IFN-γ treatment |
| Minimal residual disease (MRD) | At 6 months | Rate of complete remission (CR) with no measurable disease at 6 months. CR is defined as |
| Complete Remission (CR) | At 6 months | Proportion of patients who experience Complete Remission (CR). CR is defined by bone marrow blasts less than 5%; absence of circulating blasts; absence of extramedullary disease; absolute neutrophil count (ANC) at or greater than 1,000/mL; platelet count at or greater than 100,000/mL. The proportion of responders will be calculated as the number of responders divided by the number of evaluable patients. |
| Complete remission with partial hematologic recovery (CRh) | At 6 months | Proportion of patients who experience Complete remission with partial hematologic recovery (CRh). CRh is defined by ANC at or greater than 500/mL and platelet count at or greater than 50,000/mL otherwise all other CR criteria met. The proportion of responders will be calculated as the number of responders divided by the number of evaluable patients. |
| Complete remission with incomplete count recovery (CRi) | At 6 months | Proportion of patients who experience complete remission with incomplete count recovery (CRi). CRi is defined by all CR criteria except for residual neutropenia less than 1,000/mL or thrombocytopenia less than 100,000/mL51. The proportion of responders (CR, CRh, or CRi) will be calculated as the number of responders divided by the number of evaluable patients. The proportion of responders will be calculated as the number of responders divided by the number of evaluable patients. |
| Overall survival | Up to 1 year | Time from start of IFN-γ to death by any cause or censored on the date of last contact. |
| Rate of donor chimerism | At 6 months | Proportion of the efficacy population with ≥95% peripheral blood CD3+ and CD33+ cells and of unfractionated bone marrow being donor-derived |
| Rate of transfusion independence | At 1 year | Proportion of the subjects who achieve the absence of a red-cell or platelet transfusion for at least 56 days between the first and last day of treatment. |
| Frequency and severity of adverse events (AEs) | Up to 6 months | Number of patients who experience an Adverse Event or Serious Adverse Event related to study treatment, per CTCAE v5.0 criteria. Distinct number of patients will be determined per each event type by highest grade experienced. |
| Frequency of new onset grade 3 or 4 acute graft-versus-host disease (aGVHD) | Up to 12 months | number of patients meeting criteria for grade 3 or 4 aGVHD per MAGIC divided by the number of evaluable patients. The MAGIC criteria as follows: Overall clinical grade (based on most severe target organ involvement): Grade 0: No stage 1-4 of any organ; Grade I: Stage 1-2 skin without liver, upper GI, or lower GI involvement; Grade II: Stage 3 rash and/or stage 1 liver and/or stage 1 upper GI and/or stage 1 lower GI; Grade Ill: Stage 2-3 liver and/or stage 2-3 lower GI, with stage 0-3 skin and/or stage 0-1 upper GI; Grade IV: Stage 4 skin, liver, or lower GI involvement, with stage 0-1 upper GI. |
| Frequency of new onset moderate or severe chronic GVDH (cGVHD) | Up to 12 months | The number of patients meeting criteria for moderate or severe cGVHD per NIH Consensus Criteria divided by the number of evaluable patients. The NIH Consensus Criteria is a diagnostic assessment that evaluates hair, skin, nails, eyes, mouth, genitalia, GI tract, liver, lung, muscles and joints, hematopoietic and immune system, cardiac and neurological condition/function, to determine whether or not the GVHD is chronic. |
Countries
United States
Contacts
CONTACTLinda Elias, RN
CONTACTAmy Rodger, RN
PRINCIPAL_INVESTIGATORSawa M Ito, MD, PhD
UPMC Hillman Cancer Center
Outcome results
None listed