Flotetuzumab for Relapsed Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS) Following Allogeneic Hematopoietic Cell Transplantation (Allo-HCT)

• Flotetuzumab (Drug), also known as MGD006: Will be provided by MacroGenics Inc.
• Donor lymphocyte infusion (Procedure), also known as DLI: DLI represents a non-specific form of adoptive cell therapy which involves infusion of a pool of allogeneic immune cells, including CD4+ T cells, CD8+ T cells, regulatory T cells (T Regs), natural killer (NK) cells and professional antigen presenting cells.

Primary outcomes

• Efficacy as Measured by Number of Participants With CR(Mrd), CR, and CRi [At the end of Cycle 1 (each cycle is 28 days)]: * Complete remission without minimal residual disease (CRmrd): CR with negativity for a genetic marker by RT-qPCR, or CR with negativity by MFC * Complete remission (CR): Bone marrow blasts <5%; absence of circulating blasts and blasts with Auer rods; absence of extramedullary disease; ANC ≥1.0 × 10\^9/L (1000/µL); platelet count ≥100 × 10\^9/L (100,000/µL), transfusion independence * CR with incomplete hematologic recovery (CRi): All CR criteria except for residual neutropenia (<1.0 × 10\^9/L \[1000/µL\]) or thrombocytopenia (<100 × 10\^9/L \[100,000/µL\])

Secondary outcomes

• Efficacy as Measured by Number of Participants With CR and CRi [At the end of Cycle 2 (each cycle is 28 days)]: * Complete remission (CR): Bone marrow blasts <5%; absence of circulating blasts and blasts with Auer rods; absence of extramedullary disease; ANC ≥1.0 × 10\^9/L (1000/µL); platelet count ≥100 × 10\^9/L (100,000/µL), transfusion independence * CR with incomplete hematologic recovery (CRi): All CR criteria except for residual neutropenia (<1.0 × 10\^9/L \[1000/µL\]) or thrombocytopenia (<100 × 10\^9/L \[100,000/µL\])
• Overall Response Rate [At the end of Cycle 2 (each cycle is 28 days)]: * Defined as partial remission or better * PR: All hematologic criteria of CR; decrease of bone marrow blast percentage to 5 to 25%; and decrease of pretreatment bone marrow blast percentage by at least 50%
• Morphologic Leukemia-free State (MLFS) Rate [At the end of Cycle 2 (each cycle is 28 days)]: \- MLFS: Bone marrow blasts <5%; absence of blasts with Auer rods; absence of extramedullary disease; no hematologic recovery required
• Partial Remission (PR) Rate [At the end of Cycle 2 (each cycle is 28 days)]: \- PR: All hematologic criteria of CR; decrease of bone marrow blast percentage to 5 to 25%; and decrease of pretreatment bone marrow blast percentage by at least 50%
• Stable Disease (SD) Rate [At the end of Cycle 2 (each cycle is 28 days)]: \- SD: Absence of CR(mrd), CR, CRi, PR, MLFS; and criteria for PD not met
• Progression-free Survival (PFS) Rate [Through completion of follow-up, up to 2 years (median length of 80 days, full range of 11-149 days)]: * PFS will be calculated as the time from the start of the first dose of study drug until the occurrence of disease progression or death from any cause, respectively * Progressive disease: Evidence for an increase in bone marrow blast percentage (>50% over baseline), and/or increase of absolute blast counts in the blood (>50% to >25 × 10\^9/L) without differentiation syndrome, or new extramedullary disease
• Overall Survival (OS) [Through completion of follow-up, up to 2 years (median length of 80 days, full range of 11-149 days)]: -OS will be calculated as the time from the start of the first dose of study drug until the occurrence of death from any cause.
• Number of Participants With Adverse Events as Measured by CTCAE v5.0 [From start of treatment through 28 days following completion of treatment (median length of 59 days, full range 11-99 days).]
• Number of Participants With Cytokine Release Syndrome (CRS) Grading as Measured by ASTCT Consensus Guidelines [Through the end of Cycle 2 (each cycle is 28 days)]: * Grade 1:Symptoms are not life threatening and require symptomatic treatment only, e.g., fever, nausea, fatigue, headache, myalgias, malaise * Grade 2: Symptoms require and respond to moderate intervention; oxygen requirement < 40% or hypotension responsive to fluids or low-dose of one vasopressor or grade 2 organ toxicity * Grade 3: Symptoms require and respond to aggressive intervention; oxygen requirement ≥ 40% or hypotension requiring high-dose vasopressors or multiple vasopressors or grade 3 organ toxicity (except transaminitis) or grade 4 transaminitis * Grade 4: Life-threatening symptoms; requirement for ventilator support or grade 4 organ toxicity (excluding transaminitis) * Grade 5 Death
• Number of Participants With Neurotoxicity as Measured by 2019 ASTCT Consensus Guidelines [Through the end of Cycle 2 (each cycle is 28 days)]
• Number of Participants With Acute Graft Versus Host Disease (GvHD) as Measured by MAGIC Criteria [Through completion of follow-up, up to 2 years (median length of 80 days, full range of 11-149 days)]
• Number of Participants With Chronic Graft Versus Host Disease (GvHD) as Measured by NIH Severity Score [Through completion of follow-up, up to 2 years (median length of 80 days, full range of 11-149 days)]

Sex: All, ages: 18 Years to any

Recipient Inclusion Criteria:

* Histologically or cytologically confirmed relapsed acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS), including any AML subtype, except acute promyelocytic leukemia (APL), and including AML that has evolved from a previous MDS or MPN.
* Patients must have peripheral blast count ≤ 20,000/mm3. Use of hydroxyurea to control blast count is permitted.
* Patients must be status post allo-HCT (including: matched related, matched unrelated, haploidentical, mismatched unrelated; and cord blood HCT).
* Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 2
* Adequate organ function, defined as:

  * Hepatic transaminase (both alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels ≤2.5 times the institutional upper limit of normal (ULN),
  * Total bilirubin level ≤1.5 times the ULN (unless the patient has a history of Gilbert's Syndrome, in which case, total bilirubin must be ≤2.5 times the ULN),
  * Creatinine clearance of ≥50 ml/min
  * Adequate organ reserve including cardiovascular (ejection fraction within institutional normal limits), pulmonary (baseline pulmonary function test \[PFT\]: carbon monoxide diffusion capacity in the lung \[DLCO\] > 50%, forced expiratory volume in 1 second \[FEV1\] > 70%), renal, and hepatic functioning sufficient, in the judgment of the Investigator, to undergo therapy.
  * Normal thyroid function or stable thyroid tests on supplementation, except euthyroid sick syndrome.
* Recovery from toxicities of clinical consequence attributed to previous chemotherapy to CTCAE v4.0 Grade ≤ 1 (i.e., certain toxicities such as alopecia will not be considered in this category).
* Female patients of childbearing potential must test negative for pregnancy at enrollment and during the study. Sexually active women of child-bearing potential, unless surgically sterile, must be willing to use a highly effective method of birth control defined as those which result in a low failure rate (i.e., less than 1% per year) such as implants, injectables, combined oral contraceptives, intra-uterine devices (IUDs) or vasectomized partner. Male patients with partners of childbearing potential must be either vasectomized or agree to use a condom in addition to having their partners use another method of contraception resulting in a highly effective method of birth control defined as those which result in a low failure rate (i.e., less than 1% per year) such as implants, injectables, combined oral contraceptives, or IUDs. Patients should not have sexual intercourse with females who are either pregnant or lactating without a condom. Contraception should be employed from the time of consent through 12 weeks after MGD006 administration. Patients should also abstain from sperm/egg donation during the course of the study.
* Able to have corticosteroids weaned to ≤0.5mg/kg prednisone/day (or equivalent)
* Able to have non-steroidal immunosuppression discontinued, including:

  * mycophenolate (MMF)
  * calcineurin inhibitors (tacrolimus, cyclosporine)

    **calcineurin inhibitors must be able to be discontinued at least 14 days prior to enrolling on study.
  * JAK inhibitors (ruxolitinib)
  * MTOR inhibitors (sirolimus)
* At least 18 years of age.
* Ability to understand and willingness to sign an IRB approved written informed consent document

Recipient Exclusion Criteria:

* Active GVHD requiring systemic immunosuppression with more than 0.5 mg/day prednisone
* Currently receiving any other investigational agents.
* Any active untreated autoimmune disorders (with the exception of vitiligo, resolved childhood atopic dermatitis, prior Grave's disease now euthyroid clinically and with stable supplementation).
* Second primary malignancy that requires active therapy (adjuvant hormonal therapy is allowed).
* Antitumor therapy (chemotherapy, radiotherapy, antibody therapy, molecular- targeted therapy, retinoid therapy, or investigational agent) within 5 half-lives of Cycle 1 Day 1
* At the time of study entry, steroids >0.5mg/kg of prednisone or equivalent (except steroid inhaler, nasal spray or ophthalmic solution which are allowed).
* Use of immunosuppressant medications (other than steroids as noted) in the 2 weeks prior to study drug administration (Cycle 1 Day 1).
* Isolated extramedullary relapse (i.e., no evidence of bone marrow involvement).
* Known central nervous system (CNS) leukemia. Patients with suspected CNS leukemia must be evaluated by lumbar puncture and be free of CNS disease prior to study entry. Previously treated CNS leukemia is allowed provided adequate treatment has been provided and the patient is free of CNS disease.
* Any medical or psychiatric condition limiting full compliance or increasing the safety risk, at the discretion of the PI, such as:

  * active uncontrolled infection (including, but not limited to viral, bacterial, fungal, or mycobacterial infection),
  * known human immunodeficiency virus infection,
  * known, active, or chronic hepatitis B or C infection (appropriately treated HBV/HCV infections with documented clearance of viral titer are allowed),
  * Grade 3 or 4 bleeding,
  * significant pulmonary compromise including chronic supplemental oxygen use, history of non-infectious pneumonitis (including radiation pneumonitis), pulmonary fibrosis, or severe chronic obstructive pulmonary disease (COPD),
  * uncontrolled (persistent) hypertension (systolic pressure > 180 mm Hg or diastolic pressure > 100 mm Hg
  * clinically significant arrhythmia, clinically significant baseline QTcF >480 msec,
  * unstable angina,
  * recent myocardial infarction within 6 months prior to study drug administration (Cycle 1 Day 1),
  * clinically significant heart disease, such as, congestive heart failure, history of pericarditis, myocarditis,
  * history of stroke or transient ischemic event within 3 months prior to study drug administration (Cycle 1 Day 1),
  * untreated pulmonary embolism, or non-catheter-related deep-vein thrombosis in the 3 months prior to study drug administration (Cycle 1 Day 1),
  * pregnancy, or breast feeding,
  * major surgery or trauma within 4 weeks before enrollment.
* Known hypersensitivity to murine, yeast, or recombinant proteins; polysorbate 80; recombinant human serum albumin; benzyl alcohol; or any excipient contained in the MGD006 drug formulation.
* Dementia or altered mental status that would preclude sufficient understanding to provide informed consent.

Participant flow

Outcome results

• Efficacy as Measured by Number of Participants With CR(Mrd), CR, and CRi (Primary), Count of participants, Participants: Flotetuzumab 0
• Efficacy as Measured by Number of Participants With CR and CRi (Secondary), Count of participants, Participants: Flotetuzumab 0
• Overall Response Rate (Secondary), Count of participants, Participants: Flotetuzumab 0
• Morphologic Leukemia-free State (MLFS) Rate (Secondary), Count of participants, Participants: Flotetuzumab 0
• Partial Remission (PR) Rate (Secondary), Count of participants, Participants: Flotetuzumab 2
• Stable Disease (SD) Rate (Secondary), Count of participants, Participants: Flotetuzumab 3
• Progression-free Survival (PFS) Rate (Secondary), Median, months: Flotetuzumab 1.14 (0.79 to 2.49)
• Overall Survival (OS) (Secondary), Median, months: Flotetuzumab 2.66 (1.11 to 4.30)
• Number of Participants With Adverse Events as Measured by CTCAE v5.0 (Secondary), Count of participants, Participants: Flotetuzumab 4
• Number of Participants With Cytokine Release Syndrome (CRS) Grading as Measured by ASTCT Consensus Guidelines (Secondary), Count of participants, Participants: Flotetuzumab 1
• Number of Participants With Neurotoxicity as Measured by 2019 ASTCT Consensus Guidelines (Secondary), Count of participants, Participants: Flotetuzumab 4
• Number of Participants With Acute Graft Versus Host Disease (GvHD) as Measured by MAGIC Criteria (Secondary), Count of participants, Participants: Flotetuzumab 1
• Number of Participants With Chronic Graft Versus Host Disease (GvHD) as Measured by NIH Severity Score (Secondary), Count of participants, Participants: Flotetuzumab 1

Adverse events

Time frame: Adverse events and serious adverse events were collected from start of treatment through 28 days following discontinuation of flotetuzumab (median length of 59 days, full range 11-99 days). All-cause mortality was collected from start of treatment through completion of protocol defined follow-up (median length of 80 days, full range of 11-149 days).

Serious adverse events by term

Other adverse events by term

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• Study Protocol and Statistical Analysis Plan (PDF, 2024-02-28)
• Informed Consent Form (PDF, 2024-06-04)

• Matthew Christopher, M.D., Ph.D., Principal investigator, Washington University School of Medicine

NIH grants: P50CA171963