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

Study Overview
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Brief Summary
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The investigators hypothesize that flotetuzumab for relapsed AML following allo-HCT will be safe, tolerable and may facilitate preferential immune effector cell retargeting of leukemic cells resulting in improved patient outcomes. Furthermore, administration of a donor lymphocyte infusion (DLI) (if available) in combination with flotetuzumab will be safe, tolerable and may provide additional therapeutic efficacy.

Official Title
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A Phase 2 Trial Evaluating the Efficacy of Flotetuzumab (MGD006) for Relapsed Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS) Following Allogeneic Hematopoietic Cell Transplantation (Allo-HCT)

Conditions
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Relapsed Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: Flotetuzumab
* Procedure: Donor lymphocyte infusion


Participation Criteria
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Eligibility Criteria
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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 immunosuppresion 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 14 days or 5 half-lives of Cycle 1 Day 1, whichever is longer. 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 the requirement for supplemental oxygen, 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Flotetuzumab<br>Will start on cycle 1 day 1 on the dose escalation ramp schedule of flotetuzumab as a continuous intravenous (IV) infusion. Patients will be initiated at 30 ng/kg/day and have their dose increased daily to a target goal of 500 ng/kg/day by day 7 Patients will continue on flotetuzumab at 500 ng/kg/day for the remaining 21 days of the 28 day cycle. On cycle 1 day 28, patients will undergo bone marrow biopsy for assessment of disease status. Patients who have achieved a CR/CRi will proceed to a second cycle per protocol, while patients with a PR or SD or better may proceed to cycle 2 with permission of the investigator. Patients with available donor lymphocytes may receive DLI concurrently with flotetuzumab during Cycle 1 and/or Cycle 2. | Drug: Flotetuzumab<br>* Will be provided by MacroGenics Inc.<br>* Other names: MGD006;Procedure: Donor lymphocyte infusion<br>* 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.<br>* Other names: DLI;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy as measured by number of participants with CR(mrd), CR, and CRi | 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]) | At the end of Cycle 1 (each cycle is 28 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy as measured by number of participants with CR and CRi | 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]) | At the end of Cycle 2 (each cycle is 28 days) | 
| Overall response rate | 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% | At the end of Cycle 2 (each cycle is 28 days) | 
| Morphologic leukemia-free state (MLFS) rate | -MLFS: Bone marrow blasts <5%; absence of blasts with Auer rods; absence of extramedullary disease; no hematologic recovery required | At the end of Cycle 2 (each cycle is 28 days) | 
| Partial remission (PR) rate | -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% | At the end of Cycle 2 (each cycle is 28 days) | 
| Stable disease (SD) rate | -SD: Absence of CR(mrd), CR, CRi, PR, MLFS; and criteria for PD not met | At the end of Cycle 2 (each cycle is 28 days) | 
| Progression-free survival (PFS) rate | 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 | Through follow-up (approximately 2 years) | 
| Overall survival (OS) | -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. | Through follow-up (approximately 2 years) | 
| Incidence of adverse events as measured by CTCAE v5.0 |  | From start of treatment through 28 days following completion of treatment (estimated to be 84 days) | 
| Cytokine release syndrome (CRS) grading as measured by ASTCT Consensus Guidelines | 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 | At the end of Cycle 2 (each cycle is 28 days) | 
| Neurotoxicity grading as measured by 2019 ASTCT Consensus Guidelines |  | At the end of Cycle 2 (each cycle is 28 days) | 
| Incidence of acute Graft versus Host Disease (GvHD) as measured by MAGIC Criteria |  | Through follow-up (approximately 2 years) | 
| Incidence of chronic Graft versus Host Disease (GvHD) as measured by NIH severity score |  | Through follow-up (approximately 2 years) |