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

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)

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.

Study Overview

• Status: Terminated
• Conditions: Relapsed Acute Myeloid Leukemia
• Intervention / Treatment: Drug: Flotetuzumab; Procedure: Donor lymphocyte infusion

• Study Type: Interventional
• Enrollment (Actual): 11
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Flotetuzumab; 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; Will be provided by MacroGenics Inc.; Other Names: MGD006; Procedure: Donor lymphocyte infusion; 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.; Other Names: DLI

What is the study measuring?

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 completion of follow-up, up to 2 years (median length of 80 days, full range of 11-149 days)
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 completion of follow-up, up to 2 years (median length of 80 days, full range of 11-149 days)
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	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	Through the end of Cycle 2 (each cycle is 28 days)
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)

Collaborators and Investigators

• Sponsor: Washington University School of Medicine
• Collaborators: National Cancer Institute (NCI); MacroGenics
• Investigators: Principal Investigator: Matthew Christopher, M.D., Ph.D., Washington University School of Medicine

Publications and helpful links

Helpful Links

• Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine

Study record dates

Study Major Dates

• Study Start (Actual): May 20, 2021
• Primary Completion (Actual): March 29, 2024
• Study Completion (Actual): July 26, 2024

Study Registration Dates

• First Submitted: September 25, 2020
• First Submitted That Met QC Criteria: October 7, 2020
• First Posted (Actual): October 12, 2020

Study Record Updates

• Last Update Posted (Actual): December 6, 2024
• Last Update Submitted That Met QC Criteria: December 1, 2024
• Last Verified: December 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Histologic Type; Hematologic Diseases; Precancerous Conditions; Bone Marrow Diseases; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Preleukemia; Myelodysplastic Syndromes
• Other Study ID Numbers: 202011122; 5P50CA171963 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: De-identified participant data may be shared with other researchers.
• IPD Sharing Time Frame: From 2 years to 10 years after accrual closure
• IPD Sharing Access Criteria: IPD will be shared in de-identified form with investigators whose proposed use of the data has been approved by an independent review committee for that purpose.

Drug and device information, study documents

• 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