Clinical Trials /

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

NCT04582864

Description:

The investigators hypothesize that MGD006 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 MGD006 will be safe, tolerable and may provide additional therapeutic efficacy.

Related Conditions:
  • Acute Myeloid Leukemia
  • Myelodysplastic Syndromes
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: 20-x353
  • NCT ID: NCT04582864

Conditions

  • Relapsed Acute Myeloid Leukemia

Interventions

DrugSynonymsArms
MGD006FlotetuzumabFlotetuzumab (MGD006)

Purpose

The investigators hypothesize that MGD006 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 MGD006 will be safe, tolerable and may provide additional therapeutic efficacy.

Trial Arms

NameTypeDescriptionInterventions
Flotetuzumab (MGD006)ExperimentalWill start on cycle 1 day 1 on the dose escalation ramp schedule of MGD006 as a continuous intravenous (IV) infusion. Patients will be initiated on MGD006 at 30 ng/kg/day and have their MGD006 dose increased daily to a target goal of 500 ng/kg/day by day 7 Patients will continue on MGD006 at 500 ng/kg/day for the remaining 21 days of the 28 day cycle. On cycle 1 day 14 patients will undergo a bone marrow biopsy On cycle 1 day 28, patients will undergo bone marrow biopsy for assessment of disease status. Patients with progressive disease will go off study. Patients with stable disease (SD) or better will proceed to cycle 2. Cycle 2 treatment assignment will be further stratified based on patients achieving CRi or better versus achieving SD/partial remission (PR) Patients achieving a CRi or better will proceed to cycle 2 with MGD006 on a 28 day cycle. Patients achieving SD or a PR will proceed to cycle 2 with MGD006 + DLI at the start of cycle 2
  • MGD006

Eligibility Criteria

        Inclusion Criteria:

          -  Histologically or cytologically confirmed relapsed acute myeloid leukemia (AML) or
             myelodysplastic syndrome (MDS), including any AML subtype, except acute promyelocytic
             leukemia (APL).

          -  Patients with minimal residual disease (MRD) positive relapse, as well as overt
             hematologic/clinical relapse are eligible for the study (per IWG Response Criteria for
             AML).

          -  Patients must have peripheral blast count ≤ 20,000/mm3. Use of hydroxyurea to control
             blast count is permitted.

          -  Patients must be status post-1st 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),

               -  Serum creatinine level ≤2.5 times the ULN or a calculated or measured creatinine
                  clearance of ≤30 ml/min, whichever is more stringent.

               -  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)

               -  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 (or that of legally authorized representative, if applicable).

        Exclusion Criteria:

          -  Active GVHD, not controlled with corticosteroids ≤0.5mg/kg prednisone/day (or
             equivalent).

          -  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). As
             noted above, patients with flow cytometry or molecular evidence of bone marrow MRD
             will be allowed on the protocol.

          -  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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

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

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

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Washington University School of Medicine

Last Updated

October 7, 2020