Flotetuzumab in Primary Induction Failure (PIF) or Early Relapse (ER) Acute Myeloid Leukemia (AML) (VOYAGE)

A Phase 1/2, First in Human, Dose Escalation Study of MGD006, a CD123 x CD3 DART® Bi-Specific Antibody Based Molecule, in Patients With Relapsed or Refractory AML or Intermediate-2/High Risk Myelodysplastic Syndrome (MDS)

Open-label, multi-dose, single-arm, multi-center, Phase 1/2 study conducted in three segments: the Single Patient Dose Escalation Segment (complete), followed by the Multi-Patient Dose Escalation Segment (complete) and the Maximum Tolerated Dose and Schedule (MTDS) Expansion Cohort Segment (closed). Having characterized safety and determined the maximum tolerated dose and schedule, the primary objective of this study now is to assess the anti-neoplastic activity of flotetuzumab in patients with PIF/ER AML, as determined by the proportion of patients who achieve CR or CRh. Starting with Cycle 2, patients who are benefiting from flotetuzumab may receive up to a maximum of 8 cycles of treatment.

Patients will receive daily increasing doses of flotetuzumab for the first week of Cycle 1 (Lead-In Dosing) followed by 3 weeks of continuous intravenous infusion at a the assigned dose. Subsequent cycles are each 4 weeks of continuous infusion at the assigned dose. Dosing may continue for up to 8 cycles. Follow up visits may continue for 6 months after treatment is discontinued.

Study Overview

• Status: Terminated
• Conditions: AML
• Intervention / Treatment: Biological: Flotetuzumab 3 ng/kg/day, 4 days on and 3 days off; Biological: Flotetuzumab 10 ng/kg/day, 4 days on and 3 days off; Biological: Flotetuzumab 30 ng/kg/day, 4 days on and 3 days off; Biological: Flotetuzumab 100 ng/kg/day, 4 days on and 3 days off; Biological: Flotetuzumab 300 ng/kg/day, 4 days on 3 days off, after one-step lead-in dose; Biological: Flotetuzumab 500 ng/kg/day, 4 days on 3 days off, after one-step lead-in dose; Biological: Flotetuzumab 500 ng/kg/day, continuous infusion, after multi-step lead-in dose; Biological: Flotetuzumab 700 ng/kg/day, 4 days on 3 days off, after multi-step lead-in dose; Biological: Flotetuzumab 300 ng/kg/day, continuous infusion, after multi-step lead-in dose; Biological: Flotetuzumab 700 ng/kg/day, continuous infusion, after multi-step lead-in dose; Drug: Ruxolitinib

• Study Type: Interventional
• Enrollment (Actual): 244
• Phase: Phase 2; Phase 1

Expanded Access

No longer available outside the clinical trial. See expanded access record.

Contacts and Locations

Study Locations

• France
  • Marseille, France, 13002
    • Institut Paoli-Calmettes
  • Nantes, France, 44093
    • Centre Hospitalier Universitaire de Nantes
  • Toulouse, France, 31059
    • Institut Universitaire du Cancer de Toulouse-Oncopole
  • Tours, France, 37044
    • CHRU de Tours - Hôpital Bretonneau
• Germany
  • Berlin, Germany, 13353
    • Charite - Universitatsmedizin Berlin
  • Dresden, Germany, 01307
    • Universitatsklinikum Carl Gustav Carus An Der Technischen Universitat Dresden
  • Hamburg, Germany, 20246
    • Universitätsklinik Hamburg-Eppendorf
  • Leipzig, Germany, 04103
    • Universitatsklinikum Leipzig
  • Mainz, Germany, 55131
    • Universitätsmedizin der Johannes Gutenberg-Universität Mainz
  • Munich, Germany, 81675
    • III. Med. Klinik-Klinikum rechts der Isar-Technische Universität München
  • Würzbur, Germany, 97080
    • Medizinische Klinik und II, Universitätsklinikum Würzburg
• Israel
  • Haifa, Israel
    • Rambam Health Care Campus
  • Jerusalem, Israel
    • Shaare Zedek Medical Center
• Italy
  • Bologna, Italy, 40138
    • Policlinico Sant'Orsola Malpighi
  • Meldola, Italy, 74014
    • Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST)
  • Milano, Italy, 20132
    • University Vita-Salute San Raffaele
  • Ravenna, Italy, 48123
    • Unità Operativa di Ematologia Ospedale Santa Maria delle Croci
• Netherlands
  • Groningen, Netherlands, 9713
    • University Medical Center Groningen
  • Rotterdam, Netherlands, 3075
    • Erasmus University Medical Center
• Spain
  • Barcelona, Spain
    • Universitat Autonomaa de Barcelona (UAB) - Hospital de la Santa Creu i de Sant Pau
  • Madrid, Spain
    • Hospital Universitario 12 de Octubre
• United Kingdom
  • London, United Kingdom
    • King's Health Partners
  • Manchester, United Kingdom, M20 4BX
    • The Christie NHS Foundation Trust
• United States
  • California
    • Duarte, California, United States, 91010
      • City of Hope National Medical Center
    • La Jolla, California, United States, 92093
      • UCSD Moores Cancer Center
    • San Francisco, California, United States, 94143
      • University of California, San Francisco
    • San Francisco, California, United States, 94115
      • UCSF - Helen Diller Family Comprehensive Cancer Center
  • District of Columbia
    • Washington, District of Columbia, United States, 20057
      • Georgetown University - Lombardi Cancer Center
  • Florida
    • Tampa, Florida, United States, 33612
      • Moffitt Cancer Center
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University
  • Illinois
    • Maywood, Illinois, United States, 60153
      • Loyola University Chicago - Cardinal Bernadin Cancer Center
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • University of Maryland
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • New York
    • Stony Brook, New York, United States, 11794
      • Stony Brook Medicine
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • University of North Carolina Lineberger Comprehensive Cancer Center
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic
  • Oregon
    • Portland, Oregon, United States, 97213
      • Providence Portland Medical Center
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt-Ingram Cancer Center
  • Texas
    • Houston, Texas, United States, 77030
      • The University of Texas MD Anderson Cancer Center
  • Washington
    • Seattle, Washington, United States, 98109
      • Fred Hutchinson Cancer Research Center
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Medical College of Wisconsin

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Confirmed diagnosis of primary or secondary AML [any subtype except acute promyelocytic leukemia (APL)] according to World Health Organization (WHO) classification

• Patients with AML must meet one of the following criteria, a or b:

  1. Primary Induction Failure (PIF) AML, defined as disease refractory to either, i or ii:

     • i. An intensive induction attempt, per institution. Induction attempts include high-dose and/or standard-dose cytarabine ± an anthracyclines/anthracenedione ± an anti-metabolite, with or without growth factor or targeted therapy containing regimens. Examples include but are not limited to: 1 cycle of high dose cytarabine (HiDAC) containing regimen, 1 cycle of liposomal cytarabine and daunorubicin, 2 cycles of standard dose cytarabine containing regimen
     • ii. For adults who are age 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy; PIF is defined as AML refractory to one of the following less intensive regimens: i ≥ 2 but ≤ 4 cycles of Bcl-2 inhibitors in combination with azacitidine, decitabine, or low dose cytarabine, or ii ≥ 2 but ≤ 4 cycles of gemtuzumab ozogamicin monotherapy
  2. Early relapse (ER) AML, defined as AML in first relapse with initial CR1 duration < 6 months
• Limit of 3 prior lines of therapy (excluding focal radiation therapy for palliative purposes): up to 2 induction (induction, re-induction) or 1 induction plus/minus 1 consolidation attempt, followed by a maximum of 1 salvage/re-induction attempt.
• Eastern Cooperative Oncology Group (ECOG) performance status ≤2
• Life expectancy of at least 4 weeks
• Peripheral blast count </= 20,000/mm3 at the time of first dose
• Acceptable laboratory parameters and adequate organ reserve

Exclusion Criteria:

• History of allogeneic stem cell transplantation
• Prior treatment with an anti-CD123-directed agent
• Need for concurrent other cytoreductive chemotherapy
• 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 or investigational agent within 14 days or 5 half-lives of Cycle 1 Day 1.
• Requirement, at the time of study entry, for concurrent steroids > 10 mg/day of oral prednisone or the equivalent, except steroid inhaler, otic preparations, nasal spray or ophthalmic solution
• Use of immunosuppressant medications in the 2 weeks prior to Cycle 1 Day 1
• Use of granulocyte colony stimulating or granulocyte-macrophage colony stimulating factor in the 2 weeks prior to Cycle 1 Day 1
• Known central nervous system (CNS) leukemia
• Active uncontrolled infection (including, but not limited to viral, bacterial, fungal, or mycobacterial infection),
• Known human immunodeficiency virus infection, unless all of the following criteria are met: CD4+ count ≥ 350 cells/μL, undetectable viral load, and receiving highly active antiretroviral therapy.
• Known, active, history of or current acute or chronic hepatitis B or C virus (HBV) infection (as evidenced by detectable HBV surface antigen and HBV DNA ≥ 500 IU/mL),
• History of hepatitis C virus (HCV) infection, unless the infection has been treated and cured,
• Active SARS-CoV-2 infection. While SARS-CoV-2 testing is not mandatory for study entry, testing for ongoing infection should follow local clinical practice guidelines/standards. Participants with a positive test result for ongoing SARS-CoV-2 infection, known asymptomatic infection, or suspected infection are excluded unless or until asymptomatic and with subsequent negative SARS-CoV-2 laboratory test.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

13

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort 1	Biological: Flotetuzumab 300 ng/kg/day, 4 days on 3 days off, after one-step lead-in dose; Flotetuzumab is a CD123 x CD3 bispecific antibody-based molecular construct referred to as a DART molecule.; Other Names: MGD006
Experimental: Cohort 2	Biological: Flotetuzumab 500 ng/kg/day, 4 days on 3 days off, after one-step lead-in dose; Flotetuzumab is a CD123 x CD3 bispecific antibody-based molecular construct referred to as a DART® molecule.; Other Names: MGD006
Experimental: Cohort 3	Biological: Flotetuzumab 700 ng/kg/day, 4 days on 3 days off, after multi-step lead-in dose; Flotetuzumab is a CD123 x CD3 bispecific antibody-based molecular construct referred to as a DART molecule.; Other Names: MGD006
Experimental: Cohort 6	Biological: Flotetuzumab 300 ng/kg/day, continuous infusion, after multi-step lead-in dose; Flotetuzumab is a CD123 x CD3 bispecific antibody-based molecular construct referred to as a DART molecule.
Experimental: Cohort 7	Biological: Flotetuzumab 500 ng/kg/day, continuous infusion, after multi-step lead-in dose; Flotetuzumab is a CD123 x CD3 bispecific antibody-based molecular construct referred to as a DART molecule.; Other Names: MGD006
Experimental: Cohort 8	Biological: Flotetuzumab 700 ng/kg/day, continuous infusion, after multi-step lead-in dose; Flotetuzumab is a CD123 x CD3 bispecific antibody-based molecular construct referred to as a DART molecule.; Other Names: MGD006
Experimental: Cohort 0-a	Biological: Flotetuzumab 3 ng/kg/day, 4 days on and 3 days off; Flotetuzumab is a CD123 x CD3 bispecific antibody-based molecular construct referred to as a DART® molecule.; Other Names: MGD006
Experimental: Cohort 0-b	Biological: Flotetuzumab 10 ng/kg/day, 4 days on and 3 days off; Flotetuzumab is a CD123 x CD3 bispecific antibody-based molecular construct referred to as a DART molecule.; Other Names: MGD006
Experimental: Cohort 0-c	Biological: Flotetuzumab 30 ng/kg/day, 4 days on and 3 days off; Flotetuzumab is a CD123 x CD3 bispecific antibody-based molecular construct referred to as a DART molecule.; Other Names: MGD006
Experimental: Cohort 0-d	Biological: Flotetuzumab 100 ng/kg/day, 4 days on and 3 days off; Flotetuzumab is a CD123 x CD3 bispecific antibody-based molecular construct referred to as a DART molecule.; Other Names: MGD006
Experimental: Cohort 2a	Biological: Flotetuzumab 500 ng/kg/day, continuous infusion, after multi-step lead-in dose; Flotetuzumab is a CD123 x CD3 bispecific antibody-based molecular construct referred to as a DART molecule.; Other Names: MGD006
Experimental: MTD Expansion	Biological: Flotetuzumab 500 ng/kg/day, continuous infusion, after multi-step lead-in dose; Flotetuzumab is a CD123 x CD3 bispecific antibody-based molecular construct referred to as a DART molecule.; Other Names: MGD006
Experimental: MTD expansion with Ruxolitinib	Biological: Flotetuzumab 500 ng/kg/day, continuous infusion, after multi-step lead-in dose; Flotetuzumab is a CD123 x CD3 bispecific antibody-based molecular construct referred to as a DART molecule.; Other Names: MGD006; Drug: Ruxolitinib; Oral inhibitor of JAK kinase; Other Names: Jakafi

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Efficacy Based on CR or CRh Rate	Proportion of patients achieving a best response of CR (morphologic CR [mCR], cytogenetic CR [CRc], molecular CR [CRm], or CRh per Interworking Group AML response criteria. CR is defined as mCR, CRc, CRm or CRh. mCR is defined as: normal. neutrophil and platelet counts, less than 5% blast cells in a bone marrow (BM) smear and. no extramedullary disease. CRc is defined as: CR with no evidence of cytogenetic abnormalities in the bone marrow. CRm is defined as: CR with no evidence of molecular abnormalities in the bone marrow. CRh is defined as: CR with partial hematologic recovery.	up to 14 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Complete Response Rate	Rate of CR + CRh + CRi (CR with incomplete blood cell recovery [CR with incomplete neutrophil {CRn}or platelet recovery {CRp}]) + MLFS (morphologic leukemia-free state)	up to 14 months
CR Rate	Proportion of patients achieving a best response of CR (morphologic CR [mCR], cytogenetic CR [CRc], or molecular CR [CRm] per Interworking Group AML response criteria. CR is defined as mCR, CRc, CRm or CRh. mCR is defined as: normal. neutrophil and platelet counts, less than 5% blast cells in a bone marrow (BM) smear and. no extramedullary disease. CRc is defined as: CR with no evidence of cytogenetic abnormalities in the bone marrow. CRm is defined as: CR with no evidence of molecular abnormalities in the bone marrow. CRh is defined as: CR with partial hematologic recovery.	up to 14 months
CRh Rate	Proportion of patients achieving a best response of CRh per Interworking Group AML response criteria. CRh is defined as: CR with partial hematologic recovery.	up to 14 months
Overall Response Rate	Proportion of patients achieving a best response of CR, CRh, CRi, MLFS or partial response per Interworking Group AML response criteria. CR is defined as mCR, CRc, CRm or CRh. mCR is defined as: normal. neutrophil and platelet counts, less than 5% blast cells in a bone marrow (BM) smear and. no extramedullary disease. CRc is defined as: CR with no evidence of cytogenetic abnormalities in the bone marrow. CRm is defined as: CR with no evidence of molecular abnormalities in the bone marrow. CRh is defined as: CR with partial hematologic recovery.	up to 14 months
HSCT Rate	Rate of successful hematopoietic stem cell transplantation (HSCT) after the start flotetuzumab treatment and before subsequent therapy.	up to 8 months
Occurrence of Dose Limiting Toxicity	Maximum Tolerated Dose/Schedule: the MTDS is defined as the highest dose/schedule administered during any Cohort in the study at which the incidence of DLT is < 33% during the first cycle of MGD006 treatment.	Cycle 1 of a 28 day cycle.
Occurrence of Adverse Events (AEs)	Cycle 1 through end of treatment	up to 9 months
Occurrence of Serious Adverse Events (SAEs)		up to 9 months
Participants With Anti-drug Antibodies	Occurrence of anti-drug antibody	Study Day 1, then every 28 days through 28-days after the last dose (up to 8 months)
Number of Patients With Infusion Related Reaction (IRR)	Determine safety and efficacy of tocilizumab in the treatment of IRR/CRS as measured by incidence of IRR/CRS	During study drug administration (up to 8 months)
Number of Patients With Cytokine Release Syndrome (CRS)		up to 9 months
Maximum Serum Concentration of Flotetuzumab	Measure the pharmacokinetics (PK) of flotetuzumab	Study day 1, then every 28 days and 28 days after the last dose (up to 8 months)
Post-baseline Transfusion Independence Rate	The number of patients who were transfusion-dependent at baseline and did not receive transfusions during any consecutive 56-day period will be calculated. The number of patients who are transfusion independent at baseline and remain independent during any 56-day post-baseline period will also be calculated.	56 days
Number of Patients Alive at 6 Months		6 months
Event-free Survival	Time from the first dose of study drug until date of evidence of primary refractory disease to flotetuzumab, relapse from CR, CRh or CRi, or death from any cause, whichever occurs first.	Up to 2 years
Mortality Rate	number of deaths from any cause within 30, 60, 90, or 180 days of first dose of study drug	Throughout the study, up to 3 years.
Number of Patients Alive at 12 Months	Number of patients alive at 1 year from first dose of study drug	1 year
Median Time to Response	Time from first dose of study drug to first CR, CRh, CRi, or MLFS	up to 14 months
Duration of Response of Patients With CR or CRh	Time of initial documentation of response to the time of disease relapse or death due to any cause, whichever occurs first.	Up to 2 years
Overall Survival	Time from first dose to death from any cause	Up to 2 years
Rate of Hospitalization for Patients in the Expansion Cohort After Initial Discharge	Initial dosing procedures were performed as a hospital inpatient. Incidence rate of hospitalization after discharge from the hospital will be calculated	up to 8 months
Duration of Hospitalization for Patients in the Expansion Cohort	Duration of hospitalization will be characterized after discharge from initial dosing will be characterized	up to 8 months

Collaborators and Investigators

• Sponsor: MacroGenics
• Investigators: Study Director: Ashley L. Ward, MD, MacroGenics

Publications and helpful links

General Publications

• Uy GL, Aldoss I, Foster MC, Sayre PH, Wieduwilt MJ, Advani AS, Godwin JE, Arellano ML, Sweet KL, Emadi A, Ravandi F, Erba HP, Byrne M, Michaelis L, Topp MS, Vey N, Ciceri F, Carrabba MG, Paolini S, Huls GA, Jongen-Lavrencic M, Wermke M, Chevallier P, Gyan E, Recher C, Stiff PJ, Pettit KM, Lowenberg B, Church SE, Anderson E, Vadakekolathu J, Santaguida M, Rettig MP, Muth J, Curtis T, Fehr E, Guo K, Zhao J, Bakkacha O, Jacobs K, Tran K, Kaminker P, Kostova M, Bonvini E, Walter RB, Davidson-Moncada JK, Rutella S, DiPersio JF. Flotetuzumab as salvage immunotherapy for refractory acute myeloid leukemia. Blood. 2021 Feb 11;137(6):751-762. doi: 10.1182/blood.2020007732.

Study record dates

Study Major Dates

• Study Start (Actual): June 9, 2014
• Primary Completion (Actual): July 5, 2022
• Study Completion (Actual): July 5, 2022

Study Registration Dates

• First Submitted: May 28, 2014
• First Submitted That Met QC Criteria: May 28, 2014
• First Posted (Estimated): June 2, 2014

Study Record Updates

• Last Update Posted (Actual): January 30, 2024
• Last Update Submitted That Met QC Criteria: January 24, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: AML; refractory; leukemia; myeloid; myelogenous
• Other Study ID Numbers: CP-MGD006-01

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No