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

NCT02152956 | Terminated Phase 1 Results DMC FDA Drug

• 1 other identifier: CP-MGD006-01
• Study Type: interventional
• Target: 244
• Locations: 8 countries
• Sites: 43

Brief Summary

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.

Conditions

AML

Keywords

AML; leukemia; myelogenous; myeloid; refractory

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (22)

• Overall Complete Response Rate

  up to 14 months

• CR Rate

  up to 14 months

• CRh Rate

  up to 14 months

• Overall Response Rate

  up to 14 months

• HSCT Rate

  up to 8 months

Study Arms (13)

Cohort 0-a

EXPERIMENTAL

Biological: Flotetuzumab 3 ng/kg/day, 4 days on and 3 days off

Cohort 0-b

EXPERIMENTAL

Biological: Flotetuzumab 10 ng/kg/day, 4 days on and 3 days off

Cohort 0-c

EXPERIMENTAL

Biological: Flotetuzumab 30 ng/kg/day, 4 days on and 3 days off

Cohort 0-d

EXPERIMENTAL

Biological: Flotetuzumab 100 ng/kg/day, 4 days on and 3 days off

Cohort 1

EXPERIMENTAL

Biological: Flotetuzumab 300 ng/kg/day, 4 days on 3 days off, after one-step lead-in dose

Cohort 2

EXPERIMENTAL

Biological: Flotetuzumab 500 ng/kg/day, 4 days on 3 days off, after one-step lead-in dose

Cohort 2a

EXPERIMENTAL

Biological: Flotetuzumab 500 ng/kg/day, continuous infusion, after multi-step lead-in dose

Cohort 3

EXPERIMENTAL

Biological: Flotetuzumab 700 ng/kg/day, 4 days on 3 days off, after multi-step lead-in dose

Cohort 6

EXPERIMENTAL

Biological: Flotetuzumab 300 ng/kg/day, continuous infusion, after multi-step lead-in dose

Cohort 7

EXPERIMENTAL

Biological: Flotetuzumab 500 ng/kg/day, continuous infusion, after multi-step lead-in dose

Cohort 8

EXPERIMENTAL

Biological: Flotetuzumab 700 ng/kg/day, continuous infusion, after multi-step lead-in dose

MTD Expansion

EXPERIMENTAL

Biological: Flotetuzumab 500 ng/kg/day, continuous infusion, after multi-step lead-in dose

MTD expansion with Ruxolitinib

EXPERIMENTAL

Biological: Flotetuzumab 500 ng/kg/day, continuous infusion, after multi-step lead-in dose; Drug: Ruxolitinib

Interventions

Flotetuzumab 3 ng/kg/day, 4 days on and 3 days off BIOLOGICAL

Flotetuzumab is a CD123 x CD3 bispecific antibody-based molecular construct referred to as a DART® molecule.

Also known as: MGD006

Cohort 0-a

Flotetuzumab 10 ng/kg/day, 4 days on and 3 days off BIOLOGICAL

Flotetuzumab is a CD123 x CD3 bispecific antibody-based molecular construct referred to as a DART molecule.

Also known as: MGD006

Cohort 0-b

Flotetuzumab 30 ng/kg/day, 4 days on and 3 days off BIOLOGICAL

Flotetuzumab is a CD123 x CD3 bispecific antibody-based molecular construct referred to as a DART molecule.

Also known as: MGD006

Cohort 0-c

Flotetuzumab 100 ng/kg/day, 4 days on and 3 days off BIOLOGICAL

Flotetuzumab is a CD123 x CD3 bispecific antibody-based molecular construct referred to as a DART molecule.

Also known as: MGD006

Cohort 0-d

Flotetuzumab 300 ng/kg/day, 4 days on 3 days off, after one-step lead-in dose BIOLOGICAL

Flotetuzumab is a CD123 x CD3 bispecific antibody-based molecular construct referred to as a DART molecule.

Also known as: MGD006

Cohort 1

Flotetuzumab 500 ng/kg/day, 4 days on 3 days off, after one-step lead-in dose BIOLOGICAL

Flotetuzumab is a CD123 x CD3 bispecific antibody-based molecular construct referred to as a DART® molecule.

Also known as: MGD006

Cohort 2

Flotetuzumab 500 ng/kg/day, continuous infusion, after multi-step lead-in dose BIOLOGICAL

Flotetuzumab is a CD123 x CD3 bispecific antibody-based molecular construct referred to as a DART molecule.

Also known as: MGD006

Cohort 2a; Cohort 7; MTD Expansion; MTD expansion with Ruxolitinib

Flotetuzumab 700 ng/kg/day, 4 days on 3 days off, after multi-step lead-in dose BIOLOGICAL

Flotetuzumab is a CD123 x CD3 bispecific antibody-based molecular construct referred to as a DART molecule.

Also known as: MGD006

Cohort 3

Flotetuzumab 700 ng/kg/day, continuous infusion, after multi-step lead-in dose BIOLOGICAL

Flotetuzumab is a CD123 x CD3 bispecific antibody-based molecular construct referred to as a DART molecule.

Also known as: MGD006

Cohort 8

Ruxolitinib DRUG

Oral inhibitor of JAK kinase

Also known as: Jakafi

MTD expansion with Ruxolitinib

Flotetuzumab 300 ng/kg/day, continuous infusion, after multi-step lead-in dose BIOLOGICAL

Flotetuzumab is a CD123 x CD3 bispecific antibody-based molecular construct referred to as a DART molecule.

Cohort 6

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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:
• 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
• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• MacroGenics: lead

Study Sites (43)

City of Hope National Medical Center

Duarte, California, 91010, United States

Location

UCSD Moores Cancer Center

La Jolla, California, 92093, United States

Location

UCSF - Helen Diller Family Comprehensive Cancer Center

San Francisco, California, 94115, United States

Location

University of California, San Francisco

San Francisco, California, 94143, United States

Location

Georgetown University - Lombardi Cancer Center

Washington D.C., District of Columbia, 20057, United States

Location

Moffitt Cancer Center

Tampa, Florida, 33612, United States

Location

Emory University

Atlanta, Georgia, 30322, United States

Location

Loyola University Chicago - Cardinal Bernadin Cancer Center

Maywood, Illinois, 60153, United States

Location

University of Maryland

Baltimore, Maryland, 21201, United States

Location

University of Michigan

Ann Arbor, Michigan, 48109, United States

Location

Washington University School of Medicine

St Louis, Missouri, 63110, United States

Location

Stony Brook Medicine

Stony Brook, New York, 11794, United States

Location

University of North Carolina Lineberger Comprehensive Cancer Center

Chapel Hill, North Carolina, 27599, United States

Location

Duke University Medical Center

Durham, North Carolina, 27710, United States

Location

Cleveland Clinic

Cleveland, Ohio, 44195, United States

Location

Providence Portland Medical Center

Portland, Oregon, 97213, United States

Location

Vanderbilt-Ingram Cancer Center

Nashville, Tennessee, 37232, United States

Location

The University of Texas MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Fred Hutchinson Cancer Research Center

Seattle, Washington, 98109, United States

Location

Medical College of Wisconsin

Milwaukee, Wisconsin, 53226, United States

Location

Institut Paoli-Calmettes

Marseille, 13002, France

Location

Centre Hospitalier Universitaire de Nantes

Nantes, 44093, France

Location

Institut Universitaire du Cancer de Toulouse-Oncopole

Toulouse, 31059, France

Location

CHRU de Tours - Hôpital Bretonneau

Tours, 37044, France

Location

Charité - Universitätsmedizin Berlin

Berlin, 13353, Germany

Location

Universitätsklinikum Carl Gustav Carus an der Technischen Universität Dresden

Dresden, 01307, Germany

Location

Universitätsklinik Hamburg-Eppendorf

Hamburg, 20246, Germany

Location

Universitätsklinikum Leipzig

Leipzig, 04103, Germany

Location

Universitätsmedizin der Johannes Gutenberg-Universität Mainz

Mainz, 55131, Germany

Location

III. Med. Klinik-Klinikum rechts der Isar-Technische Universität München

Munich, 81675, Germany

Location

Medizinische Klinik und II, Universitätsklinikum Würzburg

Würzbur, 97080, Germany

Location

Rambam Health Care Campus

Haifa, Israel

Location

Shaare Zedek Medical Center

Jerusalem, Israel

Location

Policlinico Sant'Orsola Malpighi

Bologna, 40138, Italy

Location

Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST)

Meldola, 74014, Italy

Location

University Vita-Salute San Raffaele

Milan, 20132, Italy

Location

Unità Operativa di Ematologia Ospedale Santa Maria delle Croci

Ravenna, 48123, Italy

Location

University Medical Center Groningen

Groningen, 9713, Netherlands

Location

Erasmus University Medical Center

Rotterdam, 3075, Netherlands

Location

Universitat Autonomaa de Barcelona (UAB) - Hospital de la Santa Creu i de Sant Pau

Barcelona, Spain

Location

Hospital Universitario 12 de Octubre

Madrid, Spain

Location

King's Health Partners

London, United Kingdom

Location

The Christie NHS Foundation Trust

Manchester, M20 4BX, United Kingdom

Location

Related Publications (1)

• 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.

  PMID: 32929488 DERIVED

MeSH Terms

Conditions

Leukemia

Interventions

ruxolitinib

Condition Hierarchy (Ancestors)

Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases

Results Point of Contact

• Title: Chief Medical Officer
• Organization: MacroGenics, Inc.

info@macrogenics.com

301-251-5172

Study Officials

• Ashley L. Ward, MD

  MacroGenics

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR
• Expanded Access: Yes

Study Record Dates

• First Submitted: May 28, 2014
• First Posted: June 2, 2014
• Study Start: June 9, 2014
• Primary Completion: July 5, 2022
• Study Completion: July 5, 2022
• Last Updated: January 30, 2024
• Results First Posted: January 30, 2024

Record last verified: 2024-01

Locations

FR (4); IL (2); DE (7); IT (4); NL (2); ES (2); US (20); GB (2)