Clinical trial NCT02152956: Flotetuzumab in Primary Induction Failure (PIF) or Early Relapse (ER) Acute Myeloid Leukemia (AML)
Official title: 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)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: AML
Keywords: AML
leukemia
myelogenous
myeloid
refractory
Lead sponsor: MacroGenics
Sponsor class: INDUSTRY
First posted: 2014-06-02
Enrollment: 244
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.


Eligibility criteria: 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.

Primary outcomes:
measure: Efficacy Based on CR or CRh Rate
timeFrame: up to 14 months
Secondary outcomes:
measure: Overall Complete Response Rate
timeFrame: up to 14 months
measure: CR Rate
timeFrame: up to 14 months
measure: CRh Rate
timeFrame: up to 14 months
measure: Overall Response Rate
timeFrame: up to 14 months
measure: HSCT Rate
timeFrame: up to 8 months
measure: Occurrence of Dose Limiting Toxicity
timeFrame: Cycle 1 of a 28 day cycle.
measure: Occurrence of Adverse Events (AEs)
timeFrame: up to 9 months
measure: Occurrence of Serious Adverse Events (SAEs)
timeFrame: up to 9 months
measure: Participants With Anti-drug Antibodies
timeFrame: Study Day 1, then every 28 days through 28-days after the last dose (up to 8 months)
measure: Number of Patients With Infusion Related Reaction (IRR)
timeFrame: During study drug administration (up to 8 months)
measure: Number of Patients With Cytokine Release Syndrome (CRS)
timeFrame: up to 9 months
measure: Maximum Serum Concentration of Flotetuzumab
timeFrame: Study day 1, then every 28 days and 28 days after the last dose (up to 8 months)
measure: Post-baseline Transfusion Independence Rate
timeFrame: 56 days
measure: Number of Patients Alive at 6 Months
timeFrame: 6 months
measure: Event-free Survival
timeFrame: Up to 2 years
measure: Mortality Rate
timeFrame: Throughout the study, up to 3 years.
measure: Number of Patients Alive at 12 Months
timeFrame: 1 year
measure: Median Time to Response
timeFrame: up to 14 months
measure: Duration of Response of Patients With CR or CRh
timeFrame: Up to 2 years
measure: Overall Survival
timeFrame: Up to 2 years
measure: Rate of Hospitalization for Patients in the Expansion Cohort After Initial Discharge
timeFrame: up to 8 months
measure: Duration of Hospitalization for Patients in the Expansion Cohort
timeFrame: up to 8 months
Other outcomes:
Locations:
city: Duarte
country: United States
facility: City of Hope National Medical Center
state: California
city: La Jolla
country: United States
facility: UCSD Moores Cancer Center
state: California
city: San Francisco
country: United States
facility: UCSF - Helen Diller Family Comprehensive Cancer Center
state: California
city: San Francisco
country: United States
facility: University of California, San Francisco
state: California
city: Washington
country: United States
facility: Georgetown University - Lombardi Cancer Center
state: District of Columbia
city: Tampa
country: United States
facility: Moffitt Cancer Center
state: Florida
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Maywood
country: United States
facility: Loyola University Chicago - Cardinal Bernadin Cancer Center
state: Illinois
city: Baltimore
country: United States
facility: University of Maryland
state: Maryland
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Stony Brook
country: United States
facility: Stony Brook Medicine
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina Lineberger Comprehensive Cancer Center
state: North Carolina
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Portland
country: United States
facility: Providence Portland Medical Center
state: Oregon
city: Nashville
country: United States
facility: Vanderbilt-Ingram Cancer Center
state: Tennessee
city: Houston
country: United States
facility: The University of Texas MD Anderson Cancer Center
state: Texas
city: Seattle
country: United States
facility: Fred Hutchinson Cancer Research Center
state: Washington
city: Milwaukee
country: United States
facility: Medical College of Wisconsin
state: Wisconsin
city: Marseille
country: France
facility: Institut Paoli-Calmettes
city: Nantes
country: France
facility: Centre Hospitalier Universitaire de Nantes
city: Toulouse
country: France
facility: Institut Universitaire du Cancer de Toulouse-Oncopole
city: Tours
country: France
facility: CHRU de Tours - Hôpital Bretonneau
city: Berlin
country: Germany
facility: Charité - Universitätsmedizin Berlin
city: Dresden
country: Germany
facility: Universitätsklinikum Carl Gustav Carus an der Technischen Universität Dresden
city: Hamburg
country: Germany
facility: Universitätsklinik Hamburg-Eppendorf
city: Leipzig
country: Germany
facility: Universitätsklinikum Leipzig
city: Mainz
country: Germany
facility: Universitätsmedizin der Johannes Gutenberg-Universität Mainz
city: Munich
country: Germany
facility: III. Med. Klinik-Klinikum rechts der Isar-Technische Universität München
city: Würzbur
country: Germany
facility: Medizinische Klinik und II, Universitätsklinikum Würzburg
city: Haifa
country: Israel
facility: Rambam Health Care Campus
city: Jerusalem
country: Israel
facility: Shaare Zedek Medical Center
city: Bologna
country: Italy
facility: Policlinico Sant'Orsola Malpighi
city: Meldola
country: Italy
facility: Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST)
city: Milano
country: Italy
facility: University Vita-Salute San Raffaele
city: Ravenna
country: Italy
facility: Unità Operativa di Ematologia Ospedale Santa Maria delle Croci
city: Groningen
country: Netherlands
facility: University Medical Center Groningen
city: Rotterdam
country: Netherlands
facility: Erasmus University Medical Center
city: Barcelona
country: Spain
facility: Universitat Autonomaa de Barcelona (UAB) - Hospital de la Santa Creu i de Sant Pau
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: London
country: United Kingdom
facility: King's Health Partners
city: Manchester
country: United Kingdom
facility: The Christie NHS Foundation Trust
Study officials:
affiliation: MacroGenics
name: Ashley L. Ward, MD
role: STUDY_DIRECTOR
References:
citation: 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.