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

AML Clinical Trial

— VOYAGE  

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)

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT02152956
• Other study ID #: CP-MGD006-01
• Status: Terminated
• Phase: Phase 1/Phase 2
• Start date: June 9, 2014
• Est. completion date: July 5, 2022

Study information

• Verified date: January 2024
• Source: MacroGenics
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 244
• Est. completion date: July 5, 2022
• Est. primary completion date: July 5, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• AML

Intervention

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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

Drug:
• Ruxolitinib
Oral inhibitor of JAK kinase

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.

Locations

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

Sponsors (1)

Lead Sponsor	Collaborator
MacroGenics

Countries where clinical trial is conducted

United States,  France,  Germany,  Israel,  Italy,  Netherlands,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	HSCT Rate	Rate of successful hematopoietic stem cell transplantation (HSCT) after the start flotetuzumab treatment and before subsequent therapy.	up to 8 months
Secondary	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.
Secondary	Occurrence of Adverse Events (AEs)	Cycle 1 through end of treatment	up to 9 months
Secondary	Occurrence of Serious Adverse Events (SAEs)		up to 9 months
Secondary	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)
Secondary	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)
Secondary	Number of Patients With Cytokine Release Syndrome (CRS)		up to 9 months
Secondary	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)
Secondary	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
Secondary	Number of Patients Alive at 6 Months		6 months
Secondary	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
Secondary	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.
Secondary	Number of Patients Alive at 12 Months	Number of patients alive at 1 year from first dose of study drug	1 year
Secondary	Median Time to Response	Time from first dose of study drug to first CR, CRh, CRi, or MLFS	up to 14 months
Secondary	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
Secondary	Overall Survival	Time from first dose to death from any cause	Up to 2 years
Secondary	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
Secondary	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