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

Phase 1

Terminated

Conditions: AML

Interventions: 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

Registration Number: NCT02152956

Lead Sponsor: MacroGenics

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.

Detailed Description: Not available

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 244

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 & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
MTD expansion with Ruxolitinib	Ruxolitinib	-
Cohort 0-a	Flotetuzumab 3 ng/kg/day, 4 days on and 3 days off	-
Cohort 0-b	Flotetuzumab 10 ng/kg/day, 4 days on and 3 days off	-
Cohort 0-c	Flotetuzumab 30 ng/kg/day, 4 days on and 3 days off	-
Cohort 0-d	Flotetuzumab 100 ng/kg/day, 4 days on and 3 days off	-
Cohort 1	Flotetuzumab 300 ng/kg/day, 4 days on 3 days off, after one-step lead-in dose	-
Cohort 2	Flotetuzumab 500 ng/kg/day, 4 days on 3 days off, after one-step lead-in dose	-
Cohort 2a	Flotetuzumab 500 ng/kg/day, continuous infusion, after multi-step lead-in dose	-
Cohort 3	Flotetuzumab 700 ng/kg/day, 4 days on 3 days off, after multi-step lead-in dose	-
Cohort 6	Flotetuzumab 300 ng/kg/day, continuous infusion, after multi-step lead-in dose	-
Cohort 7	Flotetuzumab 500 ng/kg/day, continuous infusion, after multi-step lead-in dose	-
Cohort 8	Flotetuzumab 700 ng/kg/day, continuous infusion, after multi-step lead-in dose	-
MTD Expansion	Flotetuzumab 500 ng/kg/day, continuous infusion, after multi-step lead-in dose	-
MTD expansion with Ruxolitinib	Flotetuzumab 500 ng/kg/day, continuous infusion, after multi-step lead-in dose	-

Primary Outcome Measures

Name	Time	Method
Efficacy Based on CR or CRh Rate	up to 14 months	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.

Secondary Outcome Measures

Name	Time	Method
CR Rate	up to 14 months	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.
Overall Response Rate	up to 14 months	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.
Occurrence of Adverse Events (AEs)	up to 9 months	Cycle 1 through end of treatment
Participants With Anti-drug Antibodies	Study Day 1, then every 28 days through 28-days after the last dose (up to 8 months)	Occurrence of anti-drug antibody
Post-baseline Transfusion Independence Rate	56 days	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.
Duration of Response of Patients With CR or CRh	Up to 2 years	Time of initial documentation of response to the time of disease relapse or death due to any cause, whichever occurs first.
CRh Rate	up to 14 months	Proportion of patients achieving a best response of CRh per Interworking Group AML response criteria. CRh is defined as: CR with partial hematologic recovery.
Number of Patients With Infusion Related Reaction (IRR)	During study drug administration (up to 8 months)	Determine safety and efficacy of tocilizumab in the treatment of IRR/CRS as measured by incidence of IRR/CRS
Maximum Serum Concentration of Flotetuzumab	Study day 1, then every 28 days and 28 days after the last dose (up to 8 months)	Measure the pharmacokinetics (PK) of flotetuzumab
Number of Patients Alive at 6 Months	6 months
Mortality Rate	Throughout the study, up to 3 years.	number of deaths from any cause within 30, 60, 90, or 180 days of first dose of study drug
Overall Complete Response Rate	up to 14 months	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)
Number of Patients With Cytokine Release Syndrome (CRS)	up to 9 months
Event-free Survival	Up to 2 years	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.
HSCT Rate	up to 8 months	Rate of successful hematopoietic stem cell transplantation (HSCT) after the start flotetuzumab treatment and before subsequent therapy.
Occurrence of Dose Limiting Toxicity	Cycle 1 of a 28 day cycle.	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.
Occurrence of Serious Adverse Events (SAEs)	up to 9 months
Duration of Hospitalization for Patients in the Expansion Cohort	up to 8 months	Duration of hospitalization will be characterized after discharge from initial dosing will be characterized
Number of Patients Alive at 12 Months	1 year	Number of patients alive at 1 year from first dose of study drug
Median Time to Response	up to 14 months	Time from first dose of study drug to first CR, CRh, CRi, or MLFS
Overall Survival	Up to 2 years	Time from first dose to death from any cause
Rate of Hospitalization for Patients in the Expansion Cohort After Initial Discharge	up to 8 months	Initial dosing procedures were performed as a hospital inpatient. Incidence rate of hospitalization after discharge from the hospital will be calculated

Trial Locations

Locations (43): City of Hope National Medical Center
🇺🇸
Duarte, California, United States
UCSD Moores Cancer Center
🇺🇸
La Jolla, California, United States
UCSF - Helen Diller Family Comprehensive Cancer Center
🇺🇸
San Francisco, California, United States
University of California, San Francisco
🇺🇸
San Francisco, California, United States
Georgetown University - Lombardi Cancer Center
🇺🇸
Washington, District of Columbia, United States
Moffitt Cancer Center
🇺🇸
Tampa, Florida, United States
Emory University
🇺🇸
Atlanta, Georgia, United States
Loyola University Chicago - Cardinal Bernadin Cancer Center
🇺🇸
Maywood, Illinois, United States
University of Maryland
🇺🇸
Baltimore, Maryland, United States
University of Michigan
🇺🇸
Ann Arbor, Michigan, United States
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City of Hope National Medical Center
🇺🇸Duarte, California, United States