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

Phase 2TerminatedNCT02152956

MacroGenics244 enrolled

Overview

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 Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

244

Conditions

AML

Interventions

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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.

Outcomes

Primary Outcomes

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.

Time frame: up to 14 months

Secondary Outcomes

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)

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: up to 14 months

HSCT Rate

Rate of successful hematopoietic stem cell transplantation (HSCT) after the start flotetuzumab treatment and before subsequent therapy.

Time frame: 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.

Time frame: Cycle 1 of a 28 day cycle.

Occurrence of Adverse Events (AEs)

Cycle 1 through end of treatment

Time frame: up to 9 months

Occurrence of Serious Adverse Events (SAEs)

Time frame: up to 9 months

Participants With Anti-drug Antibodies

Occurrence of anti-drug antibody

Time frame: 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

Time frame: During study drug administration (up to 8 months)

Number of Patients With Cytokine Release Syndrome (CRS)

Time frame: up to 9 months

Maximum Serum Concentration of Flotetuzumab

Measure the pharmacokinetics (PK) of flotetuzumab

Time frame: 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.

Time frame: 56 days

Number of Patients Alive at 6 Months

Time frame: 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.

Time frame: 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

Time frame: 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

Time frame: 1 year

Median Time to Response

Time from first dose of study drug to first CR, CRh, CRi, or MLFS

Time frame: 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.

Time frame: Up to 2 years

Overall Survival

Time from first dose to death from any cause

Time frame: 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

Time frame: 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

Time frame: up to 8 months

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

Overview

Conditions

Interventions

Eligibility

Locations (43)

Outcomes

Primary Outcomes

Secondary Outcomes