Evaluating QTc, PK, Safety of Gemtuzumab Ozogamicin (GO) in Patients With CD33+ R/R AML

Study Overview
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Brief Summary
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This is a single-arm, open-label, Phase 4 study evaluating the effect of GO on the QTc, pharmacokinetics, safety, and immunogenicity of GO as a single-agent monotherapy in adult and pediatric patients with relapsed or refractory CD33-positive AML.

Detailed Description
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This is a single-arm, open-label, Phase 4 study evaluating the effect of GO on the QTc, pharmacokinetics, safety, and immunogenicity of GO as a single-agent monotherapy in adult and pediatric patients with relapsed or refractory CD33-positive AML. Approximately 50 adult (age >=18 years) and 6 pediatric (12 years =< age =< 17 years) patients who satisfy the study eligibility criteria will be enrolled. Enrolled patients will receive GO 3 mg/m2 up to 2 cycles on Days 1, 4, and 7 at each cycle. The impact of GO on VOD/SOS in the context of previous and subsequent HSCT will also be assessed. Patients enrolled in the study will receive three doses of GO 3 mg/m2 (up to one vial) as a 2-hour intravenous infusion on Cycle 1 Days 1, 4, and 7. A second cycle of GO 3mg/m² (up to one vial) on Cycle 2 Days 1, 4, and 7 will be allowed at the investigator's discretion for patients who meet the following criteria after Cycle 1: Bone marrow with a decrease of blast percentage to at least 25% or a decrease of pretreatment blast percentage by at least 50%; and Blood count with neutrophils >=1,000/µL, and platelets >=50,000/µL, except in patients with the bone marrow blasts >=5%, the decrease in neutrophils and platelets thought to be due to the underlying leukemia. After GO treatment, subsequent anticancer therapy such as consolidation or conditioning regimen and/or HSCT could be considered at the investigator's discretion. A minimum interval of 2 months is recommended between the last dose of GO and HSCT.

Official Title
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A SINGLE ARM, OPEN-LABEL, PHASE 4 STUDY EVALUATING QT INTERVAL, PHARMACOKINETICS, AND SAFETY OF GEMTUZUMAB OZOGAMICIN (MYLOTARG (TRADEMARKER)) AS A SINGLE-AGENT REGIMEN IN PATIENTS WITH RELAPSED OR REFRACTORY CD33-POSITIVE ACUTE MYELOID LEUKEMIA

Conditions
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Safety, ECG, Pharmacokinetics

Intervention / Treatment
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* Drug: Gemtuzumab Ozogamicin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Refractory or relapsed (ie, bone marrow blasts >5%) CD33-positive AML. Age >=12 years. Eastern Cooperative Oncology Group (ECOG) Performance Status 0 to 2. Initial peripheral white blood cells (WBC) counts >=30,000/mL; patients with a higher WBC count should undergo cytoreduction. Adequate renal/hepatic functions Exclusion Criteria Patients with prior treatment with gemtuzumab ozogamicin (GO). Patients with prior history of VOD/SOS. Prior HSCT is not allowed, if it was conducted within 2 months prior to study enrollment. Patients with known active central nervous system (CNS) leukemia. Uncontrolled or active infectious status. Uncontrolled cardiac dysrhythmias of NCI CTCAE Grade 2, uncontrolled atrial fibrillation of any grade. Sero-positivity to human immunodeficieny virus (HIV). Active hepatitis B or hepatitis C infection Chemotherapy, radiotherapy, or other anti-cancer therapy (except hydroxyurea as cytoreduction) within 2 weeks prior to enrollment in the study. Major surgery within 4 weeks prior to enrollment. QTc interval >470 milliseconds (msec) using the Fridericia (QTcF), family or personal history of long or short QT syndrome, Brugada syndrome or known history of QTc prolongation, or Torsade de Pointes (TdP). The use of medications known to predispose to Torsades de Pointes within 2 weeks prior to enrollment History of allergic reactions attributed to compounds of similar chemical or biologic composition to gemtuzumab ozogamicin (GO).

Ages Eligible for Study
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Minimum Age: 12 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Single arm, open-label, interventional
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Gemtuzumab Ozogamicin (GO)<br>Patients will receive three doses of Gemtuzumab Ozogamicin (GO) 3 mg/m2 (up to one vial) as a 2 hour intravenous infusion on Cycle 1 Days 1, 4, and 7. A second cycle of GO 3mg/m² (up to one vial) on Cycle 2 Days 1, 4, and 7 will be allowed at the investigator's discretion for patients who meet the criteria | Drug: Gemtuzumab Ozogamicin<br>* Three doses of GO 3 mg/m2 (up to one vial) as a 2 hour intravenous infusion on Cycle 1 Days 1, 4, and 7. A second cycle of GO 3mg/m² (up to one vial) on Cycle 2 Days 1, 4, and 7 will be allowed at the investigator's discretion for patients who meet the criteria<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Corrected QT Interval for Heart Rate Using Fridericia's Formula (QTcF) at Cycle 1 Day 1: 1 Hour | Triplicate 12-lead ECG measurements (each recording separated by approximately 2 minutes) were performed and average was calculated. QT interval was the time between the start of the Q wave and the end of the T wave in the cardiac electrical cycle. QTcF was the QT interval corrected for heart rate using Fridericia's formula: QTcF = QT divided by cube root of 60/heart rate. Change from baseline in QT interval corrected for heart rate using Fridericia's formula was reported. | Baseline, Cycle 1 Day 1: 1 Hour | 
| Change From Baseline in Corrected QT Interval for Heart Rate Using Fridericia's Formula (QTcF) at Cycle 1 Day 1: 2 Hours | Triplicate 12-lead ECG measurements (each recording separated by approximately 2 minutes) were performed and average was calculated. QT interval was the time between the start of the Q wave and the end of the T wave in the cardiac electrical cycle. QTcF was the QT interval corrected for heart rate using Fridericia's formula: QTcF = QT divided by cube root of 60/heart rate. Change from baseline in QT interval corrected for heart rate using Fridericia's formula was reported. | Baseline, Cycle 1 Day 1: 2 Hours | 
| Change From Baseline in Corrected QT Interval for Heart Rate Using Fridericia's Formula (QTcF) at Cycle 1 Day 1: 4 Hours | Triplicate 12-lead ECG measurements (each recording separated by approximately 2 minutes) were performed and average was calculated. QT interval was the time between the start of the Q wave and the end of the T wave in the cardiac electrical cycle. QTcF was the QT interval corrected for heart rate using Fridericia's formula: QTcF = QT divided by cube root of 60/heart rate. Change from baseline in QT interval corrected for heart rate using Fridericia's formula was reported. | Baseline, Cycle 1 Day 1: 4 Hours | 
| Change From Baseline in Corrected QT Interval for Heart Rate Using Fridericia's Formula (QTcF) at Cycle 1 Day 4: 0 Hour | Triplicate 12-lead ECG measurements (each recording separated by approximately 2 minutes) were performed and average was calculated. QT interval was the time between the start of the Q wave and the end of the T wave in the cardiac electrical cycle. QTcF was the QT interval corrected for heart rate using Fridericia's formula: QTcF = QT divided by cube root of 60/heart rate. Change from baseline in QT interval corrected for heart rate using Fridericia's formula was reported. | Baseline, Cycle 1 Day 4: 0 Hour | 
| Change From Baseline in Corrected QT Interval for Heart Rate Using Fridericia's Formula (QTcF) at Cycle 1 Day 4: 2 Hours | Triplicate 12-lead ECG measurements (each recording separated by approximately 2 minutes) were performed and average was calculated. QT interval was the time between the start of the Q wave and the end of the T wave in the cardiac electrical cycle. QTcF was the QT interval corrected for heart rate using Fridericia's formula: QTcF = QT divided by cube root of 60/heart rate. Change from baseline in QT interval corrected for heart rate using Fridericia's formula was reported. | Baseline, Cycle 1 Day 4: 2 Hours | 
| Change From Baseline in Corrected QT Interval for Heart Rate Using Fridericia's Formula (QTcF) at Cycle 1 Day 7: 0 Hour | Triplicate 12-lead ECG measurements (each recording separated by approximately 2 minutes) were performed and average was calculated. QT interval was the time between the start of the Q wave and the end of the T wave in the cardiac electrical cycle. QTcF was the QT interval corrected for heart rate using Fridericia's formula: QTcF = QT divided by cube root of 60/heart rate. Change from baseline in QT interval corrected for heart rate using Fridericia's formula was reported. | Baseline, Cycle 1 Day 7: 0 Hour | 
| Change From Baseline in Corrected QT Interval for Heart Rate Using Fridericia's Formula (QTcF) at Cycle 1 Day 7: 2 Hours | Triplicate 12-lead ECG measurements (each recording separated by approximately 2 minutes) were performed and average was calculated. QT interval was the time between the start of the Q wave and the end of the T wave in the cardiac electrical cycle. QTcF was the QT interval corrected for heart rate using Fridericia's formula: QTcF = QT divided by cube root of 60/heart rate. Change from baseline in QT interval corrected for heart rate using Fridericia's formula was reported. | Baseline, Cycle 1 Day 7: 2 Hours | 
| Change From Baseline in Corrected QT Interval for Heart Rate Using Fridericia's Formula (QTcF) at Cycle 1 Day 7: 4 Hours | Triplicate 12-lead ECG measurements (each recording separated by approximately 2 minutes) were performed and average was calculated. QT interval was the time between the start of the Q wave and the end of the T wave in the cardiac electrical cycle. QTcF was the QT interval corrected for heart rate using Fridericia's formula: QTcF = QT divided by cube root of 60/heart rate. Change from baseline in QT interval corrected for heart rate using Fridericia's formula was reported. | Baseline, Cycle 1 Day 7: 4 Hours | 
| Change From Baseline in Corrected QT Interval for Heart Rate Using Fridericia's Formula (QTcF) at Cycle 1 Day 7: 6 Hours | Triplicate 12-lead ECG measurements (each recording separated by approximately 2 minutes) were performed and average was calculated. QT interval was the time between the start of the Q wave and the end of the T wave in the cardiac electrical cycle. QTcF was the QT interval corrected for heart rate using Fridericia's formula: QTcF = QT divided by cube root of 60/heart rate. Change from baseline in QT interval corrected for heart rate using Fridericia's formula was reported. | Baseline, Cycle 1 Day 7: 6 Hours | 
| Change From Baseline in Corrected QT Interval for Heart Rate Using Fridericia's Formula (QTcF) at Cycle 2 Day 1: 0 Hour | Triplicate 12-lead ECG measurements (each recording separated by approximately 2 minutes) were performed and average was calculated. QT interval was the time between the start of the Q wave and the end of the T wave in the cardiac electrical cycle. QTcF was the QT interval corrected for heart rate using Fridericia's formula: QTcF = QT divided by cube root of 60/heart rate. Change from baseline in QT interval corrected for heart rate using Fridericia's formula was reported. | Baseline, Cycle 2 Day 1: 0 Hour | 
| Change From Baseline in Corrected QT Interval for Heart Rate Using Fridericia's Formula (QTcF) at Cycle 2 Day 1: 2 Hours | Triplicate 12-lead ECG measurements (each recording separated by approximately 2 minutes) were performed and average was calculated. QT interval was the time between the start of the Q wave and the end of the T wave in the cardiac electrical cycle. QTcF was the QT interval corrected for heart rate using Fridericia's formula: QTcF = QT divided by cube root of 60/heart rate. Change from baseline in QT interval corrected for heart rate using Fridericia's formula was reported. | Baseline, Cycle 2 Day 1: 2 Hours | 
| Change From Baseline in Corrected QT Interval for Heart Rate Using Fridericia's Formula (QTcF) at Cycle 2 Day 7: 0 Hour | Triplicate 12-lead ECG measurements (each recording separated by approximately 2 minutes) were performed and average was calculated. QT interval was the time between the start of the Q wave and the end of the T wave in the cardiac electrical cycle. QTcF was the QT interval corrected for heart rate using Fridericia's formula: QTcF = QT divided by cube root of 60/heart rate. Change from baseline in QT interval corrected for heart rate using Fridericia's formula was reported. | Baseline, Cycle 2 Day 7: 0 Hour | 
| Change From Baseline in Corrected QT Interval for Heart Rate Using Fridericia's Formula (QTcF) at Cycle 2 Day 7: 2 Hours | Triplicate 12-lead ECG measurements (each recording separated by approximately 2 minutes) were performed and average was calculated. QT interval was the time between the start of the Q wave and the end of the T wave in the cardiac electrical cycle. QTcF was the QT interval corrected for heart rate using Fridericia's formula: QTcF = QT divided by cube root of 60/heart rate. Change from baseline in QT interval corrected for heart rate using Fridericia's formula was reported. | Baseline, Cycle 2 Day 7: 2 Hours | 
| Change From Baseline in Corrected QT Interval for Heart Rate Using Fridericia's Formula (QTcF) at Cycle 2 Day 7: 6 Hours | Triplicate 12-lead ECG measurements (each recording separated by approximately 2 minutes) were performed and average was calculated. QT interval was the time between the start of the Q wave and the end of the T wave in the cardiac electrical cycle. QTcF was the QT interval corrected for heart rate using Fridericia's formula: QTcF = QT divided by cube root of 60/heart rate. Change from baseline in QT interval corrected for heart rate using Fridericia's formula was reported. | Baseline, Cycle 2 Day 7: 6 Hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clearance (CL) of Gemtuzumab Ozogamicin | Clearance of a drug was measure of the rate at which the drug was metabolized or eliminated by normal biological processes. | Pre dose, 2, 4, 6, 72, 192 and 336 hours post dose on Cycle 1 Day 7 | 
| Volume of Distribution of Gemtuzumab Ozogamicin | Volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. | Pre dose, 2, 4, 6, 72, 192 and 336 hours post dose on Cycle 1 Day 7 | 
| Maximum Observed Plasma Concentration (Cmax): AC-CL-184538 and CL-184538 | Cmax was defined as the maximum observed plasma concentration of GO. Calicheamicin (conjugated calicheamicin ac-CL-184538 and unconjugated CL-184538) analyte were used to determined the Cmax in this outcome measure. | Pre dose, 1, 2, 4, 6, 24 and 72 hours post dose on Cycle 1 Day 1; and Pre dose, 2, 4, 6, 72, 192 and 336 hours post dose on Cycle 1 Day 7 | 
| Maximum Observed Plasma Concentration (Cmax): Total HP67.6 Antibody | Cmax was defined as the maximum observed plasma concentration of GO. Total HP67.6 antibodies analyte was used to determined the Cmax in this outcome measure. | Pre dose, 1, 2, 4, 6, 24 and 72 hours post dose on Cycle 1 Day 1; and Pre dose, 2, 4, 6, 72, 192 and 336 hours post dose on Cycle 1 Day 7 | 
| Time to Reach Maximum Observed Plasma Concentration (Tmax) | Tmax = time (hours) to maximum plasma concentration (Cmax). | Pre dose, 1, 2, 4, 6, 24 and 72 hours post dose on Cycle 1 Day 1; and Pre dose, 2, 4, 6, 72, 192 and 336 hours post dose on Cycle 1 Day 7 | 
| Area Under the Plasma Concentration-time Profile From Time Zero to the Time of Last Quantifiable Concentration (AUClast): AC-CL-184538 and CL-184538 | Area under the plasma concentration-time curve from time zero to the time of the last measurable concentration (AUClast). Calicheamicin (conjugated calicheamicin ac-CL-184538 and unconjugated CL-184538) analytes were used to determined the AUClast in this outcome measure. | Pre dose, 1, 2, 4, 6, 24 and 72 hours post dose on Cycle 1 Day 1; and Pre dose, 2, 4, 6, 72, 192 and 336 hours post dose on Cycle 1 Day 7 | 
| Area Under the Plasma Concentration-time Profile From Time Zero to the Time of Last Quantifiable Concentration (AUClast): Total HP67.6 Antibody | Area under the plasma concentration-time curve from time zero to the time of the last measurable concentration (AUClast). Total HP67.6 antibodies analyte was used to determined the AUClast in this outcome measure. | Pre dose, 1, 2, 4, 6, 24 and 72 hours post dose on Cycle 1 Day 1; and Pre dose, 2, 4, 6, 72, 192 and 336 hours post dose on Cycle 1 Day 7 | 
| Area Under the Plasma Concentration-time Profile From Time Zero to Time 72 Hours (AUC0-72): AC-CL-184538 and CL-184538 | Area under the plasma concentration-time curve from time zero to the time 72 hours (AUC0-72). Calicheamicin (conjugated calicheamicin ac-CL-184538 and unconjugated CL-184538) analytes were used to determined the AUC0-72 in this outcome measure. | Pre dose, 1, 2, 4, 6, 24 and 72 hours post dose on Cycle 1 Day 1 | 
| Area Under the Plasma Concentration-time Profile From Time Zero to Time 72 Hours (AUC0-72): Total HP67.6 Antibody | Area under the plasma concentration-time curve from time zero to the time 72 hours (AUC0-72). Total HP67.6 antibodies analyte was used to determined the AUC0-72 in this outcome measure. | Pre dose, 1, 2, 4, 6, 24 and 72 hours post dose on Cycle 1 Day 1 | 
| Area Under the Plasma Concentration-time Profile From Time Zero to Time 336 Hours (AUC0-336): AC-CL-184538 and CL-184538 | Area under the plasma concentration-time curve from time zero to the time 336 hours (AUC0-336). Calicheamicin (conjugated calicheamicin ac-CL-184538 and unconjugated CL-184538) analytes were used to determined the AUC0-336 in this outcome measure. | Pre dose, 2, 4, 6, 72, 192 and 336 hours post dose on Cycle 1 Day 7 | 
| Area Under the Plasma Concentration-time Profile From Time Zero to Time 336 Hours (AUC0-336): Total HP67.6 Antibody | Area under the plasma concentration-time curve from time zero to the time 336 hours (AUC0-336). Total HP67.6 antibodies analyte was used to determined the AUC0-336 in this outcome measure. | Pre dose, 2, 4, 6, 72, 192 and 336 hours post dose on Cycle 1 Day 7 | 
| Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | An AE was any untoward medical occurrence in a participant who received investigational product without regard to possibility of causal relationship. SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly; medically important events. A treatment emergent AE was defined as an event between first dose of study drug and up to 36 days after the last dose of study drug, that was absent before treatment, or that worsened during the treatment period relative to the pretreatment state. AEs included all serious and non-serious adverse events. | From first dose of study drug up to 36 days after last dose (up to a maximum of 12 months) | 
| Number of Participants With Shift From Grade <=2 at Baseline to Grade 3 or 4 Post-Baseline in Clinical Laboratory Abnormalities- Hematology and Coagulation Parameters | Laboratory parameters included hematological and coagulation parameters. These included activated partial thromboplastin time prolonged, anemia, fibrinogen decreased, hemoglobin increased, international normalized ratio increased, leukocytosis, lymphocyte count decreased, lymphocyte count increased, neutrophil count decreased, platelet count decreased, white blood cell decreased. Number of participants with hematological and coagulation abnormalities by grades (as per Common Terminology Criteria for Adverse Events (CTCAE version 4.03) were reported. Grade 1= mild; Grade 2= moderate; Grade 3= severe and Grade 4= life-threatening or disabling. | From first dose of study drug up to 36 days after last dose (up to a maximum of 12 months) | 
| Number of Participants With Shift From Grade <=2 at Baseline to Grade 3 or 4 Post-Baseline in Clinical Laboratory Abnormalities- Chemistry Parameters | Laboratory parameters included chemistry parameters. These included: alanine aminotransferase increased, alkaline phosphatase increased, aspartate aminotransferase increased, blood bilirubin increased, creatinine increased, hypercalcemia, hyperglycemia, hyperkalemia, hypermagnesemia, hypernatremia, hypoalbuminemia, hypocalcemia, hypoglycemia, hypokalemia, hypomagnesemia, and hyponatremia. Number of participants with chemistry test abnormalities by grades (CTCAE version 4.03) were reported. Grade 1= mild; Grade 2= moderate; Grade 3= severe and Grade 4= life-threatening or disabling. | From first dose of study drug up to 36 days after last dose (up to a maximum of 12 months) | 
| Percentage of Participants With Positive Anti-Drug Antibody (ADA) | Percentage of participants with treatment-induced ADA positive (post baseline-positive only) and treatment-boosted ADA positive (baseline ADA titer that was boosted to a 9-fold or higher level following drug administration) were reported in this outcome measure. | From first dose of study drug up to maximum of 12 months | 
| Percentage of Participants With Positive Neutralizing Antibodies (NAb) | Percentage of participants with either treatment-induced NAb or treatment-boosted NAb were reported. | From first dose of study drug up to maximum of 12 months | 
| Percentage of Participants Who Achieved Complete Remission (CR) and Complete Remission With Incomplete Hematologic Recovery (CRi) | Percentage of participants with first dose of study drug to best overall response with CR and CRi were reported. CR was defined as the disappearance of leukemia indicated by less than (<) 5 percent (%) bone marrow blasts, absence of circulating blasts with auer rods and absence of extramedullary disease, with recovery of hematopoiesis defined by absolute neutrophil count (ANC) greater than or equal to (>=)1000 per microliter (1000/mcL) and platelets >=100,000/mcL. CRi was defined as all CR criteria except residual neutropenia; ANC <1000/mcL or thrombocytopenia and platelet count <100,000/mcL. | From first dose of study drug to 36 days after last dose (maximum up to of 12 months) | 
| Overall Survival (OS) | OS was defined as the time (in months) from the start date (first dose) of study treatment to the date of death due to any cause. Participants last known to be alive were censored at date of last contact. Analysis was performed using Kaplan-Meier method. | From the first dose of study treatment to the date of death or date of censored, whichever occurred first (maximum up to 12 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Safety, gemtuzumab ozogamicin, Mylotarg, QT interval prolongation, Pharmacokinetics, Veno-occlusive disease, Anti-drug antibody