Study to Evaluate the Effect of Cetuximab on Corrected QT (QTc) Interval Changes in Patients With Advanced Malignancies From Solid Tumors

Study Overview
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Brief Summary
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The purpose of this study is to determine whether corrected QT (QTc) interval changes occur on an electrocardiogram (ECG) when cetuximab is administered to the study population.

Official Title
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A Study to Evaluate the Relationship Between Cetuximab Therapy and Corrected QT (QTc) Interval Changes in Patients With Advanced Malignancies From Solid Tumors

Conditions
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Advanced Cancer

Intervention / Treatment
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* Drug: Cetuximab


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Advanced or metastatic malignant disease originating from solid tumors Adequate recovery from previous therapy or intervention; at least 21 days since major surgery or prior radiation therapy Measurable or evaluable disease Exclusion criteria: Women of childbearing potential (WOCBP) who are breastfeeding, pregnant, or unwilling or unable to use acceptable contraception during the study and for at least 12 weeks after the last on-study dose of cetuximab Men unwilling to use acceptable contraception during the study if engaged in sexual relations with a WOCBP Symptomatic brain metastasis History of myocardial infarction 6 months or less prior to study entry, of severe congestive heart failure, of uncontrolled angina, or of uncontrolled arrhythmias Clinically relevant abnormality on screening electrocardiogram (ECG), preventing an accurate measurement of the QT interval Congenital long QT syndrome History of risk factors for ventricular tachycardia or Torsades de pointes or history of fainting, unexplained loss of consciousness, or convulsions Prolonged QTc interval on screening ECG (greater than 470 msec) using Fridericia's correction formula Heart rate slower than 50 bpm or faster than 100 bpm at rest during screening ECG measurements Implantable pacemaker or automatic implantable cardioverter defibrillator Sustained supine systolic blood pressure higher than 150 mmHg or lower than 90 mmHg or a diastolic blood pressure lower than 45 mmHg or higher than 95 mmHg at screening Known history of arterial thrombotic events within 6 months prior to study initiation Known history of significant peripheral artery disease Current participation in a clinical trial with another investigational new drug or device Receipt of an investigational new drug or device within 21 days prior to enrollment in this study

Ages Eligible for Study
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Minimum Age: 18 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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cetuximab<br> | Drug: Cetuximab<br>* Cetuximab administered by intravenous (IV) infusion at an initial dose of 400 mg/m^2 over 120 minutes on Day 1 followed by a weekly maintenance IV dose of 250 mg/m^2 over 60 minutes.<br>* Other names: Erbitux;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Clinically Meaningful Prolongation of the QT Interval Corrected for Heart Rate (QTc) From Time-matched Baseline | 12-Lead continuous digital electrocardiogram (ECG) data were collected at preselected time points at baseline visit and on Days 1, 8, 15, 22, and 29. The QT interval is the time between the start of the Q wave and the end of the T wave in the cardiac electrical cycle. The corrected QTc is the QT interval corrected for heart rate. Prolongation of the QTc was identified as clinically meaningful at the investigator's discretion. | Baseline, Day 1, and then weekly to end of Cycle 1 (28 days) | 
| Mean Change in QTc From Time-matched Baseline Assessed Using Fridericia's Correction Formula (QTcF) by Study Day and Time Point | The QT interval is the time between the start of the Q wave and the end of the T wave in the cardiac electrical cycle. The QTc is the QT interval corrected for heart rate. The QTcF=QT/RR^1/3, where RR=RR interval in seconds. Baseline=predose. Mean change in QTc interval from baseline to time t=QTc interval at time t minus QTc interval at baseline. | Predose Day 1 (Baseline) to end of Cycle 1 (28 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Clinically Significant Changes in PR Interval, QRS Interval, and Heart Rate | 12-Lead continuous digital ECG data were collected at preselected time points at baseline visit and on Days 1, 8, 15, 22, and 29. The PR interval is the time from the onset of the P wave to the beginning of the QRS complex. The QRS interval=deflections in the ECG, comprising Q, R, and S waves, that represent depolarization of the ventricles. Clinically significant was determined at the investigator's discretion. | Baseline, Day 1, and then weekly to end of Cycle 1 (28 days) | 
| Number of Participants With Death, Treatment-related Death, Serious Adverse Events (SAEs), Treatment-related SAEs, Adverse Events (AEs) Leading to Discontinuation, and Treatment-related AEs Leading to Discontinuation | AE=any new untoward medical occurrence or worsening of a preexisting medical condition that does not necessarily have a causal relationship with treatment. SAE=any untoward medical occurrence that at any dose results in death, is life-threatening, requires or prolongs inpatient hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, results in development of drug dependency or drug abuse, or is an important medical event. Treatment related=possibly, probably, or certainly related to or of unknown relationship to study treatment. | Baseline through Cycle 1 (28 days), continuously | 
| Number of Participants With AEs of Special Interest by Worst Common Terminology Criteria (CTC) Grade | AE=any new untoward medical occurrence or worsening of a preexisting medical condition that does not necessarily have a causal relationship with treatment. AEs of special interest have been sponsor-selected based on the known clinical effects of cetuximab. Treatment related=possibly, probably, or certainly related to or of unknown relationship to study treatment. CTC Grade 1: Mild. Grade 2: Moderate. Grade 3: Severe or medically significant but not immediately life-threatening. Grade 4: Life-threatening. | Baseline through Cycle 1 (28 days), continuously | 
| Number of Participants With Serum Chemistry Abnormalities by Worst CTC Grade at Baseline and On-study | BL=baseline; OS=on-study; ULN=upper level of normal. Albumin,low (g/dL) Grade 1:<LLN-30, Grade 2:<30-20, Grades 3&4:<20. Aspartate aminotransferase (AST)(U/L) Grade 1:>ULN-2.5*ULN, Grade 2:>2.5-5.0*ULN, Grade 3:>5.0-20.0*ULN, Grade 4:>20.0*ULN. Total bilirubin, high Grade 1:ULN-1.5*ULN, Grade 2:>1.5-3.0*ULN, Grade 3:>3.0-10.0*ULN, Grade 4:>10.0*ULN. Alkaline phosphatase (ALP) (U/L) Grade 1:>ULN-2.5*ULN, Grade 2:>2.5-5.0*ULN, Grade 3:>5.0-20.0*ULN, Grade 4:>20.0*ULN. Creatinine (mg/dL) Grade 1:>ULN-1.5*ULN, Grade 2:>1.5-3.0*ULN, Grade 3:>3.0-6.0*ULN, Grade 4:>6.0*ULN. | At screening, at the end of Cycle 1 (28 days) | 
| Number of Participants With Serum Chemistry Abnormalities by Worst CTC Grade at Baseline and On-study (Continued) | BL=baseline; OS=on-study; LLN=lower level of normal; ULN=upper level of normal. Sodium, low(mmol/L) Grades 1&2:<LLN-130, Grade 3:<130-120, Grade 4:<120. Sodium, high (mmol/L) Grade 1:>ULN-150, Grade 2:>150-155, Grade 3:>155-160, Grade 4:>160. Potassium, high (mmol/L) Grade 1:>ULN-5.5, Grade 2:>5.5-6.0, Grade 3:>6.0-7.0, Grade 4:>7.0. Glucose, low(mg/dL) Grade 1:<LLN-55, Grade 2:<55-40, Grade 3:<40-30, Grade 4:<30. Glucose, high (mg/dL) Grade 1:>ULN-160, Grade 2:>160-250, Grade 3:>250-500, Grade 4:>500. Calcium, high(mg/dL) Grade 1:>ULN-11.5, Grade 2:>11.5-12.5, Grade 3:>12.5-13.5, Grade 4:>13. | At screening, at the end of Cycle 1 (28 days) | 
| Number of Participants With Hematology Abnormalities by Worst CTC Grade at Baseline and On-study | BL=baseline; OS=on-study; LLN=lower level of normal. Laboratory values assessed using CTC for AEs, Version 3.0. Hemoglobin (g/dL) Grade 1:<LLN to 10.0, Grade 2:<10.0 to 8.0, Grade 3:<8.0 to 6.5, Grade 4:<6.5. Platelets Grade 1:LLN to 75.0*10^9/L, Grade 2:<75.0 to 50.0*10^9/L, Grade 3:<50.0 to 25.0*10^9/L, Grade 4:<25.0 to 10^9/L. White blood cells Grade 1:<LLN to 3.0*10^9/L, Grade 2:<3.0 to 2.0*10^9/L, Grade 3:<2.0 to 1.0*10^9/L, Grade 4:<1.0*10^9/L. Neutrophils Grade 1:<LLN to 1.5*10^9/L, Grade 2:<1.5 to 1.0*10^9/L, Grade 3:<1.0 to 0.5*10^9/L, Grade 4:<0.5*10^9/L. | At screening, weekly prior to start of cetuximab infusion, at end of Cycle 1 (28 days), and at 30-day follow-up |