Antiemetics

Dermatologic Agents

Gastrointestinal Agents

All Drugs and Chemicals

Ondansetron

Serotonin

Serotonin 5-HT3 Receptor Antagonists

Neurotransmitter Agents

Group A will receive the standard dose of ondansetron (0.15 mg/kg) with the first cycle of chemotherapy and the high dose (0.3 mg/kg) with second cycle.

Group B patients will receive the higher dose of ondansetron (0.3 mg/kg) with the first cycle of chemotherapy and the standard dose (0.15 mg/kg) with the second.

There will be two doses investigated in each arm - standard dose (0.15 mg/kg) and high dose (0.3 mg/kg)

Rene Y McNall-Knapp, MD

Matthew Campbell, MD

We will study the effects of ondansetron on measurements of electrical activity in the heart to make sure doses we are using to prevent nausea and vomiting in children receiving chemotherapy are safe.

Children receiving chemotherapy for cancer at the Jimmy Everest Center for Cancer and Blood Disorders in Children also often receive an IV dose of an antiemetic for prophylaxis. The most common antiemetics used are in the family of 5HT3 antagonists, specifically granisetron and ondansetron. Prior to a recent recommendation by the FDA, we have used ondansetron 0.45 mg/kg IV. Based on adult ECG data, the recommended dose of ondansetron has been changed to no greater than 0.15 mg/kg. We have prior studies showing that the bigger dose is better at preventing nausea and vomiting. Therefore we are studying ECG data in patients receiving ondansetron and chemotherapy. Each subject will have two identical cycles of chemotherapy. Prior to the first of the two cycles they will be randomized to receive one of two doses of ondansetron with the first cycle and the other dose with the second cycle. The two doses are the recommended dose of 0.15 mg/kg and a higher dose of 0.3 mg/kg. The dose level the patient receives each cycle will be blinded to the investigator and the subject.

Prior to the first dose of investigational ondansetron, the patient will have an ECG. This ECG will be repeated 30 minutes after the ondansetron is administered and just before chemotherapy administration, and repeated again 30 minutes later. The change in the QTc intervals will be calculated by two independent pediatric cardiologists who are also blinded to the ondansetron dose level received. This process will be repeated with the next course of chemotherapy, with the second dose of ondansetron. Our goal is to see if there is an appreciable difference between the two doses in the QTc interval changes they induce.

Heart Safety Study of Ondansetron in Children Receiving Chemotherapy

The Effects of Ondansetron on Myocardial Repolarization in Children Receiving Chemotherapy

QTc intervals will be estimated by performing ECGs on patients pre-investigational drug administration and post-investigational drug administration. The change in the QTc interval between the two ECGs for each investigational dose is the primary endpoint.

University of Oklahoma

Associate Professor

Antineoplastic Agents

Amino Acids

Lapatinib

Tyrosine Kinase Inhibitors

Protein Kinase Inhibitors

Enzyme Inhibitors

Tyrosine

This is a crossover study where subjects will receive placebo that mimics lapatinib for 2 days and lapatinib for 2 days. Subjects will not know when they are receiving placebo vs. lapatinib.

lapatinib commercial tablet, 2000mg, will be given as three separate doses (8 tablets/dose) given 12 hours apart over a 2 day period

lapatinib

placebo matching lapatinib will be given as three separate doses (8 tablets/dose) given 12 hours apart over a 2 day period

placebo matching lapatinib

GSK Clinical Trials

This study will estimate the effect of lapatinib on cardiac repolarization (QTc interval duration) in subjects with advanced solid tumors. The study treatment period will occur over five days and an End of Study visit will be conducted on Day 8 (or no later than 3 days beyond Day 8). Subjects will receive placebo that mimics lapatinib for 2 days as three separate doses given 12 hours apart (8 tablets/dose) and lapatinib (2000mg) for 2 days as three separate doses given 12 hours apart (8 tablets/dose). Subjects will not know when they are receiving placebo vs. lapatinib. Digital 12-lead ECG recordings will be extracted from continuous ECG recordings obtained via a Holter monitor to measure QTc interval duration. Triplicate ECG measurements of QTc interval will be taken at pre-specified times at Day 1 (Baseline) and pre-dose and up to 24 hours after the third dose of placebo or lapatinib on Study Days 2 and 4. Pharmacokinetic sampling will occur immediately following each pre-specified QTc measurement in subjects dosed with placebo or lapatinib. Subjects who complete participation in this study, if they are eligible, will be offered the option to continue treatment with lapatinib, either alone or in combination with other oncology drugs in pre-selected anticancer regimens, in a continuation protocol, EGF111767.

A Study in Cancer Patients to Evaluate the Effect of Lapatinib on the QTc Interval

A Phase IV, Placebo-controlled Single Sequence Crossover Study to Evaluate the Effect of Repeat Oral Doses of Lapatinib on Cardiac Repolarization in Patients With Advanced Cancer

A Holter monitor is an ambulatory portable device used for continuously monitoring the cardiovascular system. Three replicate electrocardiograms (ECGs) were collected at 30, 15, and 0 minutes prior to the administration of study treatment (trt) on Days 1 and 3 and pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hr post-dose on Days 2 and 4. The 3 readings at each time point (TP) were averaged prior to any analysis. BL is the average of the pre-dose QTcF values (triplicate) taken on Day 1 for PBO and on Day 3 for LAP. Mean change from BL was calculated by subtracting the BL values from individual QTcF for each TP. BL adjusted mean difference in absolute QTcF between LAB and PBO (trt difference) with the corresponding 90% confidence interval (CI) was estimated for each TP (pre-dose and 1, 2, 3, 4, 6, 8, 10, 12, and 24-hr post-dose). Trt difference analysis was performed by a repeated measures analysis of variance adjusted for trt group, TP, and trt group\*TP interaction.

A Holter monitor is an ambulatory portable device for continuously monitoring the cardiovascular system. Change from Baseline in QT interval, QTc interval, QTcB interval, QTcI interval, RR interval, PR interval, and QRS duration at each time point for lapatinib was assessed in comparison with time-matched placebo. Three replicate ECGs were collected at 30, 15, and 0 minutes prior to the administration of study treatment on Days 1 and 3 and pre-dose and 1, 2, 3, 4, 6, 8, 10, and 24 hours post dose on Days 2 and 4. The three readings at each time point were averaged prior to any analysis. Baseline is the average of the pre-dose ECGs (triplicate) taken on Day 1 for placebo and Day 3 for lapatinib. Change from Baseline was calculated by subtracting the Baseline values from individual post-Baseline values for each time point.

The number of participants with 12-lead Holter ECG findings of normal (NL), abnormal not clinically significant (Abn NCS), and abnormal clinically significant (Abn CS) are reported. Abnormal ECG findings or change in ECG morphological patterns were based on the ECG interpretations provided by the ECG core lab. Three replicate 12-lead Holter ECGs were collected at -30, -15, and 0 minutes prior to the administration of study treatment on Days 1 (Baseline for placebo) and 3 (Baseline for lapatinib) and pre-dose and 1, 2, 3, 4, 6, 8, 10,12, and 24 hours post dose on Days 2 and 4. The three readings at each time point were averaged prior to any analysis. Baseline is the pre-dose ECGs (triplicate) taken on Day 1 for placebo and on Day 3 for lapatinib.

Abnormal ECG findings or change in ECG morphological patterns were based on the ECG interpretations provided by the ECG core lab. Three replicate Holter ECGs were collected at 30, 15, and 0 minutes prior to the administration of study treatment on Days 1 (Baseline for placebo) and 3 (Baseline for lapatinib) and pre-dose and 1, 2, 3, 4, 6, 8, 10, and 24 hours post dose on Days 2 and 4. The three readings at each time point were averaged prior to any analysis. Baseline is the pre-dose ECGs (triplicate) taken on Day 1 for placebo and Day 3 for lapatinib. The number of participants with the worst-case post-Baseline 12-lead Holter ECG findings with significant ST, T wave, and U wave abnormalities were analyzed.

An AE is defined as any untoward medical occurrence in a participant temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity or is a congenital anomaly/birth defect, or is an important medical eventsthat jeopardizes the participant or may require medical or surgical intervention to prevent one of the other outcomes listed in the above definition, new primary cancers, liver events, cardiac dysfunction, pneumonitis, and laboratory abnormalities.

Blood samples were collected for the measurement of albumin and hemoglobin at Baseline; Days 5 and 8-11. Baseline is defined as the most recent, non-missing value from a central laboratory prior to or on the first study treatment dose date.

Blood samples were collected for the measurement of ALP, ALT, and AST at Baseline; Days 5 and 8-11. Baseline is defined as the most recent, non-missing value from a central laboratory prior to or on the first study treatment dose date.

Blood samples were collected for the measurement of direct bilirubin, total bilirubin, and creatinine at Baseline; Days 5 and 8-11; Baseline is defined as the most recent, non-missing value from a central laboratory prior to or on the first study treatment dose date.

Blood samples were collected for the measurement of calcium, chloride, CO2, potassium, sodium, magnesium and urea at Baseline; at Days 5 and 8-11. Baseline is defined as the most recent, non-missing value from a central laboratory prior to or on the first study treatment dose date.

Blood samples were collected for the measurement of total neutrophils (ANC), platelets, and leukocyte count at Baseline; Days 5 and 8-11. Baseline was defined as the most recent, non-missing value from a central laboratory prior to or on the first study treatment dose date.

Blood pressure measurements included SBP and DBP and were obtained at Baseline; on Day 2 (at pre-dose, 4, 8, 12 and 24 hours post dose), and on Day 4 (at pre-dose, 4, 8, 12 and 24 hours post dose). Baseline is defined as the most recent, non-missing value prior to or on the first study treatment dose date. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.

Heart rate were measured at Baseline; on Day 2 (at pre-dose, 4, 8, 12 and 24 hours post dose), and on Day 4 (at pre-dose, 4, 8, 12 and 24 hours post dose. Baseline is defined as the most recent, non-missing value prior to or on the first study treatment dose date. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.

The number of participants with the 12-lead ECG findings normal (NL), abnormal not clinically significant (Abn NCS), and abnormal clinically significant (Abn CS) are reported. Clinical significance was based on the medical and scientific judgement of the investigator or qualified designee. A single safety 12-lead ECG was performed using a standard 12-lead ECG machine at Baseline; on Day 1 (at pre-dose); on Day 2 (at pre-dose, 4, 8, 12 and 24 hours post-last- dose); on Day 4 (at pre-dose, 4, 8, 12 and 24 hours post-last-dose); at the End of Study visit (Day 8-11); and at the post-treatment Follow-up visit (if applicable).

AUC is defined as the area under the lapatinib concentration-time curve as a measure of drug exposure. AUC(0-t) and AUC(0-24) were determined from the plasma concentration-time data using the linear trapezoidal rule for increased concentrations and the logarithmic trapezoidal rule for decreased concentrations. For PK analysis, one blood sample was collected on Day 1 for placebo Baseline. The 24 hour blood sample on Day 2 also served for lapatinib Baseline. Pre-dose blood samples were collected 30 minutes prior to the administration of study medication on Day 2 (placebo) and Day 4 (lapatinib). Serial blood samples were collected on Day 2 (for placebo) and on Day 4 (for lapatinib) at the following post-last-dose time points 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours.

The first occurrence of Cmax and C24 was determined directly from the raw concentration-time data. For PK analysis, one blood sample was collected on Day 1 for placebo Baseline. The 24 hour blood sample on Day 2 also served for lapatinib Baseline. Pre-dose blood samples were collected 30 minutes prior to the administration of study medication on Day 2 (placebo) and Day 4 (lapatinib). Serial blood samples were collected on Day 2 (for placebo) and on Day 4 (for lapatinib) at the following post-last-dose time points 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours.

For each participant, the time at which Cmax was observed (tmax) was determined directly from the raw concentration-time data. For each participant, the time prior to the first quantifiable (non-zero) concentration (tlag) was determined directly from the raw concentration-time data. Since all participants received 2 doses of study medication prior to the collection of the first (pre-dose) blood sample on Day 4, tlag was expected to be zero. For PK analysis, one blood sample was collected on Day 1 for placebo Baseline. The 24 hour blood sample on Day 2 also served for lapatinib Baseline. Pre-dose blood samples were collected 30 minutes prior to the administration of study medication on Day 2 (placebo) and Day 4 (lapatinib). Serial blood samples were collected on Day 2 (for placebo) and on Day 4 (for lapatinib) at the following post-last-dose time points 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours.

GlaxoSmithKline

The number of participants in 1st Period - placebo (57) is different from 2nd Period - lapatinib (58) because one participant was "double dosed" with lapatinib (i.e., received lapatinib during both the 1st period and 2nd period) due to dosing error.

Participants received three doses of matching placebo in the morning and evening on Day 1 and in the morning on Day 2.

Placebo

Participants received three doses of lapatinib 2000 mg (250 mg x 8 tablets/dose) in the morning and evening on Day 3 and in the morning on Day 4.

Lapatinib 2000 mg

Participants received three doses of matching placebo in the morning and evening on Day 1 and in the morning on Day 2. Participants then received three doses of lapatinib 2000 mg (250 mg x 8 tablets/dose) in the morning and evening on Day 3 and in the morning on Day 4.

Placebo and Lapatinib 2000 mg

Age, Continuous

Sex: Female, Male

African American/African Heritage

Asian - East Asian Heritage

Asian - South East Asian Heritage

White - White/Caucasian/European Heritage

missing

Race/Ethnicity, Customized

GSK Response Center

Pre-dose

1 hour

2 hour

3 hour

4 hour

6 hour

8 hour

10 hour

12 hour

24 hour

Evaluable Population: all participants in the All-Treated Subjects (ATS) Population who met the criteria for dosing compliance, ECG acquisition, and Baseline ECG acquisition. The ATS Population is comprised of all participants who received at least one dose of study medication (placebo or lapatinib).

Treatment Difference in Duration of Cardiac Ventricular Depolarization and Repolarization Interval (QT) in Fridericia-corrected QT Interval (QTcF) Values Between Placebo and Lapatinib 2000mg

QT interval (predose), n=37, 37

QT interval (1 hour), n=37, 37

QT interval (2 hour), n=37, 37

QT interval (3 hour), n=37, 37

QT interval (4 hour), n=37, 37

QT interval (6 hour), n=37, 36

QT interval (8 hour), n=37, 36

QT interval (10 hour), n=37, 37

QT interval (12 hour), n=37, 37

QT interval (24 hour), n=37, 35

QTcI interval (predose), n=37, 37

QTcI interval (1 hour), n=37, 37

QTcI interval (2 hour), n=37, 37

QTcI interval (3 hour), n=37, 37

QTcI interval (4 hour), n=37, 37

QTcI interval (6 hour), n=37, 36

QTcI interval (8 hour), n=37, 36

QTcI interval (10 hour), n=37, 37

QTcI interval (12 hour), n=37, 37

QTcI interval (24 hour), n=37, 35

QTcB interval (predose), n=37, 37

QTc B interval (1 hour), n=37, 37

QTcB interval (2 hour), n=37, 37

QTcB interval (3 hour), n=37, 37

QTcB interval (4 hour), n=37, 37

QTcB interval (6 hour), n=37, 36

QTcB interval (8 hour), n=37, 36

QTcB interval (10 hour), n=37, 37

QTcB interval (12 hour), n=37, 37

QTcB interval (24 hour), n=37, 35

RR interval (predose), n=37, 37

RR interval (1 hour), n=37, 37

RR interval (2 hour), n=37, 37

RR interval (3 hour), n=37, 37

RR interval (4 hour), n=37, 37

RR interval (6 hour), n=37, 36

RR interval (8 hour), n=37, 36

RR interval (10 hour), n=37, 37

RR interval (12 hour), n=37, 37

RR interval (24 hour), n=37, 35

PR interval (predose), n=37, 37

PR interval (1 hour), n=37, 37

PR interval (2 hour), n=37, 37

PR interval (3 hour), n=37, 37

PR interval (4 hour), n=37, 37

PR interval (6 hour), n=37, 36

PR interval (8 hour), n=37, 36

PR interval (10 hour), n=37, 37

PR interval (12 hour), n=37, 37

PR interval (24 hour), n=37, 35

QRS interval (predose), n=37, 37

QRS interval (1 hour), n=37, 37

QRS interval (2 hour), n=37, 37

QRS interval (3 hour), n=37, 37

QRS interval (4 hour), n=37, 37

QRS interval (6 hour), n=37, 36

QRS interval (8 hour), n=37, 36

QRS interval (10 hour), n=37, 37

QRS interval (12 hour), n=37, 37

QRS interval (24 hour), n=37, 35

Evaluable Population. Only participants available at the specified time point (represented as n=X, X in the category title) were analyzed.

Change From Baseline in the Holter ECG Parameters of QT Interval, Corrected QT Interval (QTc), Bazett Corrected QTc Interval (QTcB), Individual-corrected QT Interval (QTcI), RR Interval, PR Interval, and QRS Duration at Indicated Time Points

-30 minutes (NL), n=35, 32

-30 minutes (Abn NCS), n=35, 32

-30 minutes (Abn CS), n=35, 32

-15 minutes (NL), n=34, 32

-15 minutes (Abn NCS), n=34, 32

-15 minutes (Abn CS), n=34, 32

0 minutes (NL), n=34, 32

0 minutes (Abn NCS), n=34, 32

0 minutes (Abn CS), n=34, 32

Pre dose (NL), n=33, 31

Pre dose (Abn NCS), n=33, 31

Pre dose (Abn CS), n=33, 31

1 hour (NL), n=33, 30

1 hour (Abn NCS), n=33, 30

1 hour (Abn CS), n=33, 30

2 hour (NL), n=31, 28

2 hour (Abn NCS), n=31, 28

2 hour (Abn CS), n=31, 28

3 hour (NL), n=31, 27

3 hour (Abn NCS), n=31, 27

3 hour (Abn CS), n=31, 27

4 hour (NL), n=34, 28

4 hour (Abn NCS), n=34, 28

4 hour (Abn CS), n=34, 28

6 hour (NL), n=31, 27

6 hour (Abn NCS), n=31, 27

6 hour (Abn CS), n=31, 27

8 hour (NL), n=31, 27

8 hour (Abn NCS), n=31, 27

8 hour (Abn CS), n=31, 27

10 hour (NL), n=32, 31

10 hour (Abn NCS), n=32, 31

10 hour (Abn CS), n=32, 31

12 hour (NL), n=31, 29

12 hour (Abn NCS), n=31, 29

12 hour (Abn CS), n=31, 29

24 hour (NL), n=0, 27

24 hour (Abn NCS), n=0, 27

24 hour (Abn CS), n=0, 27

Number of Participants With 12-lead Holter ECG Findings at the Indicated Time Points

Participants received three doses of lapatinib 2000 mg (250 mg x 8 tablets/dose) in the morning and evening on Day 3 and in the morning on Day 4

Pharmacodynamic (PD) Population: all participants from the All Treated Subjects Population (ATS) who completed the ECG acquisition via Holter monitoring of at least one time point on Days 1, 2, 3 and 4.

Number of Participants With the Worst-case Post-Baseline 12-lead Holter ECG Findings With Significant ST, T Wave, and U Wave Abnormalities

Any AE

Any SAEs

Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE)

Albumin (Baseline), n=58

Albumin (Day 5), n=49

Albumin (Day 8-11), n=55

Hemoglobin (Baseline), n=58

Hemoglobin (Day 5), n=48

Hemoglobin (Day 8-11), n=55

Placebo/Lapatinib 2000 mg

ATS Population. Only participants available at the specified time point (represented as n=X in the category title) were analyzed.

Mean Albumin, and Hemoglobin at the Indicated Time Points

ALP (baseline), n=58

ALP (Day 5), n=49

ALP (Day 8-11), n=55

Mean Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), and Aspartate Aminotransferase (AST) at the Indicated Time Points

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Heart Safety Study of Ondansetron in Children Receiving Chemotherapy	NCT01896440	Malignant Child...	Ondansetron	6 Months - 18 Years	University of Oklahoma
Heart Safety Study of Ondansetron in Children Receiving Chemotherapy	NCT01896440	Malignant Child...	Ondansetron	6 Months - 18 Years	University of Oklahoma
A Study in Cancer Patients to Evaluate the Effect of Lapatinib on the QTc Interval	NCT01328054	Cancer	lapatinib placebo matchin...	18 Years -	GlaxoSmithKline
A Study in Cancer Patients to Evaluate the Effect of Lapatinib on the QTc Interval	NCT01328054	Cancer	lapatinib placebo matchin...	18 Years -	GlaxoSmithKline

Spots Global Cancer Trial Database for cardiac repolarization