Vincristine Pharmacokinetics in Infants

Study Overview
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Brief Summary
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This pilot trial compares drug exposure levels using a new method for dosing vincristine in infants and young children compared to the standard dosing method based on body surface area (BSA) in older children. Vincristine is an anticancer drug used to a variety of childhood cancers. The doses anticancer drugs in children must be adjusted based on the size of the child because children vary significantly in size (height, weight, and BSA) and ability to metabolize drugs from infancy to adolescence. The dose of most anticancer drugs is adjusted to BSA, which is calculated from a patient's weight and height. However, infants and young children have more severe side effects if the BSA is used to calculate their dose, so new dosing models have to be made to safely give anticancer drugs to the youngest patients. This new method uses a BSA-banded approach to determine the dose. Collecting blood samples before and after a dose of the drug will help researchers determine whether this new vincristine dosing method results in equivalent drug levels in the blood over time in infants and young children compared to older children.

Detailed Description
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PRIMARY OBJECTIVE: I. To validate body surface area (BSA)-banded infant dosing tables by comparing vinCRIStine drug exposure, defined as the area under the concentration-time curve for the elimination phase (AUCelim), in infants and young children dosed according to the table to older children dosed according to BSA. SECONDARY OBJECTIVE: I. To estimate intra- and inter-age group variability (CV) using non-compartmental analysis (NCA) and population pharmacokinetic (PK) methods. EXPLORATORY OBJECTIVES: I. To correlate higher AUCelim with the presence of functionally impaired single nucleotide polymorphisms (SNP) of CYP3A4 and CYP3A5. II. To assess vinCRIStine dose modifications in infants receiving weekly vinCRIStine dosed according to the BSA-banded infant dosing tables. OUTLINE: Patients receive vincristine intravenously (IV) per standard of care. Patients undergo collection of blood samples at baseline (before first vincristine dose), and 2, 6-8, and 18-24 hours after a dose of vincristine. Patients may also undergo collection of blood samples with a second vincristine dose at the same time points. Patients are followed for dose modifications for a period of 42 days (when receiving weekly dosing of vincristine).

Official Title
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A Pharmacokinetic Study of VinCRIStine in Infants Dosed According to BSA-Banded Infant Dosing Tables and Older Children Dosed by Traditional BSA Methods

Conditions
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Hematopoietic and Lymphoid Cell Neoplasm, Malignant Solid Neoplasm

Intervention / Treatment
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* Procedure: Biospecimen Collection
* Drug: Vincristine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must be =< 12 years of age at the time of study enrollment. Patients will be stratified into 4 age groups: 0 to 6 months 6 months and 1 day to 12 months 12 months and 1 day to 36 months 36 months and 1 day to 12 years Newly diagnosed and relapsed cancer diagnosis that is being treated with vinCRIStine at the 1.5 mg/m^2 dose level Any disease status Patients must have a Lansky performance status of 50 or higher Patients must be receiving a treatment regimen that includes 1.5 mg/m^2 vinCRIStine (maximum dose 2 mg) Patients with a BSA < 0.6 m^2 must be dosed according to the Children's Oncology Group (COG) BSA-banded infant dosing table for the 1.5mg/m2 dose level for vinCRIStine Note: Patients can be studied after any dose of vinCRIStine Patients who are NOT enrolled on a COG clinical trial and who have a BSA < 0.6 m^2 and who are being dosed according to another infant dosing method (e.g., the 30-Rule) can receive a dose of vinCRIStine from the infant dosing table for the pharmacokinetic study. These patients will NOT be part of the Dose Modification Assessment Patients with a seizure disorder may be enrolled if on allowable anticonvulsants and well controlled as evidenced by no increase in seizure frequency in the prior 7 days Nervous system toxicities (Common Terminology Criteria for Adverse Events [CTCAE]) version (v)5 resulting from prior therapy must be grade =< 2 Central venous access device in place (e.g., percutaneous indwelling central catheter [PICC], port, Broviac) or scheduled to be placed prior to the dose of vinCRIStine and that can be used for pharmacokinetic (PK) sampling VinCRIStine may be given as an outpatient, as long as all sample time points can be collected, which will require return for hour 24 sampling Exclusion Criteria: Azoles antifungals and macrolide antibiotics: Patients who are currently receiving an azole or macrolide (e.g., fluconazole, isavuconazole, itraconazole, posaconazole, voriconazole, ketoconazole, eryromycin, clarithromycin, azithromycin, roxithromycin, or telithromycin) are not eligible CYP3A4/5 inducers/inhibitors: Patients receiving any medications or substances that are considered moderate or strong inhibitors or inducers of CYP3A4/5 are not eligible. Moderate or strong inducers or inhibitors of CYP3A4/5 should be avoided from 14 days prior to enrollment to the end of the study. Note the following are allowed: Dexamethasone for CNS tumors or metastases, on a stable dose Aprepitant for management of nausea and vomiting Anticonvulsants: Patients receiving moderate or strong CYP3A4/5 enzyme inducing anticonvulsants are not eligible. Patients with Charcot-Marie-Tooth disease A baseline neurological disorder with manifestations that overlap with vinCRIStine-associated neurotoxicities Patients being treated on a Children Oncology Group (COG) clinical trial, that does not use the infant dosing tables for vinCRIStine are not eligible for this study. Patients receiving a modified dose (< 1.5 mg/m^2) of vinCRIStine due to prior toxicity Patients who in the opinion of the investigator may not be able to comply with the sampling requirements of the study

Ages Eligible for Study
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Maximum 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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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Treatment (vincristine, biospecimen collection)<br>Patients receive vincristine IV per standard of care. Patients undergo collection of blood samples at baseline (before first vincristine dose), and 2, 6-8, and 18-24 hours after a dose of vincristine. Patients may also undergo collection of blood samples with a second vincristine dose at the same time points. | Procedure: Biospecimen Collection<br>* Undergo collection of blood samples<br>* Other names: Specimen Collection;Drug: Vincristine<br>* Given IV<br>* Other names: Vincrystine;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in area under the concentration time curve for the elimination phase by age in months | Estimate (95% CI) of the change in area under the concentration time curve for the elimination phase by age of patient (in months). | Up to 24 hours post vincristine dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determine intra- and inter-age group variability (CV) | Estimate using non-compartmental analysis (NCA) and population pharmacokinetic (PK) methods. | Up to 2 years |