Vincristine PK and PD in the AYA Population Compared to Younger Children
Information source: Children's Hospital Los Angeles
ClinicalTrials.gov processed this data on August 23, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Leukemia, Acute Lymphoblastic; Leukemia
Phase: N/A
Status: Active, not recruiting
Sponsored by: Children's Hospital Los Angeles Official(s) and/or principal investigator(s): Lakshmi Damerla, Study Director, Affiliation: Children's Hospital Los Angeles
Summary
The trial is to determine if a difference exists in the way that adolescents and young
adults metabolize the chemotherapy agent vincristine compared to younger children.
Clinical Details
Official title: The Pharmacokinetics and Pharmacodynamics of Vincristine in the Adolescent and Young Adult Population Compared to Younger Children
Study design: Observational Model: Cohort, Time Perspective: Prospective
Primary outcome: Vincristine (concentration of vincristine)
Secondary outcome: Calpain levelCytochrome P450 3A5 genotype Development of Vincristine Induced Neuropathy
Detailed description:
The purpose of the study is to refine the PK model for planning a future definitive study.
This is a pilot study to obtain preliminary data on the pharmacokinetics of VCR and the way
it differs in the AYA population compared to the younger children as defined by Tanner
staging. Additionally, we want to determine if Calpain levels correlate with vincristine and
its PK and to determine if it can be used as biomarker for VRNT.
Specific Aim 1: Develop a non-parametric population model of vincristine and M1 PK in
children and adolescents.
Hypothesis: The PK of vincristine and its metabolite M1 will differ between young children
and AYA as defined by Tanner stage
Specific Aim 2: Measure repeated serum calpain with initiation of vincristine and again
after four weeks of therapy.
Hypothesis: Compared to baseline, serum calpain will increase after administration of
vincristine.
For the first time, patients will be classified based on their physiologic maturity—rather
than age—to determine whether having a more adult phenotype is associated with prolonged
vincristine exposure. This will increase our likelihood of detecting a
developmentally-driven difference in vincristine metabolism and, if successful, provide
evidence that Tanner staging is a more reliable method for classifying adolescents for
purposes of chemotherapy dosing. Further, we will not only characterize vincristine PK
differences between the two groups, but will for the first time examine differences in the
PK of M1. We are analyzing calpain levels as a separate entity from Tanner staging. We are
trying to establish if there is an association between calpain and vincristine
administration, as well as vincristine induced peripheral neuropathy. However, in
evaluating the association between vincristine dose, PK and calpain levels, we will be
adjusting for age and Tanner stage in the analysis.
To account for enzyme polymorphism in the metabolism of vincristine, we will analyze each
patient for CYP3A5 genotype, which has been associated with increase in clearance of
vincristine and less peripheral neuropathy and decrease severity of vincristine induced
peripheral neuropathy. Additionally, we will determine the vincristine's PK which will allow
us to probe the impact of polymorphism with regards to VCR disposition.
For all of the following aims, we will enroll a total of 30 patients with a unified
diagnosis of acute lymphoblastic leukemia (ALL),6 months to 21 in Induction phase or in
Maintenance phase of therapy. Patients will be stratified by phase of treatment, and they
will be classified into Tanner stage ≤ 2 or ≥ 4, based on physical examination. We plan to
have 15 patients in Tanner staging ≤ 2 and 15 patients in Tanner staging ≥ 45. Each patient
will receive vincristine weekly x 4 (Induction) or monthly (Maintenance), at a standard dose
specified by the treatment protocol. Since PK measurements will be obtained around a single
VCR dose; it is appropriate to include patients with ALL from two phases of treatment. The
study will be conducted at a single institution, Children's Hospital Los Angeles (CHLA).
From the newly diagnosed patients in Induction phase, we will collect optimally timed blood
samples prior to and 10 minutes, 30 minutes, 1 hour, 12 hours and 24 hours following the
first dose of vincristine. We will also measure serum calpain, a candidate biomarker for
nerve injury, before and after the first dose of vincristine, and again after the 4th weekly
dose. For the ALL patients in the Maintenance phase, we will collect optimally timed blood
samples prior to and 10 minutes, 30 minutes, 1 hours and 24 hours following the dose of
vincristine. In ALL patients in Maintenance, a 12 hour blood sample will not be feasible
since these patients are treated in the outpatient setting. We will also measure serum
calpain levels prior to vincristine dose, 24 hours after and 4 weeks after the measured
vincristine level. The study period for ALL patients in Maintenance phase will be completed
4 weeks after initial measured VCR PK level.
Eligibility
Minimum age: 1 Year.
Maximum age: 24 Years.
Gender(s): Both.
Criteria:
Inclusion Criteria:
- Patients ages 1-24 years of age with Acute Lymphoblastic Leukemia
- Patient diagnosed with Acute Lymphoblastic Leukemia (ALL) in Induction phase of
therapy
- Patient diagnosed with Acute Lymphoblastic Leukemia (ALL) in first remission in
Maintenance phase of therapy Treatment plan for induction therapy includes
vincristine given at weekly intervals.
- Treatment plan for Maintenance therapy includes vincristine given at monthly
intervals.
Exclusion Criteria:
- Patients without a central line in induction phase of therapy
Locations and Contacts
Children's Hospital Los Angeles, Los Angeles, California 90027, United States
Additional Information
Starting date: September 2014
Last updated: June 18, 2015
|