| Protocol No: | ECCT/22/03/05 | Date of Protocol: | 05-12-2019 |
| Study Title: | CHildren treated with vincristine: A trial regarding Pharmacokinetics, DNA And Toxicity of targeted therapy In pediatric oncology patients. |
| Study Objectives: | 1. To determine the optimal vincristine dose among children receiving chemotherapy at MTRH 2. To evaluate the development and severity of peripheral neuropathy and liver toxicity in paediatric oncology patients receiving optimized vincristine doses in MTRH 3. To study genetic variants that are associated with vincristine metabolism as well as the development and severity of peripheral neuropathy |
| Laymans Summary: | The aim of the study is to optimize treatment and improve survival for children on treatment for cancer by maximizing the use of Vincristine, a drug which is used in treatment of childhood cancer. Baseline assessment to check presence of nerve injury, bilirubin levels and malnutrition will be done before 1st administration of regular Vincristine dose. Blood sample will be obtained by a finger prick for analysis of Vincristine concentration after the dose has been given. The dose of Vincristine will be increased during the next administration when the Vincristine concentration below the level calculated as safe and in the absence of severe vincristine induced peripheral neuropathy or any other severe side effect. A second, third and fourth dose adaptation will be given if the above criteria is met after each dose adaptation. The information from this study might lead to a change in treatment of a wide range of cancers for black African children worldwide, by demonstrating that these children benefit from higher doses of VCR without severely increasing Vincristine induced peripheral neuropathy. |
| Abstract of Study: | Background: Vincristine is among the most widely used and potentially effective chemotherapeutic agents in pediatric oncology patients. However, in black African children it is often sub optimally dosed due to genetic differences in the metabolism of vincristine. This study aims to optimize the dosing regimen of vincristine using therapeutic drug monitoring while carefully monitoring toxicity. Design This will be a prospective cohort study. All children aged 2-14 years diagnosed with cancer and scheduled to receive vincristine can be included. After the administration of vincristine, blood samples will be taken. These will be shipped to and analyzed in the Netherlands to determine the vincristine concentration in each sample. Based on this, a dose advise will be given for subsequent vincristine administrations. This cycle will be repeated in total 3 times. Toxicity will be monitored by determination of the bilirubin, by questionnaires and by physical examination to check for signs of peripheral neuropathy. Results We aim to include 100 patients. The required dose to achieve a therapeutic vincristine level, will be compared to a historic cohort. The results will lead to an alteration in the dosing regimen of vincristine in all pediatric oncology patients in Kenya. |
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Objective
Vincristine is among the most widely used and potentially effective chemotherapeutic agents
in pediatric oncology patients. Vincristine-induced peripheral neuropathy (VIPN), the main
side-effect of vincristine, is very rare in black Kenyan patients compared to non-black
patients. The CHildren treated with vincristine: A trial regarding Pharmacokinetics, DNA,
And Toxicity of targeted therapy In pediatric oncology patients (CHAPATI) feasibility study
was a pharmacokinetically guided dose-escalation study of vincristine in Kenyan children
with cancer. The results of the feasibility study showed that despite having relatively high
early exposure to vincristine, Kenyan children did not develop VIPN or other side-effects. A
purely pharmacokinetic rationale for the lack of VIPN in this population thus seems unlikely.
The maximum tolerated dose (MTD) is clearly not reached in Kenyan children. The objective
of the CHAPATI clinical study is to perform a conventional toxicity guided dose-escalation
study of vincristine.
Design
This is a prospective cohort study consisting of a feasibility study (completed) and a clinical
study. In the feasibility study, 15 black children aged 5-14 years diagnosed with cancer and
scheduled to receive at least two vincristine dosages were included. In the clinical study, we
aim to include 85 children according to the same criteria. The dose-escalation criteria are: no
VIPN, hyperbilirubinemia, severe malnourishment and other grade 3-4 toxicity. A dose-
escalation of +20% will be advised for children who meet the dose-escalation criteria. The
criteria will be evaluated before every on-study vincristine administration and monthly after
each vincristine administration during the study. Maximum two dose-escalations may be
given in one individual patient. PK sampling (plasma and whole blood) will be done after the
dose-escalations.
Results
The goal of the CHAPATI clinical study is to determine the MTD of vincristine in black
Kenyan children with cancer. To avoid excessive toxicity, VIPN and other toxicity will be
evaluated before every on-study vincristine administration and monitored a month after a
dose-escalation and maximum two dose-escalations can be given. The results may lead to an
alteration in the dosing regimen of vincristine in Kenyan children with cancer. We aim to
improve therapeutic efficacy and therefore treatment outcome in this patient group.
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