Use of Levocarnitine to Reduce Asparaginase Hepatotoxicity in Patients With Acute Lymphoblastic Leukemia

Study Overview
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Brief Summary
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Acute lymphoblastic leukemia (ALL) is the most common cancer seen in pediatric oncology. The necessary chemotherapy for pediatric and adolescent and young adult (AYA) patients with ALL includes steroids, anthracyclines, asparaginase, and vincristine. One of the most hepatotoxic chemotherapy agents is asparaginase, with treatment-associated hepatotoxicity (TAH) observed in up to 60% of patients. The frequency of TAH is increased in overweight or obese patients of Latino heritage. Carnitine is a naturally-derived compound that is produced in the liver and kidneys; it is found in certain foods, such as meat, poultry, fish, and some dairy products. Endogenous carnitine transports long-chain fatty acids into the mitochondria, where they are oxidized to produce energy, and acts as scavengers of oxygen free radicals. Thus, carnitine can reduce oxidative stress and modulate inflammatory response. Levocarnitine is a supplement form of carnitine used typically in the care and management of patients with carnitine deficiency. Pediatric and AYAs with ALL will be given oral levocarnitine as a supplement during their initial phases of treatment, when the most hepatotoxic agents are administered, to determine if the incidence of liver toxicity can be reduced or eliminated.

Detailed Description
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Primary Aims Prospectively evaluate whether the prophylactic use of levocarnitine during Induction and Consolidation (phases with asparaginase therapy) in ALL patients receiving treatment according to a Children's Oncology Group (COG) treatment protocol reduces hepatotoxicity. Demonstrate an association between ethnicity and liver function test abnormalities in children and AYAs with ALL. Specifically, that Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 grade ≥ 3 elevated liver function tests is more prevalent in self-identified Latinos as compared to other ethnicities in a retrospective control group. Secondary Aims Determine whether obesity or overweight status, as measured by body mass index, at diagnosis increases the risk of hepatic dysfunction. Quantify the disease response, based on the end of Induction minimal residual disease (MRD) in the bone marrow of patients receiving levocarnitine, compared to historical controls to determine that levocarnitine does not have a negative impact on MRD. Assess incidence of nonalcoholic fatty liver disease (NAFLD), via non-invasive ultrasound elastography, in pediatric and AYA patients newly diagnosed with ALL. Assess incidence of other known toxicities of asparaginase treatment, including hyper/hypoglycemia, hypertriglyceridemia, pancreatitis, and thrombosis that are CTCAE version 5.0 grade ≥ 3 with onset ≤ 30 days (or next dose if sooner) of asparaginase. Study Design: The proposal is a non-randomized case-control pilot study that will use retrospective case-control data as comparison (i.e., control group). Participants: A sample of 20 pediatric and AYA patients, ages 5 to < 30 years, newly diagnosed with ALL will be enrolled to study. Participants who withdraw or who are withdrawn from study, who have taken less than 50% of planned levocarnitine supplementation, and who did not have a post-levocarnitine supplementation laboratory testing will be replaced. An additional 20 retrospective cases -- matched by age at diagnosis, biological sex, and risk classification at initial diagnosis -- will be included to provide control data. Study Intervention: Levocarnitine will be administered by mouth twice daily during Induction and Consolidation phases of treatment for patients with ALL who are treated as per a COG treatment plan (either on study or treated according to the protocol). The duration of intervention is expected to be approximately three months.

Official Title
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Use of Levocarnitine to Reduce Asparaginase Hepatotoxicity in Patients With Acute Lymphoblastic Leukemia

Conditions
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Acute Lymphoblastic Leukemia, Hepatotoxicity

Intervention / Treatment
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* Drug: Levocarnitine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients aged 5 to < 30 years Newly diagnosed with ALL designated as NCI high-risk (HR) ALL Treatment for ALL to be according to a Children's Oncology Group (COG) treatment protocol (on study or according to study) Ability to take oral medications and willing to adhere to the levocarnitine regimen Exclusion Criteria: Known allergic reaction to levocarnitine or its components Presence of severely compromised renal function or end-stage renal disease Pregnancy or lactation Warfarin therapy History of seizures prior to ALL diagnosis Known inborn error of metabolism

Ages Eligible for Study
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Minimum Age: 5 Years
Maximum Age: 29 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: Supportive Care
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment Arm (single arm)<br> | Drug: Levocarnitine<br>* Adults, or patients ≥ 50 kg: 990 mg PO (by mouth) bis in die (BID, twice a day) Children, or patients < 50 kg: 50 mg/kg/day PO divided BID (maximum daily dose of 2,000 mg)<br>* Other names: Carnitor®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Primary Outcome #1 | Calculate proportion of patients who experience hepatotoxicity, as measured by the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 grade ≥ 3 elevated alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total and direct bilirubin. | 1.5 years | 
| Primary Outcome #2 | Calculate prevalence of hepatotoxicity in patients who self-identify as Latino or non-Latino, using laboratory assessments and self-reported measures of ethnicity and/or race. | 1.5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Secondary Outcome #1 | Calculate body mass index (BMI), from recorded height and weight obtained at time of initial diagnosis and determine if there is increased risk of hepatotoxicity in patients who are overweight or obese at diagnosis as determined by Centers for Disease Control and Prevention (CDC) clinical growth charts for study participants 5 to < 20 years of age and by a BMI of ≥ 25.0 for study participants 20 to < 30 years of age. | 1.5 years | 
| Secondary Outcome #2 | Quantify disease response, using end of Induction minimal residual disease (MRD) results, where an MRD value < 0.01 is considered negative. | 1.5 years | 
| Secondary Outcome #3 | Calculate incidence of nonalcoholic fatty liver disease (NAFLD), using ultrasound elastography, in pediatric and AYA patients newly diagnosed with ALL. | 1.5 years | 
| Secondary Outcome #4 | Calculate proportion of patients who experience other known toxicities of asparaginase treatment, as measured by CTCAE version 5.0 grade ≥ 3 hyper/hypoglycemia, hypertriglyceridemia, pancreatitis, and thrombosis. | 1.5 years |