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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT05501899
Recruitment Status : Not yet recruiting
First Posted : August 16, 2022
Last Update Posted : August 16, 2022
Sponsor:
Collaborator:
University of California, Irvine
Information provided by (Responsible Party):
Children's Hospital of Orange County

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Acute Lymphoblastic Leukemia Hepatotoxicity Drug: Levocarnitine Early Phase 1

Detailed Description:

Primary Aims

  1. 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.
  2. 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

  1. Determine whether obesity or overweight status, as measured by body mass index, at diagnosis increases the risk of hepatic dysfunction.
  2. 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.
  3. Assess incidence of nonalcoholic fatty liver disease (NAFLD), via non-invasive ultrasound elastography, in pediatric and AYA patients newly diagnosed with ALL.
  4. 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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Supportive Care
Official Title: Use of Levocarnitine to Reduce Asparaginase Hepatotoxicity in Patients With Acute Lymphoblastic Leukemia
Estimated Study Start Date : September 1, 2022
Estimated Primary Completion Date : December 31, 2023
Estimated Study Completion Date : December 31, 2023


Arm Intervention/treatment
Experimental: Treatment Arm (single arm) Drug: Levocarnitine
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)
Other Name: Carnitor®




Primary Outcome Measures :
  1. Primary Outcome #1 [ Time Frame: 1.5 years ]
    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.

  2. Primary Outcome #2 [ Time Frame: 1.5 years ]
    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.


Secondary Outcome Measures :
  1. Secondary Outcome #1 [ Time Frame: 1.5 years ]
    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.

  2. Secondary Outcome #2 [ Time Frame: 1.5 years ]
    Quantify disease response, using end of Induction minimal residual disease (MRD) results, where an MRD value < 0.01 is considered "negative."

  3. Secondary Outcome #3 [ Time Frame: 1.5 years ]
    Calculate incidence of nonalcoholic fatty liver disease (NAFLD), using ultrasound elastography, in pediatric and AYA patients newly diagnosed with ALL.

  4. Secondary Outcome #4 [ Time Frame: 1.5 years ]
    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.



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Ages Eligible for Study:   5 Years to 29 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05501899


Contacts
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Contact: Van T. Huynh, M.D. (714) 509-4348 vahuynh@choc.org

Locations
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United States, California
Chao Family Comprehensive Cancer Center, University of California, Irvine
Orange, California, United States, 92868
Contact: Deepa Jeyakumar, MD    714-456-5153    djeyakum@uci.edu   
Children's Hospital of Orange County
Orange, California, United States, 92868
Sponsors and Collaborators
Children's Hospital of Orange County
University of California, Irvine
Additional Information:
Publications:

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Responsible Party: Children's Hospital of Orange County
ClinicalTrials.gov Identifier: NCT05501899    
Other Study ID Numbers: 2110145
First Posted: August 16, 2022    Key Record Dates
Last Update Posted: August 16, 2022
Last Verified: August 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Additional relevant MeSH terms:
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Leukemia
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Lymphoid
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases