Studying the Effect of Levocarnitine in Protecting the Liver From Chemotherapy for Leukemia or Lymphoma

Study Overview
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Brief Summary
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This phase III trial compares the effect of adding levocarnitine to standard chemotherapy vs. standard chemotherapy alone in protecting the liver in patients with leukemia or lymphoma. Asparaginase is part of the standard of care chemotherapy for the treatment of acute lymphoblastic leukemia (ALL), lymphoblastic lymphoma (LL), and mixed phenotype acute leukemia (MPAL). However, in adolescent and young adults (AYA) ages 15-39 years, liver toxicity from asparaginase is common and often prevents delivery of planned chemotherapy, thereby potentially compromising outcomes. Some groups of people may also be at higher risk for liver damage due to the presence of fat in the liver even before starting chemotherapy. Patients who are of Japanese descent, Native Hawaiians, or are Hispanic or Latinx may be at greater risk for liver damage from chemotherapy for this reason. Carnitine is a naturally occurring nutrient that is part of a typical diet and is also made by the body. Carnitine is necessary for metabolism and whose deficiency or absence is associated with liver and other organ damage. Levocarnitine is a drug used to provide extra carnitine. Laboratory and real-world usage of the dietary supplement levocarnitine suggests its potential to prevent or reduce liver toxicity from asparaginase, The overall goal of this study is to determine whether adding levocarnitine to standard of care chemotherapy treatment will reduce the chances of developing severe liver damage from asparaginase chemotherapy in ALL, LL and/or MPAL patients.

Detailed Description
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PRIMARY OBJECTIVE: I. To determine in a randomized manner whether the addition of levocarnitine prophylaxis to asparaginase-containing regimens will decrease the incidence of conjugated hyperbilirubinemia (> 3 mg/dL) during ALL induction therapy for adolescents and young adults (adolescents and young adults [AYAs], age 15-39 years). SECONDARY OBJECTIVES: I. To examine the impact of levocarnitine prophylaxis on differences in the incidence of grade >= 3 alanine aminotransferase (ALT) or aspartate aminotransferase (AST) elevations during ALL Induction. II. To compare rates of minimal residual disease (MRD) positivity at end of Induction and describe MRD+ by end of consolidation (EOC) in those receiving ALL induction chemotherapy with and without levocarnitine. EXPLORATORY OBJECTIVES: I. To compare rates of toxicity and associated dose reductions for chemotherapy administered with and without concomitant levocarnitine supplementation. II. To compare across study arms the peak levels during Induction of conjugated and total bilirubin, AST, ALT, and duration of conjugated hyperbilirubinemia from onset > 3 mg/dL to =< 3 mg/dL. III. To describe the efficacy of levocarnitine prophylaxis to reduce the incidence and/or severity of early patient-reported chemotherapy-induced peripheral neuropathy. IV. To describe the three-year event-free and overall survival (EFS/OS) in those treated with and without levocarnitine prophylaxis. V. To examine the association of age with asparaginase activity and asparaginase-associated hepatotoxicity during induction. VI. To examine the association of body-mass-index (BMI) percentile (or absolute BMI for young adults) with asparaginase activity and asparaginase-associated hepatotoxicity during induction. VII. To describe adherence by self-report and pill-count to oral levocarnitine in patients randomized to the intervention arm. VIII. To examine the association of plasma levels of carnitine and related markers with the efficacy of levocarnitine supplementation. IX. To determine the impact of inherited genetic variation on hepatoxicity and levocarnitine efficacy. OUTLINE: Patients are randomized to 1 of 2 arms (arm A vs. B). ARM A: Patients receive levocarnitine orally (PO) or intravenously (IV) prior to standard of care induction chemotherapy with pegaspargase or calaspargase pegol on study. Patients may also undergo blood sample collection during screening and on study. ARM B: Patients receive standard of care induction chemotherapy with pegaspargase or calaspargase pegol on study. Patients may also undergo blood sample collection during screening and on study. ARM C (RESCUE): Patients in Arms A and B who develop conjugated hyperbilirubinemia > 3 mg/dL during induction may receive levocarnitine rescue PO or IV supplementation until resolution of conjugated hyperbilirubinemia =< 3 mg/dL (or start of consolidation or the next treatment phase, whichever occurs first).

Official Title
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A Randomized Trial of Levocarnitine Prophylaxis to Prevent Asparaginase-Associated Hepatotoxicity in Adolescents and Young Adults Receiving Acute Lymphoblastic Leukemia Therapy

Conditions
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B Acute Lymphoblastic Leukemia, B Acute Lymphoblastic Leukemia With t(9;22)(q34.1;q11.2); BCR-ABL1, B Acute Lymphoblastic Leukemia, BCR-ABL1-Like, Lymphoblastic Lymphoma, Mixed Phenotype Acute Leukemia, T Acute Lymphoblastic Leukemia

Intervention / Treatment
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* Procedure: Biospecimen Collection
* Drug: Calaspargase Pegol
* Dietary Supplement: Levocarnitine
* Drug: Pegaspargase
* Other: Quality-of-Life Assessment


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: >= 15 and < 40 years at time of diagnosis Newly diagnosed B-ALL, T-ALL, lymphoblastic lymphoma (LLy), or mixed-phenotype acute leukemia/lymphoma (MPAL) Note: Philadelphia chromosome (PH)+ and PH-like acute leukemia are eligible (use of tyrosine kinase inhibitors [TKI] or CRLF2- targeted concomitant medication must be documented, if used) Conjugated bilirubin =< 1.5 x upper limit of normal (ULN) for age, regardless of baseline bilirubin (within 7 days prior to enrollment), and Serum glutamate pyruvate transaminase (SGPT) (ALT) =< 225 U/L (=< 5x ULN) (within 7 days prior to enrollment), and Note: For the purpose of this study, the ULN for SGPT (ALT) has been set to the value of 45 U/L and serum glutamic oxaloacetic transaminase (SGOT) (AST) to 50 U/L regardless of baseline SGOT (AST) =< 250 U/L (=< 5x ULN) (within 7 days prior to enrollment) Note: For the purpose of this study, the ULN for SGPT (ALT) has been set to the value of 45 U/L and SGOT (AST) to 50 U/L regardless of baseline Berlin-Frankfurt-Munich (BFM), Children's Oncology Group (COG), or C10403-based Induction regimen and must be inclusive of >= 1 dose of pegaspargase or calaspargase pegol, and First dose of asparaginase must be planned within the first week of induction therapy, and Dose of pegaspargase or calaspargase pegol must be >= 1,000 IU/ m^2 (dose-capping permitted per primary regimen) Note: Co-enrollment on a therapeutic consortia trial is not required All patients and/or their parents or legal guardians must sign a written informed consent All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met Exclusion Criteria: Down syndrome Known inherited or autoimmune liver disease impacting conjugated bilirubin (e.g., Alagille syndrome, primary sclerosing cholangitis, other) Known biopsy (or imaging) proven severe liver fibrosis (Batts-Ludwig >= stage 3) Patients who received chemotherapy or treatment for a prior malignancy are not eligible The following are permitted: steroid prophase, hydroxyurea, or other cytoreduction prior to initiation of Induction chemotherapy (must be documented) and chemotherapy for current diagnosis (i.e. initiation of Induction therapy within enrollment window). Chemotherapy prior to enrollment for treatment of a non-malignancy (e.g., steroid or methotrexate for autoimmune disease) is also permitted and must be documented Female patients who are pregnant since fetal toxicities and teratogenic effects in humans are unknown for study drug. A pregnancy test is required for female patients of childbearing potential Lactating females who plan to breastfeed their infants Sexually active patients of reproductive potential who have not agreed to use an effective contraceptive method for the duration of their study participation

Ages Eligible for Study
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Minimum Age: 15 Years
Maximum Age: 40 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A (levocarnitine, standard of care chemotherapy)<br>Patients receive levocarnitine PO or IV prior to standard of care induction chemotherapy with pegaspargase or calaspargase pegol on study. Patients may also undergo blood sample collection during screening and on study. | Procedure: Biospecimen Collection<br>* Undergo blood sample collection<br>* Other names: Specimen Collection;Drug: Calaspargase Pegol<br>* Given standard of care calaspargase pegol<br>* Other names: Succinimidyl Carbonate Monomethoxypolyethylene Glycol E. coli L-Asparaginase;Dietary Supplement: Levocarnitine<br>* Given PO or IV<br>* Other names: L-carnitine;Drug: Pegaspargase<br>* Given standard of care pegaspargase<br>* Other names: Polyethylene Glycol-L-Asparaginase;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;|
| Active Comparator: Arm B (standard of care chemotherapy)<br>Patients receive standard of care induction chemotherapy with pegaspargase or calaspargase pegol on study. Patients may also undergo blood sample collection during screening and on study. | Procedure: Biospecimen Collection<br>* Undergo blood sample collection<br>* Other names: Specimen Collection;Drug: Calaspargase Pegol<br>* Given standard of care calaspargase pegol<br>* Other names: Succinimidyl Carbonate Monomethoxypolyethylene Glycol E. coli L-Asparaginase;Drug: Pegaspargase<br>* Given standard of care pegaspargase<br>* Other names: Polyethylene Glycol-L-Asparaginase;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;|
| Experimental: Arm C (rescue levocarnitine)<br>Patients in Arms A and B who develop conjugated hyperbilirubinemia > 3 mg/dL during induction may receive levocarnitine rescue PO or IV supplementation until resolution of conjugated hyperbilirubinemia =< 3 mg/dL (or start of consolidation or the next treatment phase, whichever occurs first). | Dietary Supplement: Levocarnitine<br>* Given PO or IV<br>* Other names: L-carnitine;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of conjugated hyperbilirubinemia >3 mg/dL during induction therapy | For patients assigned to arms A and B, the investigators will separately estimate the proportion of patients who experience conjugated hyperbilirubinemia > 3mg/dL during induction chemotherapy by arm along with corresponding 95% confidence intervals. | During induction therapy (up-to 35-days after initiating induction chemotherapy) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of grade >= 3 alanine aminotransferase (ALT) or aspartate aminotransferase (AST) elevations during induction therapy | For patients assigned to arms A and B, the investigators will separately estimate the proportion of patients who experience grade >= 3 alanine aminotransferase (ALT) or aspartate aminotransferase (AST) elevations during induction chemotherapy by arm along with corresponding 95% confidence intervals. | During induction therapy (up-to 35-days after initiating induction chemotherapy) | 
| Incidence of minimal residual disease (MRD) positivity (MRD >= 0.01%) | For patients assigned to arms A and B, the proportion having MRD positivity at the end of induction chemotherapy will be estimated separately by arm along with corresponding 95% confidence intervals. For patients assigned to arms A and B, the proportion having MRD positivity at the end of consolidation chemotherapy will be estimated separately by arm along with corresponding 95% confidence intervals (only patients with end of consolidation MRD evaluated and who did not get placed on the rescue arm C will be included). | At end of induction chemotherapy (up-to 35-days after initiating induction chemotherapy), and at end of consolidation chemotherapy (up-to day 56 days after initiating induction chemotherapy) |