Levocarnitine To Protect the Liver From Chemotherapy for Leukemia or Lymphoma

Sponsor

Children's Oncology Group (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05602194

Collaborator

(none)

440

Enrollment

Arms

45.3

Anticipated Duration (Months)

Study Details

Study Description

Brief Summary

This phase III trial compares the effect of adding levocarnitine to chemotherapy versus chemotherapy alone in protecting the liver in patients with leukemia and lymphoma. Standard of care chemotherapy treatment for leukemia and lymphoma includes a type of chemotherapy named asparaginase, given either as the drug pegaspargase, or a similar drug, calaspargase pegol. This type of chemotherapy can cause severe liver damage. Levocarnitine is a drug used to provide extra carnitine, a naturally occurring nutrient that is part of a typical diet and is also made by the body. Carnitine is important to keep the liver healthy and may be able to prevent damage to the liver from chemotherapy and other drugs. Taking levocarnitine may reduce the rate of severe liver damage caused by asparaginase chemotherapy in patients with leukemia and lymphoma.

Condition or Disease	Intervention/Treatment	Phase
B Acute Lymphoblastic Leukemia B Acute Lymphoblastic Leukemia With t(9;22)(q34.1;q11.2); BCR-ABL1 Lymphoblastic Lymphoma Mixed Phenotype Acute Leukemia Ph-Like Acute Lymphoblastic Leukemia T Acute Lymphoblastic Leukemia	Procedure: Biospecimen Collection Drug: Calaspargase Pegol-mknl Dietary Supplement: Levocarnitine Drug: Pegaspargase Other: Quality-of-Life Assessment	Phase 3

Detailed Description

PRIMARY OBJECTIVE:

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 acute lymphoblastic leukemia (ALL) induction therapy for adolescents and young adults (adolescents and young adults [AYAs], age 15-39 years).

SECONDARY OBJECTIVES:

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.
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:

To compare rates of toxicity and associated dose reductions for chemotherapy administered with and without concomitant levocarnitine supplementation.
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.
To describe the efficacy of levocarnitine prophylaxis to reduce the incidence and/or severity of early patient-reported chemotherapy-induced peripheral neuropathy.
To describe the three-year event-free and overall survival (EFS/OS) in those treated with and without levocarnitine prophylaxis.
To examine the association of age with asparaginase activity and asparaginase-associated hepatotoxicity during induction.
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.
To describe adherence by self-report and pill-count to oral levocarnitine in patients randomized to the intervention arm.
To examine the association of plasma levels of carnitine and related markers with the efficacy of levocarnitine supplementation.
To determine the impact of inherited genetic variation on hepatoxicity and levocarnitine efficacy.

OUTLINE: Patients are randomized to 1 of 2 arms.

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).

Study Design

Study Type:

Interventional

Anticipated Enrollment :

440 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Supportive Care

Official Title:

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

Anticipated Study Start Date :

Mar 22, 2023

Anticipated Primary Completion Date :

Dec 30, 2026

Anticipated Study Completion Date :

Dec 30, 2026

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm A (levocarnitine, standard of care chemotherapy) 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 Undergo blood sample collection Other Names: Biological Sample Collection Biospecimen Collected Specimen Collection Drug: Calaspargase Pegol-mknl Given standard of care calaspargase pegol Other Names: Asparaginase (Escherichia coli Isoenzyme II), Conjugate with alpha-(((2,5-Dioxo-1-pyrrolidinyl)oxy)carbonyl)-omega-methoxypoly(oxy-1,2-ethanediyl) Asparlas Calaspargase Pegol EZN-2285 SC-PEG E. Coli L-Asparaginase Succinimidyl Carbonate Monomethoxypolyethylene Glycol E. coli L-Asparaginase Dietary Supplement: Levocarnitine Given PO or IV Other Names: Carnitor L-carnitine Drug: Pegaspargase Given standard of care pegaspargase Other Names: L-Asparaginase with Polyethylene Glycol Oncaspar Oncaspar-IV PEG-Asparaginase PEG-L-Asparaginase PEG-L-Asparaginase (Enzon - Kyowa Hakko) PEGLA Polyethylene Glycol L-Asparaginase Polyethylene Glycol-L-Asparaginase Other: Quality-of-Life Assessment Ancillary studies Other Names: Quality of Life Assessment
Active Comparator: Arm B (standard of care chemotherapy) 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 Undergo blood sample collection Other Names: Biological Sample Collection Biospecimen Collected Specimen Collection Drug: Calaspargase Pegol-mknl Given standard of care calaspargase pegol Other Names: Asparaginase (Escherichia coli Isoenzyme II), Conjugate with alpha-(((2,5-Dioxo-1-pyrrolidinyl)oxy)carbonyl)-omega-methoxypoly(oxy-1,2-ethanediyl) Asparlas Calaspargase Pegol EZN-2285 SC-PEG E. Coli L-Asparaginase Succinimidyl Carbonate Monomethoxypolyethylene Glycol E. coli L-Asparaginase Drug: Pegaspargase Given standard of care pegaspargase Other Names: L-Asparaginase with Polyethylene Glycol Oncaspar Oncaspar-IV PEG-Asparaginase PEG-L-Asparaginase PEG-L-Asparaginase (Enzon - Kyowa Hakko) PEGLA Polyethylene Glycol L-Asparaginase Polyethylene Glycol-L-Asparaginase Other: Quality-of-Life Assessment Ancillary studies Other Names: Quality of Life Assessment
Experimental: Arm C (rescue levocarnitine) 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 Given PO or IV Other Names: Carnitor L-carnitine

Arm

Intervention/Treatment

Experimental: Arm A (levocarnitine, standard of care chemotherapy)

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

Undergo blood sample collection

Other Names:

Biological Sample Collection

Biospecimen Collected

Specimen Collection

Drug: Calaspargase Pegol-mknl

Given standard of care calaspargase pegol

Other Names:

Asparaginase (Escherichia coli Isoenzyme II), Conjugate with alpha-(((2,5-Dioxo-1-pyrrolidinyl)oxy)carbonyl)-omega-methoxypoly(oxy-1,2-ethanediyl)

Asparlas

Calaspargase Pegol

EZN-2285

SC-PEG E. Coli L-Asparaginase

Succinimidyl Carbonate Monomethoxypolyethylene Glycol E. coli L-Asparaginase

Dietary Supplement: Levocarnitine

Given PO or IV

Other Names:

Carnitor

L-carnitine

Drug: Pegaspargase

Given standard of care pegaspargase

Other Names:

L-Asparaginase with Polyethylene Glycol

Oncaspar

Oncaspar-IV

PEG-Asparaginase

PEG-L-Asparaginase

PEG-L-Asparaginase (Enzon - Kyowa Hakko)

PEGLA

Polyethylene Glycol L-Asparaginase

Polyethylene Glycol-L-Asparaginase

Other: Quality-of-Life Assessment

Ancillary studies

Other Names:

Quality of Life Assessment

Active Comparator: Arm B (standard of care chemotherapy)

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

Undergo blood sample collection

Other Names:

Biological Sample Collection

Biospecimen Collected

Specimen Collection

Drug: Calaspargase Pegol-mknl

Given standard of care calaspargase pegol

Other Names:

Asparaginase (Escherichia coli Isoenzyme II), Conjugate with alpha-(((2,5-Dioxo-1-pyrrolidinyl)oxy)carbonyl)-omega-methoxypoly(oxy-1,2-ethanediyl)

Asparlas

Calaspargase Pegol

EZN-2285

SC-PEG E. Coli L-Asparaginase

Succinimidyl Carbonate Monomethoxypolyethylene Glycol E. coli L-Asparaginase

Drug: Pegaspargase

Given standard of care pegaspargase

Other Names:

L-Asparaginase with Polyethylene Glycol

Oncaspar

Oncaspar-IV

PEG-Asparaginase

PEG-L-Asparaginase

PEG-L-Asparaginase (Enzon - Kyowa Hakko)

PEGLA

Polyethylene Glycol L-Asparaginase

Polyethylene Glycol-L-Asparaginase

Other: Quality-of-Life Assessment

Ancillary studies

Other Names:

Quality of Life Assessment

Experimental: Arm C (rescue levocarnitine)

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

Given PO or IV

Other Names:

Carnitor

L-carnitine

Outcome Measures

Primary Outcome Measures

Incidence of conjugated hyperbilirubinemia >3 mg/dL during induction therapy [During induction therapy (up-to ~35-days after treatment starting induction chemotherapy)]
For patients assigned to arms A and B, the proportion having conjugated hyperbilirubinemia > 3mg/dL during induction chemotherapy will be estimated along with 95% confidence intervals.

Secondary Outcome Measures

Incidence of grade >= 3 alanine aminotransferase (ALT) or aspartate aminotransferase (AST) elevations during induction therapy [Up to 35 days (induction phase)]
For patients assigned to arms A and B, the proportion having >= 3 ALT or AST elevations during induction chemotherapy will be estimated along with 95% confidence intervals.
Minimal residual disease (MRD) positivity [At end of induction chemotherapy and at end of consolidation chemotherapy (up-to day ~56 after initiation induction chemotherapy)]
For patients assigned to arms A and B, the proportion having MRD positivity at the end of induction chemotherapy will be estimated along with 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 along with 95% confidence intervals.

Other Outcome Measures

Incidence of CTCAE grade >= 4 adverse events during induction chemotherapy [Up to 35 days (induction phase)]
For patients assigned to arms A and B, the proportion experiencing CTCAE grade >=4 adverse events by the end of induction chemotherapy will be estimated along with 95% confidence intervals.
Incidence of daunorubicin, vincristine, and/or asparaginase chemotherapy dose reductions during induction chemotherapy [Up to 35 days (induction phase)]
For patients assigned to arms A and B, the proportion receiving a dose reduction during induction chemotherapy relative to planned doses at the beginning of induction chemotherapy for daunorubicin, vincristine, and/or asparaginase will be estimated along with 95% confidence intervals.
Percentage of planned dose given for daunorubicin, vincristine, and/or asparaginase during induction chemotherapy [Up to 35 days (induction phase)]
For patients assigned to arms A and b, the median percent planned dose given during induction will also be calculated as well as 95% confidence intervals.
Peak levels during induction of conjugated bilirubin [Up to 35 days (induction phase)]
For patients assigned to arms A and B, the investigators will calculate median peak conjugated bilirubin as well as corresponding 95% confidence intervals.
Peak levels of total bilirubin during induction chemotherapy [Up to 35 days (induction phase)]
For patients assigned to arms A and B, the investigators will calculate median peak total bilirubin as well as corresponding 95% confidence intervals.
Peak levels of AST during induction chemotherapy [Up to 35 days (induction phase)]
For patients assigned to arms A and B, the investigators will calculate median peak AST as well as corresponding 95% confidence intervals.
Peak levels of ALT during induction chemotherapy [Up to 35 days (induction phase)]
For patients assigned to arms A and B, the investigators will calculate median peak ALT as well as corresponding 95% confidence intervals.
Days of conjugated hyperbilirubinemia (>3 mg/dL) to <=3 mg/dL during induction [Up to 35 days (induction phase)]
For patients assigned to arms A, B, and C, the investigators will calculate the median days from onset of conjugated hyperbilirubinemia as well as 95% confidence intervals.
Severity of patient-reported chemotherapy induced peripheral neuropathy (CIPN) as measured by the 11-question Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-NTX) survey [Up to 35 days (induction phase)]
The 11-question FACT/GOG-NTX survey will be used to assess patient reported CIPN, where a higher score indicates more severe CIPN. For patients on arms A and B, a median and corresponding 95% confidence interval will be estimated and reported.
Event free survival (EFS) [The time from randomization to first event (relapse, second malignant neoplasm, remission or death) or date of last contact for those who are disease-free, assessed up to 3 years]
For EFS analysis, 3-year EFS probabilities and corresponding 95% CI will be estimated for Arms A and B, separately, using the Kaplan Meier method.
Overall survival (OS) [Time from study entry to death or date of last contact for those alive at last contact, assessed up to 3 years]
For OS analysis, 3-year OS probabilities and corresponding 95% CI will be estimated for Arms A and B, separately, using the Kaplan Meier method.
Asparaginase activity [Days 8, 15, and 22]
Spearman's correlation coefficients and corresponding 95% confidence intervals will be reported comparing asparaginase activity to age and BMI.
Adherence to oral levocarnitine during induction chemotherapy measured by percentage of pills returned relative to those prescribed [Up to 35 days (induction phase)]
The investigators will report the median percentage of tables returned at the end of induction chemotherapy across patients assigned to arm A as well as a 95% confidence interval.
Adherence to oral levocarnitine measured by percentage dose compliance (% doses reported taken relative to prescribed) [Up to 35 days (induction phase)]
The investigators will report the median percentage dose compliance across patients assigned to arm A as well as a 95% confidence interval.
Mean plasma levels of carnitine [up to 35 days (induction phase)]
The investigators will calculate mean plasma levels of carnitine at baseline and at steady state for patients in arms A and B who do and do not experience conjugated hyperbilirubinemia >3 mg/dL and will calculate corresponding 95% confidence intervals.

Eligibility Criteria

Criteria

Ages Eligible for Study:

15 Years to 40 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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