Neoplasms

All Conditions

Musculoskeletal Diseases

Skin and Connective Tissue Diseases

Wounds and Injuries

Nervous System Diseases

Rare Diseases

Giant Cell Tumors

Giant Cell Tumor of Tendon Sheath

Neoplasms, Connective Tissue

Neoplasms, Connective and Soft Tissue

Neoplasms by Histologic Type

Synovitis

Joint Diseases

Tendinopathy

Muscular Diseases

Pigmented Villonodular Synovitis

Adult patients with symptomatic TGCT associated with severe morbidity or functional limitations and not amenable to improvement with surgery, and who experience moderate or severe hepatotoxicity due to use of TURALIO™ (pexidartinib).

This is a non-interventional, observational study to evaluate long-term risk of hepatic failure associated with TURALIO™ (pexidartinib) treatment. No study medication will be provided to the participants.

TURALIO™

Daiichi Sankyo Contact for Clinical Trial Information

Principal Investigator

Global Clinical Leader

A study to evaluate the long-term risk of hepatic failure with TURALIO™ (pexidartinib) and the mechanism of liver injury based upon liver biopsy information among patients who received or are receiving TURALIO™ (pexidartinib) and experience hepatotoxicity.

This FDA post-marketing requirement study will evaluate the long-term risk of hepatic failure with TURALIO™ (pexidartinib) and the mechanism of liver injury based upon liver biopsy information among patients who received or are receiving TURALIO™ (pexidartinib) for symptomatic tenosynovial giant cell tumor (TGCT) associated with severe morbidity or functional limitations and not amenable to improvement with surgery, and who experience hepatotoxicity. A liver biopsy will be collected from enrolled patients for central laboratory analysis of macrophage and immune cell profiles to investigate possible mechanisms of the hepatotoxicity. Additionally, 4 blood samples will be collected to evaluate liver function, other relevant safety tests, peripheral immune cells, and for pharmacogenomic testing. Enrolled patients will be followed at least yearly for 10 years to assess long-term risk of hepatic failure.

The liver biopsy will be performed as soon as reasonably possible after the liver test abnormality criteria are first met and before liver tests have returned to normal. Four blood samples will be drawn on the day of, or up to 4 days before, the biopsy. One sample will evaluate liver test results (alanine aminotransferase \[ALT\], aspartate aminotransferase \[AST\], alkaline phosphatase \[ALP\], gammaglutamyl transferase \[GGT\], total bilirubin \[TBIL\], direct bilirubin), serum creatinine, and blood urea nitrogen (BUN) at the study site. The remaining three samples will be used for central laboratory analysis.

A Long-term Study Evaluating Hepatotoxicity Associated With TURALIO™ (Pexidartinib) Treatment

A Long-term Study to Further Evaluate the Risk of Hepatotoxicity Associated With TURALIO™ (Pexidartinib) Treatment

De-identified individual participant data (IPD) and applicable supporting clinical trial documents may be available upon request at https://vivli.org/. In cases where clinical trial data and supporting documents are provided pursuant to our company policies and procedures, Daiichi Sankyo will continue to protect the privacy of our clinical trial participants. Details on data sharing criteria and the procedure for requesting access can be found at this web address: https://vivli.org/ourmember/daiichi-sankyo/

Hepatic failure is defined as severe liver injury with encephalopathy and impaired synthetic function (INR \>= 1.5) as well as liver transplant and hepatic-related death.

Liver test abnormalities were defined as the following: Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) \>3 × upper limit of normal (ULN) with concurrent total bilirubin (TBIL) \>2 × ULN; Isolated TBIL \>2 × ULN (excluding patients with Gilbert's syndrome); Isolated AST or ALT \>10 × ULN; Alkaline phosphatase (ALP) \>2 x ULN with gamma-glutamyl transferase (GGT) \>2 x ULN.

Daiichi Sankyo

Blood and Lymph Conditions

Immune System Diseases

Leukemia

Precursor Cell Lymphoblastic Leukemia-Lymphoma

Leukemia, Lymphoid

Lymphoma

Hematologic Diseases

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Acute Lymphoblastic Leukemia

Lymphoblastic Lymphoma

Acute Graft Versus Host Disease

Lymphosarcoma

Antineoplastic Agents

All Drugs and Chemicals

Other Dietary Supplements

Asparaginase

Carnitine

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)

Levocarnitine

Van T. Huynh, M.D.

Deepa Jeyakumar, MD

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.

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.

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

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.

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.

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.

Quantify disease response, using end of Induction minimal residual disease (MRD) results, where an MRD value \< 0.01 is considered "negative."

Calculate incidence of nonalcoholic fatty liver disease (NAFLD), using ultrasound elastography, in pediatric and AYA patients newly diagnosed with ALL.

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.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A Long-term Study Evaluating Hepatotoxicity Associated With TURALIO™ (Pexidartinib) Treatment	NCT04635111	Hepatotoxicity Tenosynovial Gi...	TURALIO™	18 Years -	Daiichi Sankyo
Use of Levocarnitine to Reduce Asparaginase Hepatotoxicity in Patients With Acute Lymphoblastic Leukemia	NCT05501899	Acute Lymphobla... Hepatotoxicity	Levocarnitine	5 Years - 29 Years	Children's Hospital of Orange County
Use of Levocarnitine to Reduce Asparaginase Hepatotoxicity in Patients With Acute Lymphoblastic Leukemia	NCT05501899	Acute Lymphobla... Hepatotoxicity	Levocarnitine	5 Years - 29 Years	Children's Hospital of Orange County

Spots Global Cancer Trial Database for hepatotoxicity