Evaluating Safe Methotrexate Blood Levels for Hospital Discharge in Newly Diagnosed Localized or Metastatic Osteosarcoma Patients Receiving High Dose Methotrexate, The CATSINDO Trial

Status: approved

This phase II trial tests the effect of hospital discharge when blood levels of methotrexate are slightly higher than the usual past threshold in patients with high-grade osteosarcoma that has not spread to other parts of the body (localized) or that has spread from where it first started (primary site) to other places in the body (metastatic) receiving high-dose methotrexate. Standard of care (SOC) chemotherapy for osteosarcoma includes high dose methotrexate, doxorubicin and cisplatin (MAP). Methotrexate is in a class of medications called antimetabolites. It is also a type of antifolate. Methotrexate stops cells from using folic acid to make deoxyribonucleic acid (DNA) and may kill tumor cells. Doxorubicin damages DNA and may kill tumor cells. It is a type of anthracycline antitumor antibiotic. Cisplatin is in a class of medications known as platinum-containing compounds. It works by killing, stopping or slowing the growth of tumor cells. High dose methotrexate requires hospital admission for each dose given and length of stay can vary between patients based on levels of methotrexate, side effects and supportive care needs. Frequent and longer stays in the hospital can have a significant negative impact on therapy. Currently, the maximum blood level of methotrexate that is safe for an earlier discharge is not known. Hospital discharge at a slightly higher methotrexate level than past thresholds previously used may be safe and tolerable in treating patients with localized or metastatic high-grade osteosarcoma receiving high dose methotrexate. This clinical trial also evaluates whether tumor cells can be grown from tissue and blood samples to create three-dimensional models (organoids) of the tumor. This may help researchers understand how the tumor responds to chemotherapy and how it changes over time.

Inclusion Criteria

PRE-ENROLLMENT: Eligibility for this section allows for the collection of tumor tissue for correlative research prior to confirmation of histologic diagnosis. These participants may later be considered for full (intervention/subsequent collection) study enrollment
PRE-ENROLLMENT: Suspected diagnosis of high-grade osteosarcoma based on clinical and radiographic findings
PRE-ENROLLMENT: Informed consent (and assent, if applicable) obtained, per institutional guidelines
PRE-ENROLLMENT: Participants must be ≤ 22 years of age at the time of consent
PRE-ENROLLMENT: NOTE: Participants who consent to pre-enrollment sample collection must meet all eligibility criteria, including confirmed histologic diagnosis of high-grade osteosarcoma, prior to full study enrollment
FULL STUDY: Confirmed histologic diagnosis of high-grade osteosarcoma. * Both localized and metastatic disease are eligible * Participants with secondary osteosarcoma related to prior treatment who are eligible to receive MAP therapy are also eligible
FULL STUDY: Participants with localized or metastatic high-grade osteosarcoma
FULL STUDY: Participants must be ≤ 22 years of age at the time of consent
FULL STUDY: Participants must have a body surface area of greater than or equal to 0.8 m^2
FULL STUDY: Participants receiving or planning to receive induction/neoadjuvant MAP chemotherapy with HD-MTX given at the standard dose of 12 gm/m^2 (maximum 20 gm) * NOTE: Participants may be participating on other clinical studies such as the Children's Oncology Group (COG) trial AOST2032 or any other clinical trial as long as their treatment includes MAP chemotherapy with the standard HD-MTX dose of 12 gm/m^2 (maximum 20 gm)
FULL STUDY: Participants may receive other chemotherapy agents in their treatment provided that drug(s) are not known to interfere with HD-MTX clearance when given concurrently
FULL STUDY: Total bilirubin ≤ 1.5 x upper limit of normal (ULN) for age at the time of consent
FULL STUDY: Alanine aminotransferase (ALT/serum glutamic pyruvic transaminase [SGPT]) ≤ 135 U/L for age at the time of consent
FULL STUDY: A serum creatinine based on age/gender as follows: * Age 1 month to < 6 months: Male 0.4; female 0.4 * Age 6 months to < 1 year: Male 0.5; female 0.5 * Age 1 to < 2 years: Male 0.6; female 0.6 * Age 2 to < 6 years: Male 0.8; female 0.8 * Age 6 to < 10 years: male 1; female 1 * Age 10 to < 13 years: Male 1.2; female 1.2 * Age 13 to < 16 years: Male 1.5; female 1.4 * Age ≥ 16 years: Male 1.7; female 1.4 * OR- A 24-hour urine Creatinine clearance ≥ 70 mL/min/1.73 m^2 * OR - An estimated glomerular filtration rate (GFR) of greater than or equal to 70 mL/min/1.73 m^2 for age at the time of consent
FULL STUDY: Peripheral absolute neutrophil count (ANC) ≥ 1000/uL
FULL STUDY: Platelet count ≥ 100,000/uL (transfusion independent, defined as not receiving platelet transfusions within a 7-day period prior to enrollment)
FULL STUDY: Hemoglobin ≥ 8.0 g/dL (transfusion independent, defined as not receiving red blood cell transfusions within a 7-day period prior to enrollment)
FULL STUDY: Adequate cardiac function, defined as a left ventricular ejection fraction (LVEF) ≥ 50%, assessed per institutional standard of care using non-invasive imaging modalities such as a multi-gated acquisition (MUGA) scan or echocardiogram (echo) * NOTE: Cardiac function assessment will be performed as part of routine clinical care. No additional imaging or procedures will be mandated by the research protocol
FULL STUDY: Informed consent, and assent when appropriate, must be obtained, per institutional guidelines
FULL STUDY: Participants can enroll after initiation of induction MAP chemotherapy so long as they are enrolled prior to the second cycle of chemotherapy (prior to week 6 cisplatin and doxorubicin)
FULL STUDY: Participants must be willing and able to comply with all study procedures for the entire length of the study
RETROSPECTIVE PARTICIPANT: Age ≤ 22 years at time of HD-MTX administration
RETROSPECTIVE PARTICIPANT: Diagnosis consistent with newly diagnosed high-grade osteosarcoma
RETROSPECTIVE PARTICIPANT: Received first-dose HD-MTX between January 1, 2017, and May 31, 2025, and completed by October 31, 2025

Exclusion Criteria

Female participants who are pregnant and/or lactating and breast feeding their infant(s) * NOTE: Pregnancy testing will follow institutional standard of care practice and is not mandated by the protocol
Sexually active participants of reproductive potential who have not agreed to use an effective contraceptive method for the duration of protocol therapy, at the discretion of the investigator

Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT07560826.

United States

North Carolina

Charlotte

Carolinas Medical Center/Levine Cancer Institute

Status: Approved

Contact: Thomas Bennett Russell

Phone: 704-381-9900

Email: Thomas.Russell@advocatehealth.org

Winston-Salem

Wake Forest University Health Sciences

Status: Approved

Contact: Sarah Supples

Email: sarah.supples@wfusm.edu

PRIMARY OBJECTIVES:

I. Assess the safety of hospital discharge at a serum methotrexate (MTX) level less than 0.15 and no greater than 0.20 uM relying on a threshold level schema in high-grade osteosarcoma participants receiving high dose (HD)-MTX.

II. Assess the feasibility of generating participant-derived high-grade osteosarcoma tumor organoids in a multi-institutional setting.

SECONDARY OBJECTIVES:

I. Compare the length of hospital stay for participants discharged at a serum MTX level at threshold levels 3 (≤ 0.15 uM) and 4 (≤ 0.20 uM) versus historical controls discharged at serum MTX levels < 0.1 uM.

II. Compare differences in average inpatient costs associated with discharge at a serum MTX level at threshold levels 3 (≤ 0.15 uM) and 4 (≤ 0.20 uM) versus historical controls discharged at serum MTX levels < 0.1 uM.

III. Compare sensitivity of high-grade osteosarcoma organoids to MAP versus extent of histologic tumor necrosis at time of surgical resection.

EXPLORATORY OBJECTIVES:

I. Assess changes in chemosensitivity and molecular signatures of participant-derived high-grade osteosarcoma organoids longitudinally over the course of treatment.

II. To assess the feasibility of generating participant-derived high-grade osteosarcoma circulating tumor cell organoids.

ANCILLARY OBJECTIVES (RETROSPECTIVE CHART REVIEW):

I. To perform a retrospective chart review of about 50 pediatric patients who received their first dose of HD-MTX for newly diagnosed high-grade osteosarcoma between January 2017 and May 2025 and completed therapy by October 2025 to:

Ia. Quantify the distribution of discharge MTX levels in historical practice;

Ib. Evaluate post-discharge safety outcomes (e.g., acute kidney injury [AKI], emergency department [ED] visits, and hospital re-admissions) in relation to discharge thresholds.

2. Contextualize and support the interventional study hypothesis that discharge at MTX levels > 0.15 uM is safe when standard mitigation measures are used.

OUTLINE:

Patients receive doxorubicin on weeks 1, 6, 12, 17, 20, and 26, cisplatin on weeks 1, 6, 12, and 17 and methotrexate intravenously (IV) over 4 hours on weeks 4, 5, 9, 10, 15, 16, 20, 21, 23, 24, 28, and 29 of each cycle and undergo surgery at week 11 per standard of care. Cycles repeat every 5 weeks for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo methotrexate monitoring until discharge criteria are met. Additionally, patients undergo echocardiography at pre-enrollment and blood sample collection throughout the study.

After completion of study treatment, patients are followed up in 4-6 weeks, every 3 months for the first 2 years then every 6 months for up to 3 years from the date of enrollment.

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Evaluating Safe Methotrexate Blood Levels for Hospital Discharge in Newly Diagnosed Localized or Metastatic Osteosarcoma Patients Receiving High Dose Methotrexate, The CATSINDO Trial

Description

Eligibility Criteria

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Trial Objectives and Outline

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