The CATSINDO Trial - Clinical and Translational Study in Newly Diagnosed Osteosarcoma

This Phase II, multi-institutional study evaluates the safety of hospital discharge at higher serum methotrexate (MTX) levels in children, adolescents, and young adults with newly diagnosed high-grade osteosarcoma receiving standard-of-care high-dose methotrexate (HD-MTX) as part of MAP chemotherapy.

Participants are discharged once they meet the pre-defined MTX clearance, kidney function, and clinical safety criteria. Methotrexate discharge thresholds are evaluated using an adaptive Bayesian threshold-finding design, starting at a serum MTX level of less than or equal to 0.15 micromolar, with possible escalation or de-escalation based on observed toxicity.

Secondary objectives include comparison of hospital length of stay and estimated inpatient costs with historical controls using traditional discharge criteria. Optional correlative studies include patient-derived osteosarcoma tumor organoids and circulating tumor cells to evaluate chemotherapy sensitivity and other future research. A separate retrospective chart review of prior patients treated with HD-MTX is included to understand safety outcomes and MTX clearance patterns.

• High-dose Methotrexate (Drug): High-dose methotrexate (HD-MTX) is administered intravenously at a dose of 12 g/m² (maximum dose 20 g) over 4 hours as part of standard-of-care MAP chemotherapy for participants with newly diagnosed high-grade osteosarcoma. HD-MTX is delivered with standard supportive care measures, including alkalinized intravenous hydration, serial serum methotrexate level monitoring, and leucovorin rescue beginning 24 hours after methotrexate initiation and continued until discharge criteria are met. Treatment is administered according to institutional standards throughout neoadjuvant/induction and adjuvant/consolidation therapy.

Primary outcomes

• Incidence of Dose Limiting Toxicity (DLT) [Within 7-days post-discharge of methotrexate visit]: A binary response for dose-limiting toxicity following MTX visit discharge defined as rehospitalization due to acute toxicity or serious adverse event of special interest

Secondary outcomes

• Length of Stay (LOS) [From time of admission to time of discharge in hours for each HD-MTX inpatient cycle, assessed across [up to] 12 cycles per participant, through completion of HD-MTX therapy (up to approximately 30 weeks per participant from first week of treatment)]: Length of hospital stay measured in hours from time of admission to time of discharge for each HD-MTX inpatient cycle
• Patient Cost Per Visit [Approximately 30 weeks per participant from first week of treatment]: Total estimated cost associated with each HD-MTX inpatient cycle, based on hospital billing charges and nights of stay

Sex: All, ages: 7 Years to 22 Years

Pre-Enrollment Criteria:

1. Suspected diagnosis of high-grade osteosarcoma based on clinical and radiographic findings.
2. Informed consent (and assent, if applicable) obtained, per institutional guidelines.
3. Participants must be ≤ 22 years of age at the time of consent.

Inclusion Criteria:

1. Participants with localized or metastatic high-grade osteosarcoma.
2. Participants must be ≤ 22 years of age at the time of consent.
3. Participants must have a body surface area of greater than or equal to 0.8 m2.
4. Participants receiving or planning to receive induction/neoadjuvant MAP chemotherapy with HD-MTX given at the standard dose of 12 gm/m2 (maximum 20 gm).

   NOTE: Participants may be participating on other clinical studies such as the 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/m2 (maximum 20 gm).
5. 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. Medications known to interfere with HD-MTX clearance are listed in Appendix A.
6. Participants must meet minimum organ function requirements to receive HD-MTX:

   * Adequate liver function defined as: total bilirubin ≤ 1.5x upper limit of normal (ULN) for age at the time of consent and alanine aminotransferase (ALT/SGPT) ≤ 135 U/L for age at the time of consent.
   * Adequate renal function defined as: a serum creatinine based on age/gender OR - a 24-hour urine Creatinine clearance ≥ 70 mL/min/1.73 m2, OR - an estimated glomerular filtration rate (GFR) of greater than or equal to 70 mL/min/1.73 m2 for age at the time of consent.
   * Adequate bone marrow function defined as: peripheral absolute neutrophil count (ANC) ≥ 1000/µL, platelet count ≥ 100,000/µL (transfusion independent, defined as not receiving platelet transfusions within a 7-day period prior to enrollment), and hemoglobin ≥ 8.0 g/dL (transfusion independent, defined as not receiving red blood cell transfusions within a 7-day period prior to enrollment)
7. 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.
8. Informed consent, and assent when appropriate, must be obtained, per institutional guidelines.
9. 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).
10. Participants must be willing and able to comply with all study procedures for the entire length of the study.

Exclusion Criteria:

1. 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.
2. 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.

• Thomas Russell, MD, Principal investigator, Alliance for Research and Innovations in Pediatric Oncology (ARISE) Cancer Consortium