UGT1A1 Genotype-drien Phase I Study of Irinotecan in VIT Regimen for the Treatment of Pediatric R/R Solid Tumors

Irinotecan is a commonly used salvage chemotherapy drug for children with relapsed and refractory solid tumors. Common dose-limiting toxicities of irinotecan include abdominal pain and diarrhea. Studies have shown that patients with UGT1A16 gene mutations have a higher incidence of these side effects, thereby limiting the dosage of irinotecan. The combination of irinotecan with temozolomide and vincristine is a common salvage chemotherapy regimen for children with relapsed and refractory solid tumors. Currently, the recommended dose of irinotecan is 50mg/m², but there is still significant room for improvement in the efficacy of VIT for these children. Whether patients with wild-type UGT1A16 can further increase the dosage of irinotecan, thereby enhancing the efficacy of the VIT regimen, is the focus of our research.

Children with relapsed and refractory solid tumors and wild-type UGT1A1 gene are enrolled in this study. The doses of temozolomide and vincristine are fixed, while irinotecan in the VIT regimen begins at a starting dose of 50mg/m² and escalates across five dosage groups, with the highest dose group being 110mg/m². This study aims to determine the maximum tolerated dose of irinotecan and the safety of incremental irinotecan dosing, as well as the objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). This will lay the foundation for future Phase II/III clinical studies.

Eligibility Criteria:
Inclusion Criteria:

1. Age \< 18 years.
2. Relapsed and refractory childhood solid tumors (pathologically confirmed). Definition of relapsed and refractory patients: 1. Patients who fail to achieve GPR or CR after first-line treatment are defined as refractory; 2. Patients who achieve CR after first-line treatment but relapse after more than 1 month are defined as relapsed.
3. Must have undergone UGT1A1\*6 genotype testing (provided free of charge by Jiangsu Hengrui Medicine Co., Ltd.), with results being wild type (T/T).
4. Patients must be at least 3 weeks post the last myelosuppressive chemotherapy and at least 6 months post hematopoietic stem cell transplantation, 2 weeks post local radiotherapy, 6 months post craniospinal or extensive pelvic radiotherapy, or 6 weeks post extensive bone marrow radiotherapy.
5. Must have at least one measurable lesion as defined by RECIST criteria;
6. Karnofsky score (for ages \> 10, see Annex I) or Lansky score (for ages ≤ 10, see Annex II) ≥ 50 points;
7. Expected survival time ≥ 6 months;
8. Patients must have fully recovered from all acute toxic effects of previous anticancer chemotherapy: a) Bone marrow suppression chemotherapy: at least 21 days post the last bone marrow suppressive chemotherapy; b) Hematopoietic growth factors: at least 14 days post the last dose of long-acting growth factor or 7 days post the last dose of short-acting growth factor;
9. For patients known not to involve the BM: a) Absolute neutrophil count (ANC) ≥ 1.0×10⁹/L; b) Non-transfused platelet count ≥ 100.0×10⁹/L; c) Hemoglobin ≥ 80 g/L;
10. Liver and kidney functions must meet the following criteria: a) Total bilirubin (conjugated + unconjugated) ≤ 1.5× upper limit of normal (ULN) for age; b) Aspartate aminotransferase (AST) ≤ 2.5×ULN (≤ 110 U/L); c) Glomerular filtration rate or creatinine clearance ≥ 70 mL/min/1.73 m² or corresponding age-normal serum creatinine; d) Serum albumin ≥ 20 g/L.
11. Capable of adhering to outpatient treatment, laboratory monitoring, and necessary clinical visits during the study period;
12. Parents/guardians of children or adolescent subjects must be able to understand, consent to, and sign the informed consent form (ICF) and applicable child consent forms before initiating any protocol-related procedures; if parents/guardians agree, subjects must be capable of expressing consent (when applicable).

Exclusion Criteria:

1. Patients who have previously received chemotherapy with irinotecan combined with temozolomide and vincristine, or patients who have progressed after receiving treatment with irinotecan or temozolomide;
2. Patients receiving P450 enzyme-inducing antiepileptic drugs (antiepileptic drugs affect the clearance of irinotecan);
3. During the study period, patients must not receive any other chemotherapy, radiotherapy, or granulocyte colony-stimulating therapy;
4. Patients positive for hepatitis B surface antigen;
5. Patients infected with HIV or syphilis;
6. Patients who have previously undergone organ transplantation;
7. Uncontrolled active systemic bacterial, viral, or fungal infections; Clostridium difficile infection requiring treatment;
8. Patients allergic to dacarbazine or cephalosporin drugs;
9. Patients requiring high-dose dexamethasone treatment;
10. Patients with a severe history of neurological or psychiatric disorders, including epilepsy or autism.