Apatinib Combined With Liposomal Irinotecan for Refractory or Metastatic Osteosarcoma

Safety and Efficacy of Apatinib Combined With Irinotecan Liposome Injection in the Treatment of Recurrent or Metastatic Osteosarcoma: A Single-Arm, Open-Label, Prospective Multicenter Clinical Study

In advanced osteosarcoma where traditional chemotherapy has failed, the multi-targeted tyrosine kinase inhibitor apatinib has become a mainstream systemic treatment option in China. However, for patients with a high tumor burden or extra-pulmonary lesions, these drugs are prone to secondary resistance, necessitating combination with chemotherapy for more effective comprehensive control. Liposomal irinotecan, a newly approved topoisomerase inhibitor, exhibits lower toxicity compared to traditional irinotecan and is one of the second-line chemotherapy agents for osteosarcoma, making it a suitable candidate for combination therapy with apatinib.

The primary objective of this study is to determine the optimal regimen of apatinib combined with liposomal irinotecan injection, while the secondary objective is to evaluate the safety and efficacy of this combination in patients with refractory osteosarcoma who have progressed after second-line chemotherapy.

Osteosarcoma is the most common primary malignant bone tumor in adolescents and young adults. Although multimodal treatment including surgery and multi-agent chemotherapy has improved survival for patients with localized disease, the prognosis of patients with recurrent or metastatic osteosarcoma remains poor.

Targeting tumor angiogenesis has emerged as a promising therapeutic strategy for osteosarcoma. Apatinib is an oral small-molecule tyrosine kinase inhibitor that selectively inhibits VEGFR-2 and has demonstrated clinical activity in advanced osteosarcoma in previous studies.

Irinotecan is a topoisomerase I inhibitor with antitumor activity in several malignancies. Liposomal irinotecan is a nanoliposomal formulation that improves the pharmacokinetic profile and intratumoral delivery of irinotecan, potentially enhancing its antitumor effect.

This investigator-initiated study is designed to evaluate the safety, tolerability, and preliminary efficacy of apatinib combined with liposomal irinotecan in patients with recurrent or refractory osteosarcoma. Patients will receive oral apatinib daily in combination with intravenous liposomal irinotecan administered every two weeks until disease progression, unacceptable toxicity, or withdrawal of consent.

The primary objective is to evaluate the safety and tolerability of the combination therapy. Secondary objectives include evaluation of antitumor activity such as objective response rate, progression-free survival, and overall survival.

Inclusion Criteria:

1. The subject or their legal representative must sign a written informed consent form prior to enrollment.
2. Diagnosis of refractory osteosarcoma confirmed by histopathology. Pathological confirmation is mandatory for localized tumors and isolated pulmonary lesions; it is not required for multiple pulmonary metastases.
3. Disease progression after standard, adequate first-line and second-line chemotherapy regimens for osteosarcoma, or progression within 6 months of stopping such therapy.
4. At least one measurable target lesion according to RECIST version 1.1 criteria.
5. ECOG Performance Status score of 0 or 1, with an expected survival of ≥3 months.
6. Recovery from prior therapies: all side effects (except alopecia) must have resolved to Grade 1 or lower per NCI-CTCAE version 5.0.
7. Adequate organ function as indicated by the following peripheral blood counts and serum biochemistry results
8. Women of childbearing potential must agree to use effective contraception (e.g., intrauterine device, oral contraceptives, or condoms) during the study and for 6 months after study completion; they must have a negative serum or urine pregnancy test within 7 days prior to study enrollment and must not be breastfeeding. Male participants must agree to use effective contraception or have undergone surgical sterilization during the study and for 6 months after its completion.

Exclusion Criteria:

1. Prior treatment with apatinib.
2. Prior use of irinotecan or other analogues of topoisomerase inhibitors.
3. Known allergic reactions, hypersensitivity, or intolerance to apatinib, liposomal irinotecan, or any of their excipients.
4. Within 3 weeks after the last dose of any prior therapy, including systemic cytotoxic drug therapy, targeted therapy, radiotherapy, immunotherapy, or any other investigational therapy.
5. Diagnosis of other malignancies within the past 3 years, except for adequately treated cutaneous basal cell carcinoma, carcinoma in situ of the cervix, or breast cancer that has undergone radical resection and remained disease-free for >3 years.
6. Patients with known brain metastasis, spinal cord compression, carcinomatous meningitis, or those with imaging evidence of leptomeningeal disease or unstable brain lesions detected by CT or MRI during screening.
7. Patients with symptomatic serous cavity effusions (e.g., pleural effusion, ascites, or pericardial effusion) requiring surgical intervention.
8. Uncontrolled hypertension (systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg despite optimal medical therapy).
9. Other poorly controlled diseases.
10. Participation in clinical trials of other antitumor drugs within the 4 weeks prior to enrollment.
11. Treatment with strong CYP3A4 inhibitors within 7 days prior to study participation, or treatment with strong CYP3A4 inducers within 12 days prior to study participation.
12. Patients currently receiving concurrent antitumor therapy.
13. Patients with target lesions having previously received radiotherapy, but without subsequent progression.
14. Patients who have received any vaccination during the treatment period, or have received an adenovirus-based vaccine within 4 weeks.
15. Lactating women.
16. Any condition that, in the investigator's judgment, may compromise the subject's well-being or ability to comply with or fulfill the study requirements.