A Study to Test the Addition of the Drug Cabozantinib to Chemotherapy in Patients With Newly Diagnosed Osteosarcoma

Metastatic Osteosarcoma Clinical Trial

Official title: A Feasibility and Randomized Phase 2/3 Study of the VEFGR2/MET Inhibitor Cabozantinib in Combination With Cytotoxic Chemotherapy for Newly Diagnosed Osteosarcoma

Status Suspended

Clinical Trial Summary

This phase II/III trial tests the safety, side effects, and best dose of the drug cabozantinib in combination with standard chemotherapy, and to compare the effect of adding cabozantinib to standard chemotherapy alone in treating patients with newly diagnosed osteosarcoma. Cabozantinib is in a class of medications called kinase inhibitors which block protein signals affecting new blood vessel formation and the ability to activate growth signaling pathways. This may help slow the growth of tumor cells. The drugs used in standard chemotherapy for this trial are methotrexate, doxorubicin, and cisplatin (MAP). Methotrexate stops cells from making DNA and may kill tumor cells. It is a type of antimetabolite. Doxorubicin is in a class of medications called anthracyclines. It works by slowing or stopping the growth of tumor cells in the body. Cisplatin is in a class of medications known as platinum-containing compounds. It works by killing, stopping or slowing the growth of tumor cells. Adding cabozantinib to standard chemotherapy may work better in treating newly diagnosed osteosarcoma.

Clinical Trial Description

PRIMARY OBJECTIVES:

I. To determine the feasibility of adding cabozantinib S-malate (cabozantinib) to standard MAP (high dose methotrexate, doxorubicin hydrochloride [doxorubicin], and cisplatin) chemotherapy in patients with newly diagnosed metastatic osteosarcoma with a resectable primary tumor.

II. To determine whether MAP chemotherapy plus cabozantinib results in more favorable event-free survival (EFS) than MAP chemotherapy alone in patients with localized, resectable osteosarcoma.

III. To determine whether MAP chemotherapy plus cabozantinib results in more favorable event-free survival (EFS) than MAP chemotherapy alone in patients with metastatic, pelvic and unresectable osteosarcoma.

SECONDARY OBJECTIVES:

I. To determine whether MAP chemotherapy plus cabozantinib results in more favorable overall survival (OS) than MAP chemotherapy alone in patients with localized, resectable osteosarcoma.

II. To determine whether MAP chemotherapy plus cabozantinib results in more favorable overall survival (OS) than MAP chemotherapy alone in patients with metastatic, pelvic and unresectable osteosarcoma.

EXPLORATORY OBJECTIVES:

I. To determine the rate of good histologic response (> 90%) of resected primary tumor specimens following neoadjuvant chemotherapy with MAP plus cabozantinib and compare with response rates for MAP chemotherapy alone.

II. To describe the toxicities of the addition of cabozantinib to MAP chemotherapy in patients with newly diagnosed osteosarcoma.

III. To describe frequency of application of local control methods (surgery, hypofractionated stereotactic body radiotherapy, or radiofrequency ablation) for extrapulmonary metastatic osteosarcoma.

IV. To compare total cumulative delivered doses of MAP chemotherapy agents between standard and experimental arms across multiple phases of therapy.

V. To assess the pharmacokinetics of cabozantinib when administered concomitantly with standard chemotherapy agents during feasibility.

VI. To collect pulmonary metastatic lesions, paired primary tumor tissue, and serial blood samples for tumor profiling, liquid biopsies, and future testing of correlative biology studies.

OUTLINE: This is a dose-escalation study of cabozantinib (Feasibility Phase) followed by a randomized phase II/III study (Efficacy Phase).

FEASIBILITY PHASE: Patients receive cabozantinib orally (PO), methotrexate intravenously (IV), doxorubicin IV, and cisplatin IV for two 35-day "induction" cycles. Patients are then considered for appropriate local control. Then they receive "consolidation" with methotrexate IV, doxorubicin IV, and cisplatin IV for one 35-day cycle, followed by cabozantinib PO, methotrexate IV, doxorubicin IV, and cisplatin IV for one 35-day cycle, and cabozantinib PO, methotrexate IV, and doxorubicin IV for two 35-day cycles. Patients then receive cabozantinib PO for six 28-day "maintenance" cycles.

EFFICACY PHASE: Patients with standard risk osteosarcoma are randomized to Arm A or Arm B. Patients with high risk osteosarcoma are randomized to Arm C or Arm D.

ARM A: Standard risk patients receive methotrexate IV, doxorubicin IV, and cisplatin IV for two 35-day "induction" cycles, followed by appropriate local control. Patients then receive "consolidation" with methotrexate IV, doxorubicin IV, and cisplatin IV for two 35-day cycles and methotrexate IV and doxorubicin IV for two additional 35-day cycles.

ARM B: Standard risk patients receive cabozantinib PO, methotrexate IV, doxorubicin IV, and cisplatin IV for two 35-day "induction" cycles, followed by appropriate local control. Patients then receive "consolidation" with cabozantinib PO, methotrexate IV, doxorubicin IV, and cisplatin IV for two 35-day "consolidation" cycles, and cabozantinib PO, methotrexate IV, and doxorubicin IV for two additional 35-day cycles. Patients then receive cabozantinib PO for six 28-day "maintenance" cycles.

ARM C: High risk patients receive methotrexate IV, doxorubicin IV, and cisplatin IV for two 35-day "induction" cycles, followed by appropriate local control. Patients then receive "consolidation" with methotrexate IV, doxorubicin IV, and cisplatin IV for two 35-day cycles and methotrexate IV and doxorubicin IV for two additional 35-day cycles.

ARM D: High risk patients receive cabozantinib PO, methotrexate IV, doxorubicin IV, and cisplatin IV for two 35-day "induction" cycles, followed by appropriate local control. Patients then receive "consolidation" with methotrexate IV, doxorubicin IV, and cisplatin IV for one 35-day cycle, followed by cabozantinib PO, methotrexate IV, doxorubicin IV, and cisplatin IV for one 35-day cycle and cabozantinib PO, methotrexate IV, and doxorubicin IV for two additional 35-day cycles. Patients then receive cabozantinib PO for six 28-day "maintenance" cycles.

All patients also undergo X-ray, computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET) or bone scintigraphy at diagnosis and additonal time points throughout the trial. All patients also undergo collection of blood samples during screening and on study. ;

Related Conditions & MeSH terms

• High Grade Osteosarcoma
• Localized Osteosarcoma
• Metastatic Osteosarcoma
• Osteosarcoma

• NCT number: NCT05691478
• Study type: Interventional
• Source: National Cancer Institute (NCI)
• Status: Suspended
• Phase: Phase 2/Phase 3
• Start date: March 3, 2023
• Completion date: March 20, 2030