AOST2032 Supplemental Per Case Reimbursement (Feasibility Phase)

ABSTRACT Osteosarcoma is the most common primary bone malignancy of childhood and adolescence. Standard treatment is comprised of chemotherapy and complete surgical resection of macroscopic disease when achievable. Survival rates for patients with standard risk (localized, resectable primary tumors) and high- risk disease (presence of metastases, unresectable or primary pelvic tumors) are 70% and 20-30%, respectively, and have remained unchanged for several decades despite numerous attempts to augment standard therapies. Multi-targeted receptor tyrosine kinase inhibitors (MTKIs), such as cabozantinib, can target signaling pathways that are known to be altered in osteosarcoma. Several MTKIs including cabozantinib have recently shown clinical evidence of activity in prospective studies for both pediatric and adult patients with advanced osteosarcoma. Furthermore, feasibility of administering MTKIs in combination with cytotoxic chemotherapy has previously been shown in patients with AML, hepatocellular carcinoma, and soft tissue sarcomas. This trial will consist of three parts: a feasibility study, followed by a randomized phase 2/3 study in the efficacy phase. The first portion of the study will determine the feasibility of the adding cabozantinib to standard MAP (methotrexate, doxorubicin, cisplatin) chemotherapy in patients with newly diagnosed metastatic osteosarcoma, with either concomitant or sequential dosing of cabozantinib. After establishing feasibility, this study will proceed to the phase 2 portion and will randomize a pooled cohort of standard and high-risk patients with newly diagnosed osteosarcoma to receive either a standard arm with MAP chemotherapy or the experimental arm with MAP chemotherapy and the addition of cabozantinib. Event-free survival will be evaluated as well as careful monitoring of cabozantinib-related toxicities. Should the phase 2 experimental arm show a promising signal of activity, the study will advance to the third portion as a randomized phase 3 study with expanded enrollment and analysis of outcomes for the separate standard and high-risk cohorts. The primary endpoints of the trial are feasibility and event-free survival. The phase 2 portion will enroll 374 (252 standard, 122 high-risk) eligible and evaluable patients, potentially expanding to 996 (672 standard, 324 high-risk) eligible and evaluable patients to complete the phase 3 trial. Continuous monitoring of targeted toxicities and wound healing complications will be conducted throughout the trial to evaluate the safety of adding cabozantinib to standard therapy for osteosarcoma.