AOST2032: Cabozantinib with Chemotherapy for Osteosarcoma

Osteosarcoma is one of the most common primary bone malignancies of childhood and adolescence. The standard treatment is chemotherapy and complete surgical resection of macroscopic disease when possible. Survival rates for patients with standard risk (localized, resectable primary tumors) and high-risk disease (metastases, unresectable, or primary pelvic tumors) are 70% and 20–30%, respectively. These survival rates have remained unchanged for several decades despite numerous attempts to augment standard therapies.

Adding the drug cabozantinib to a standard chemotherapy regimen may work better in treating newly diagnosed osteosarcoma patients.

This clinical trial tests the use of cabozantinib combined with standard MAP chemotherapy (methotrexate, doxorubicin, cisplatin) to treat newly diagnosed osteosarcoma. Cabozantinib is a tyrosine kinase inhibitor that blocks signals affecting new blood vessel formation and the ability to activate growth signaling pathways. This may help slow the growth of tumor cells.

The trial consists of:

• A feasibility study: During this stage, cabozantinib is added to the standard MAP therapy with either concomitant or sequential dosing of cabozantinib. Only patients with high-risk disease will be enrolled to this portion.
• Efficacy phases: Phases 2/3 will test the safety, side effects, and best dose of cabozantinib in combination with MAP and compare the effect of adding cabozantinib to standard MAP alone.

Patients will be defined as 2 cohorts:

• Those with standard-risk disease (localized and resectable primary tumors without evidence of metastatic disease)
• Those with high-risk disease (presence of metastases and/or primary pelvic or unresectable tumor)

Primary Objectives

• Determine the feasibility of adding cabozantinib to standard MAP (high dose methotrexate, doxorubicin] and cisplatin) chemotherapy in patients with newly diagnosed metastatic osteosarcoma with a resectable primary tumor
• Determine whether MAP chemotherapy plus cabozantinib results in more favorable event-free survival than MAP alone in patients with localized, resectable osteosarcoma
  
• Determine whether MAP chemotherapy plus cabozantinib results in more favorable event-free survival than MAP alone in patients with metastatic, pelvic, and unresectable osteosarcoma

Eligibility Criteria

Inclusion criteria include:

• Less than 40 years old
• Newly diagnosed high-grade osteosarcoma
  • For the feasibility phase, patients must have metastatic disease and a resectable primary tumor.
  • For efficacy phases (Phase 2/3), patients with both localized and metastatic disease are eligible and will be enrolled in standard- and high-risk cohorts.
• Adequate renal, liver, cardiac, and bone marrow function
• Adequate coagulation

Exclusion criteria include:

• Previous systemic therapy for osteosarcoma or a prior oncologic diagnosis
• Central nervous system metastases
• Central cavitating pulmonary lesions invading or encasing any major blood vessels in the lung
• Certain gastrointestinal and bleeding disorders
• Primary tumor resection or attempted curative resection of metastases 
• Other major surgical procedures within 14 days of enrollment
• A history of serious or non-healing wounds or bone fractures 
• Any medical or surgical conditions that would interfere with gastrointestinal absorption of cabozantinib
• Female patients who are pregnant, lactating who plan to breastfeed, sexually active patients who have not agreed to use an effective contraceptive method during the protocol therapy

Study Sites

St. Jude Children’s Research Hospital, Memphis, Tennessee
Collaborating sites in the U.S. (Children’s Oncology Group)

About this study

In this study, we want to learn how to better treat the bone cancer osteosarcoma. It is usually treated with surgery and a combination of 3 chemotherapy drugs called “MAP” (methotrexate, doxorubicin, and cisplatin).

We want to find out if adding a new drug, cabozantinib, to this therapy will treat osteosarcoma better. We do not know whether adding cabozantinib will improve the outcome.

Part 1 of this trial will study whether cabozantinib and MAP therapy is safe without bad side effects. We hope to find the highest and safest dose of cabozantinib that we can use with MAP therapy.

In parts 2 and 3 of this study, we will compare any side effects of using cabozantinib along with the MAP chemotherapy and surgery.

Patients will be put into 2 groups:

1. Those who get MAP chemotherapy and surgery to remove the tumor
2. Those who get cabozantinib along with MAP chemotherapy and surgery

The effects of treatment from both groups will be compared to see which group does better.

Purpose of this clinical trial

• Find the highest dose of cabozantinib that can be given safely along with MAP chemotherapy
• Compare the effects of cabozantinib along with MAP and surgery versus MAP and surgery alone to find out which is better

Eligibility overview

• Less than 40 years old
• A new diagnosis of high-grade osteosarcoma