Effects of Maintenance Cabozantinib+BSC Versus BSC in Children and AYA With Osteosarcoma

A Phase II, Randomized, Open-label Study to Assess the Efficacy, Safety, and Pharmacokinetics (PK) of Maintenance Cabozantinib (XL184) Plus Best Supportive Care (BSC) Versus BSC in Children, Adolescents and Young Adults (AYA) With Unresectable Residual Osteosarcoma Either at Diagnosis or at First Relapse After Standard Treatment

The participants of this study will be children, adolescents, and young adults with residual osteosarcoma, which cannot be removed completely through surgery.

Participants will have achieved a partial response or stable disease at the end of conventional chemotherapy. Osteosarcoma is cancer of the bone. The cancer cells make immature bone cells, known as osteoid.

Osteosarcoma is very rare, but it is the most common type of bone cancer in children and teens. It is most common in teens and young adults.

In this study, participants will receive either cabozantinib and best supportive care or the best supportive care alone. Best supportive care will be provided at the investigator's discretion and according to institutional guidelines.

It includes antibiotics, nutritional support, correction of metabolic disorders, optimal symptom control and pain management (including radiotherapy), etc. but does not include tumor specific therapy.

Cabozantinib will be taken by mouth (orally), as a tablet, once a day. Cabozantinib will be provided to participants who tolerate it for as long as their disease does not progress. Participants in the study receiving best supportive care alone may switch to treatment with cabozantinib and best supportive care if their disease progresses and if other eligibility criteria are met.

Participants may withdraw consent to participate at any time.

The estimated duration of the study for participants is 24 months, however a participant could remain in the study longer if demonstrating treatment benefit.

Inclusion Criteria :

• Participants must be ≥5 and ≤30 years of age at the time of study entry.
• Histologically or cytologically confirmed diagnosis of high-grade osteosarcoma as defined by a local pathologist
• Participants with unresectable residual disease after standard chemotherapy treatment at diagnosis or first relapse (treated with systemic chemotherapy). A minimum of 4 cycles of systemic chemotherapy (or minimum of 2 cycles if chemotherapy was stopped early due to toxicity) must have been received.
• Measurable residual or evaluable disease by RECIST version 1.1. Participants will be considered with evaluable disease if they have only non-measurable disease as per RECIST version 1.1 criteria.
• Absence of Progressive Disease (PD) (defined by the investigator according to RECIST version 1.1) at study entry. Note, the two most recent radiological evaluations (e.g. computerised tomography (CT) or magnetic resonance resonance imaging (MRI) scan) including the one following completion of chemotherapy should be available later to facilitate BIRC review.
• Chemotherapy must be the last anticancer treatment received by participants before study entry and must have been completed at least 4 weeks but no longer than 2 months before randomization.
• Participants must have recovered to Grade ≤1, except for alopecia, ototoxicity, and Grade ≤2 peripheral neuropathy, per Common Terminology Criteria for Adverse Events (CTCAE) version 5.0) from the acute toxic effects of all prior anticancer therapy at study entry, unless AEs are clinically non significant and/or stable on supportive therapy, per investigator clinical judgment.
• Life expectancy >6 months.
• Performance level: participants must have a Lansky or Karnofsky performance status score of ≥70 corresponding to Eastern Cooperative Oncology Group (ECOG) categories 0-1.
• Adequate organ and marrow function.
• Adequately controlled blood pressure (BP) with or without antihypertensive medications.
• Male and/or female (according to their reproductive organs and functions assigned by chromosomal complement) (FDA 2016)
• Contraception and barriers as well as pregnancy testing is required as appropriate for the age and sexual activity of pediatric participants and as required by local regulations.
• All participants (typically ≥18 years) and/or their parents or legal guardians must sign a written informed consent and assent must be obtained from minor participants according to local guidelines.

Exclusion Criteria :

• Low grade osteosarcoma and periosteal osteosarcoma
• Previous treatment with cabozantinib or another Mesenchymal-epithelial transition (MET)/hepatocyte growth factor (HGF) inhibitor (e.g., tivantinib, crizotinib).
• Receipt of any type of small molecule kinase inhibitor (including investigational kinase inhibitor) within 2 weeks or 5 half-lives of the agent, whichever is longer, before first dose of study intervention.
• Receipt of any type of cytotoxic, biologic or other systemic anticancer therapy (including investigational) within 4 weeks before first dose of study intervention (or washout of at least 5 half-lives, whichever is shorter).
• Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery (including radiosurgery or major surgery e.g., removal or biopsy of brain metastasis) and stable for at least 4 weeks prior to randomization. Eligible participants must be neurologically asymptomatic and without systemic corticosteroid treatment at the time of randomization. Note: Participants with a known seizure disorder who are receiving non-enzyme inducing anticonvulsants and have well-controlled seizures on a stable dose of anti-convulsant may be enrolled.
• Participants who have an uncontrolled/active infection requiring systemic therapy.
• Participants who are unable to swallow intact tablets.
• Participants with uncontrolled, significant intercurrent or recent illness.
• Previously identified allergy or hypersensitivity to components of the study treatment formulations.
• Any other active malignancy at time of first dose of study intervention or diagnosis of another malignancy within 3 years prior to first dose of study intervention that requires active treatment.
• Pregnancy or breast-feeding.
• Participants who in the opinion of the investigator may not be able to comply with the requirements of the study are not eligible
• Major surgery (eg, orthopaedic surgery, removal or biopsy of brain metastasis) within 8 weeks before randomization. Complete wound healing from major surgery must have occurred 4 weeks before randomization and from minor surgery (eg, simple excision, tooth extraction) at least 10 days before randomization. Participants with clinically relevant ongoing complications from prior surgery are not eligible.