QuadW Tissue Incentives: APEC14B1, AOST2031, AOST2032

APEC14B1 Abstract: The next generation of therapy for childhood cancers will be based upon in-depth molecular phenotyping that may facilitate the development of rational risk-adapted and target-based therapies. In order to support current and future molecularly-guided therapeutic trials and the basic science discovery efforts that will lead to more effective therapies, prevention, early detection and a reduction in early and late-onset toxicities, it is critical to implement universal, high-quality collection of annotated biospecimens from children with cancer. This protocol provides for the collection of biospecimens and accompanying demographic, epidemiologic, therapeutic, and outcome data from all children diagnosed with cancer at participating COG institutions, independent of the patient’s enrollment on a therapeutic clinical trial. Through this approach, the correlation of phenotypic and genotypic or other –omic data with the relevant outcomes at the individual, disease, and protocol levels will be ensured. Biospecimen requirements and handling may be disease specific and thus a detailed manual of procedures will provide disease specific information regarding sample collection and processing based on the clinical diagnosis. AOST2031 Abstract: Patients with osteosarcoma typically receive a combination of systemic therapy and surgical control of the primary tumor site. Surgical control of pulmonary metastases, the most common site of metastasis for patients with osteosarcoma, is also considered necessary for long term survival. Surgical resection via open surgery (thoracotomy or sternotomy) has been the mainstay of surgical management, and allows for identification, localization, and resection of all metastatic disease. With the advent of minimally invasive surgery, thoracoscopy is now applied to all aspects of chest pathology including cancer operations. The benefits of thoracoscopy include faster patient recovery and healing times, and improved quality of life. While thoracoscopy limits the use of haptic sense achieved by palpation of tissue, randomized controlled trials for adult patients with non-small cell lung cancer have not identified thoracotomy or sternotomy to be superior to thoracoscopy in thoracic event rates. Data for thoracoscopic surgery in pulmonary metastatic osteosarcoma are limited to retrospective reports. This study will be the first randomized controlled trial of surgical approach for pulmonary metastatic osteosarcoma. This study will reduce pulmonary disease heterogeneity by only enrolling patients with 4 or fewer CT identified nodules per lung (henceforth referred to as “oligometastatic”), and preoperative chest CTs will receive central radiologic review to confirm eligibility. Enrolled patients will be stratified by disease status at time of enrollment (newly diagnosed and recurrent disease), each further characterized by risk (considered average and poor) on the basis of the number of pulmonary nodules (1 vs ≥ 2), site of pulmonary nodules (unilateral vs. bilateral), and primary tumor histological response to chemotherapy for newly diagnosed patients (< 10% or > 10% viable tumor in resected specimen). Patients with recurrent disease will also be stratified by the treating oncologists’ intent to treat with chemotherapy for recurrence (yes vs. no). Primary outcome will be thoracic event free survival (thoracic event is defined as intrathoracic tumor recurrence by chest CT or death that results from the procedure or a complication related to the procedure). Correlative outcomes include quality of life from patient- reported outcomes, along with imaging and laboratory studies. AOST2032 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.