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Age ≥ 5 years at the time of enrollment. Every effort will be made to ensure that 50% of patients will be ≤ 21 years of age |
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Histologically confirmed high grade osteosarcoma (excluding osteosarcoma associated with Paget disease of bone or extraskeletal osteosarcoma) at diagnosis or relapse |
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Must have relapsed or refractory osteosarcoma following at least one line of systemic |
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therapy for the initial treatment of osteosarcoma |
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Must be able to swallow intact pills |
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Performance Status: Lansky (≤ 16 years of age) or Karnofsky (>16 years of age) |
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performance score of ≥ 70, or Eastern Cooperative Oncology Group (ECOG) performance |
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Absolute Neutrophil Count (ANC) ≥ 1000/mm3 |
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score 0 or 1. See Appendix A. Patients who are unable to walk because of paralysis |
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Platelets ≥ 75 000/mm3 |
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but who are up and about in a wheelchair, will be considered ambulatory for the |
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Hemoglobin ≥ 8 g/ dL (transfusions allowed) |
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purpose of assessing the performance score |
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At least one site of measurable disease on CT/MRI scan as defined by RECIST 1.1 |
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Serum albumin ≥ 3 g/dL |
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Baseline imaging must be performed within 21 days of Day 1 of study therapy |
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Adequate organ and bone marrow function within 7 days of Day 1 of study therapy |
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Normal free T4. Replacement therapy allowed |
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defined as |
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Serum lipase ≤ 1.5 x ULN |
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INR ≤ 1.5 x ULN |
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Adequate pulmonary function defined as |
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ALT and AST ≤ 3 x institutional upper limit of normal (ULN) or ≤ 5.0 x institutional |
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No evidence of dyspnea at rest |
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ULN if considered due to tumor |
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Pulse Oximetry >92% on room air |
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Serum total bilirubin ≤ 1.5 x institutional ULN. NOTE: Patients with elevated |
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Adequate cardiac function defined as |
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bilirubin secondary to Gilbert's disease are eligible to participate in the study |
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QTc ≤ 480 msec |
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Serum creatinine ≤ 3 x institutional ULN or 24-hour creatinine clearance ≥ 30 ml/min |
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(calculated creatinine clearance using Cockcroft formula is acceptable) |
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Urine protein: Meets one of the following criteria: (i) urinary protein by urine |
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dipstick is ≤ 100mg/dL or ≤ 2+ (ii) Urine Protein Creatinine(UPC) ratio <3.5 (iii) |
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-hour urine protein was measured, urinary protein ≤ 3500 mg |
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No activity limitation due to pulmonary insufficiency |
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Voluntary, written informed consent |
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Shortening fraction ≥ 27% by echocardiogram or ejection fraction ≥ 50% by gated |
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radionuclide study or echocardiogram |
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No congestive heart failure (CHF) worse than New York Heart Association Functional |
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Classification Class I |
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No clinically significant cardiac arrhythmias, stroke or myocardial infarction within |
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months prior to enrollment |
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Prior Therapy: All prior treatment-related toxicities must have resolved to ≤ Grade 1 |
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or be determined clinically stable by the Investigator |
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Myelosuppressive chemotherapy: Patients must not have received myelosuppressive |
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chemotherapy within 3 weeks of enrollment |
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Hematopoietic growth factors: At least 7 days must have elapsed since the completion |
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of therapy with a white blood cell or platelet growth factor. At least 14 days must |
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have elapsed after receiving pegfilgrastim |
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Biologic (anti-neoplastic agent): At least 7 days must have elapsed since completion |
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of therapy with a biologic agent |
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Monoclonal antibodies: At least 21 days must have elapsed since prior therapy that |
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included a monoclonal antibody (e.g., dinutuximab, denosumab, bevacizumab) |
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Radiotherapy: ≥ 2 weeks must have elapsed since local palliative XRT (small port); ≥ 3 |
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months must have elapsed if prior craniospinal XRT was received, if ≥ 50% of the |
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pelvis was irradiated, or if TBI was received; ≥ 6 weeks must have elapsed if other |
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substantial bone marrow irradiation was given |
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Autologous Stem Cell Transplant or Rescue or Cellular Therapy: ≥ 2 months must have |
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elapsed since transplant/cellular therapy |
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Negative urine or serum pregnancy test in women of childbearing potential. Women of |
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childbearing potential includes pre-menarchal girls with evidence of puberty onset |
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and adult women through the end of the first 2 years of the onset of menopause |
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Testing should be completed ≤ 7 days prior to Day 1 of study |
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Fertile men and women of childbearing potential must agree to use an effective method |
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of birth control from Day 1 of study and for 5 months after last dose of nivolumab or |
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for 8 weeks after last dose of regorafenib, whichever is longer |
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Effective methods of birth control include: surgical sterility (subject or subject's |
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partner), barrier device (condom, diaphragm), contraceptive coil (IUD), abstinence, or |
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oral contraception |
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Patients with central nervous system (CNS) disease are eligible if they have received |
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prior radiotherapy or surgery to sites of CNS metastatic disease and are without |
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evidence of progression for at least 4 weeks after CNS therapy |
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Patients >18 years must be willing to undergo tumor biopsy at study entry and |
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post-treatment biopsy for biologic correlates. If biopsy is contra-indicated, enrollment |
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must be approved by study PI and archival tissue must be available |
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Women who are pregnant or nursing/breastfeeding
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Inability to comply with protocol required procedures
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Patients with autoimmune disease
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Chronic use of immunosuppressive therapies
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Received any investigational drug within 28 days of study enrollment
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Uncontrolled infection
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Live/attenuated vaccine administered within 30 days of enrollment
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Any hemorrhage or bleeding event CTCAE ≥ Grade 3 within 28 days of study enrollment
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Body surface area (BSA) < 0.4 m2
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Patients with prior or concurrent malignancy whose natural history or treatment has
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the potential to interfere with the safety or efficacy assessment of the
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investigational regimen in this trial
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Patients with severe and/or uncontrolled concurrent medical disease that in the
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opinion of the investigator could cause unacceptable safety risks or compromise
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compliance with the protocol
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Major surgery (thoracotomy or laparotomy, etc.), laparoscopic biopsy, or significant
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traumatic injury within 28 days prior to Day 1 of study or who have not recovered
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adequately from prior surgery
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Known hypersensitivity to excipients of the formulations of regorafenib or nivolumab
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or similar agents
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Prior therapy with an immune checkpoint inhibitor or a tyrosine kinase inhibitor
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targeting VEGF
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Known active HIV. Testing is not required. HIV-infected patients on effective
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anti-retroviral therapy with undetectable viral load within 6 months are eligible for
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this trial. However, strong CYP3A4 inhibitors are prohibited
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Known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA
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[qualitative] is detected)
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Prior allogeneic hematopoietic stem cell/bone marrow transplant or solid organ
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transplant
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Uncontrolled hypertension defined as on average, > 140 systolic pressure or > 90
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diastolic pressure in patient ≥ 18 y/o or > 95th percentile for age/gender in patients
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< 18 y/o despite medical management. If blood pressure is borderline, ensure patient
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is properly prepared (relaxed, sitting in chair for > 3 minutes), proper technique is
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used (correct cuff size and positioning), and document 2 separate recordings, each at
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least >5 minutes apart
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History of clinically significant venous or arterial thrombotic or embolic event
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requiring systemic anticoagulation within 6 months of enrollment
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Requirement of oral anticoagulant therapy with oral vitamin K antagonists (warfarin)
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Low-dose anticoagulants for maintenance of patency of central venous device or
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prevention of deep venous thrombosis is allowed. Therapeutic use of low molecular
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weight heparin or direct oral anticoagulants is allowed, providing the event prompting
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treatment occurred > 6 months prior. Subjects who are prophylactically being treated
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with an agent such as heparin will be allowed to participate, provided no prior
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evidence of underlying abnormality in coagulation parameters exists
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Presence of non-healing wound, non-healing ulcer or fracture (excluding pathologic
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fracture)
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Pleural effusion or ascites that causes respiratory compromise (≥ CTCAE Grade 2
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dyspnea)
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Significant currently active gastrointestinal disorders with diarrhea as a major
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symptom e.g., Crohn's disease, malabsorption, or CTCAE Grade ≥ 2 diarrhea of any
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etiology
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Patients with history of bowel perforation or fistula formation
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Patients receiving or requiring strong CYP3A4 inhibitors (e.g., clarithromycin
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grapefruit juice, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir
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posaconazole, ritonavir, saquinavir, telithromycin, voriconazole) or strong CYP3A4
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inducers (e.g., carbamazepine, phenobarbital, phenytoin, rifampin, St. John's wort)
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