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