SARC038: A Phase 2 Study of Regorafenib in Combination With Nivolumab in Patients With Refractory or Recurrent Osteosarcoma

• 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.

• Histologically confirmed high grade osteosarcoma (excluding osteosarcoma associated with Paget disease of bone or extraskeletal osteosarcoma) at diagnosis or relapse.

⁃ Must have relapsed or refractory osteosarcoma following at least one line of systemic therapy for the initial treatment of osteosarcoma.

• 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 defined as:

• 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 activity limitation 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

• No congestive heart failure (CHF) worse than New York Heart Association Functional Classification Class I.

• 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-menarchal 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 oral contraception.

• 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 \>18 years must be willing to undergo tumor biopsy at study entry and post-treatment biopsy for biologic correlates. If biopsy is contra-indicated, enrollment must be approved by study PI and archival tissue must be available.