Atezolizumab with Stereotactic Body Radiation Therapy and Surgery for the Treatment of Patients with Osteosarcoma with Pulmonary Metastasis

Inclusion Criteria

• Subjects must be ≤ 50 years of age at the time of study enrollment
• Patients must have had histologic verification of osteosarcoma at original diagnosis or relapse
• Patients must be in first or greater relapse of osteosarcoma
• Recurrence must be limited to the lung, but can be unilateral or bilateral
• All pulmonary nodules must be resectable as determined by institutional surgeon. Resectable pulmonary nodules are defined as nodules that can be removed without performing a pneumonectomy (e.g., nodules immediately adjacent to the main stem bronchus or main pulmonary vessels). There is no max number of lesions provided the surgeon thinks a complete surgical remission can be achieved
• Patients must have at least 1 lesion that is ≥ 5 mm and meets criteria to receive SBRT AND an additional nodule(s) that meets protocol definition for a metastatic nodule necessitating surgical resection: single nodule ≥ 5 mm, or ≥ 2 nodules ≥ 3 mm in size
• Patients must have a Lansky (≤ 16 years) or Karnofsky (> 16 years) score of ≥ 60, or Eastern Cooperative Oncology Group (ECOG) performance score ≤ 2 NOTE: Patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score
• All prior treatment-related toxicities must have resolved to ≤ grade 1 OR be determined clinically stable by the treating investigator. * Myelosuppressive chemotherapy: ≥ 14 days after the last dose of myelosuppressive chemotherapy. * Hematopoietic growth factors: ≥ 14 days after the last dose of a long-acting growth factor (e.g., Pegfilgrastim) or 7 days for a short acting growth factor. ** For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur. The duration of this interval must be discussed with the study principal investigator (PI). * Biologic (anti-neoplastic) agent: ≥ 7 days after the last dose of a biologic agent. ** For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur. The duration of this interval must be discussed with the study PI. * Cellular therapy: ≥ 21 days must have elapsed from last dose of any type of cellular therapy (e.g., modified T cells, natural killer [NK] cells, dendritic cells, etc.) with resolution of any associated toxicities. * Interleukins, interferons, and cytokines (other than hematopoietic growth factors): ≥ 21 days must have elapsed from the last dose of interleukins, interferon, or cytokines (other than hematopoietic growth factors). * Antibodies: 7 days or 3 half-lives (whichever is longer) but not longer than 30 days, and toxicity related to prior antibody therapy must be recovered to grade ≤ 1. * Autologous Stem Cell Transplant or Rescue: ≥ 6 weeks must have elapsed since stem cell transplant or rescue * Radiotherapy (XRT): ≥ 14 days after 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 total body irradiation (TBI) was received; ≥ 6 weeks must have elapsed if other substantial bone marrow radiation was given * Investigational Agents Not Otherwise Specified: ≥ 28 days must have elapsed since the last dose of any investigational agent not specified above. For agents with an uncertain washout period or for any questions or uncertainty the study PI should be notified * Thoracic Surgery or Procedure: ≥ 28 days must have elapsed since prior thoracotomy, thoracoscopy, or thoracentesis
• Peripheral absolute neutrophil count (ANC) ≥ 750/mm^3 * Must be performed within seven (7) days prior to enrollment unless otherwise indicated. Laboratory values used to assess eligibility must be no older than 7 days at the start of therapy. Laboratory tests need not be repeated if therapy starts within 7 days of obtaining labs to assess eligibility.
• Platelet count ≥ 50,000/mm^3. Must be transfusion independent defined as not receiving platelet transfusions for at least 7 days prior to enrollment * Must be performed within seven (7) days prior to enrollment unless otherwise indicated. Laboratory values used to assess eligibility must be no older than 7 days at the start of therapy. Laboratory tests need not be repeated if therapy starts within 7 days of obtaining labs to assess eligibility.
• A serum creatinine based on age/gender as follows: * < 6 years - Male (maximum serum creatinine 0.8 mg/dL) Female (maximum serum creatinine 0.8 mg/dL) * 6 to < 10 years - Male (maximum serum creatinine 1 mg/dL) Female (maximum serum creatinine 1 mg/dL) * 10 to < 13 years - Male (maximum serum creatinine 1.2 mg/dL) Female (maximum serum creatinine 1.2 mg/dL) * 13 to < 16 years - Male (maximum serum creatinine 1.5 mg/dL) Female (maximum serum creatinine 1.4 mg/dL) * ≥ 16 years - Male (maximum serum creatinine 1.7 mg/dL) Female (maximum serum creatinine 1.4 mg/dL) OR * Creatinine clearance or radioisotope ≥ glomerular filtration rate (GFR) 70ml/min/1.73 m^2 ** Must be performed within seven (7) days prior to enrollment unless otherwise indicated. Laboratory values used to assess eligibility must be no older than 7 days at the start of therapy. Laboratory tests need not be repeated if therapy starts within 7 days of obtaining labs to assess eligibility. ** If a post-enrollment lab value is outside the limits of eligibility, or laboratory values are older than 7 days, then serum creatinine must be re-checked within 72 hours prior to initiating therapy. If the recheck is outside the limits of eligibility, the subject may not receive protocol therapy and will be considered off protocol therapy
• Total bilirubin ≤ 1.5 x the upper limit of normal (ULN) for age * Must be performed within seven (7) days prior to enrollment unless otherwise indicated. Laboratory values used to assess eligibility must be no older than 7 days at the start of therapy. Laboratory tests need not be repeated if therapy starts within 7 days of obtaining labs to assess eligibility. * If a post-enrollment lab value is outside the limits of eligibility, or laboratory values are older than 7 days, then total bilirubin must be re-checked within 72 hours prior to initiating therapy. If the recheck is outside the limits of eligibility, the subject may not receive protocol therapy and will be considered off protocol therapy.
• ALT (SGPT) ≤ 3 x the ULN. For the purpose of this study, the ULN for ALT (SGPT) is 45 U/L * Must be performed within seven (7) days prior to enrollment unless otherwise indicated. Laboratory values used to assess eligibility must be no older than 7 days at the start of therapy. Laboratory tests need not be repeated if therapy starts within 7 days of obtaining labs to assess eligibility. * If a post-enrollment lab value is outside the limits of eligibility, or laboratory values are older than 7 days, then ALT (SGPT) must be re-checked within 72 hours prior to initiating therapy. If the recheck is outside the limits of eligibility, the subject may not receive protocol therapy and will be considered off protocol therapy.
• Serum lipase ≤ 1.5 x ULN * Must be performed within seven (7) days prior to enrollment unless otherwise indicated. Laboratory values used to assess eligibility must be no older than 7 days at the start of therapy. Laboratory tests need not be repeated if therapy starts within 7 days of obtaining labs to assess eligibility.
• Normal free T4 (replacement therapy allowed) * Must be performed within seven (7) days prior to enrollment unless otherwise indicated. Laboratory values used to assess eligibility must be no older than 7 days at the start of therapy. Laboratory tests need not be repeated if therapy starts within 7 days of obtaining labs to assess eligibility.
• No dyspnea at rest
• Pulse oximetry > 92% on room air
• Corrected QT interval (QTc) ≤ 480 msec
• Shortening fraction ≥ 27% by echocardiogram or ejection fraction ≥ 50% by gated radionuclide study or echocardiogram
• Urine protein: Meets one of the following criteria: (1) urinary protein by urine dipstick is ≤ 100 mg/dL or ≤ 2+; OR (2) urine protein creatinine (UPC) ratio < 3.5; OR (3) if 24-hour urine protein was measured, urinary protein ≤ 3500 mg.
• Life expectancy of at least 4 months
• Negative urine or serum pregnancy test in women of childbearing potential
• Sexually active patients of reproductive potential are not eligible unless they have agreed to use an effective contraceptive method for the duration of their study participation. Patients should maintain adequate contraception for at least 5 months after the last dose of atezolizumab. Adequate contraception is defined as abstinence or use of contraceptive with a failure rate of < 1% per year
• All patients and/or their parents or legal guardians must sign a written informed consent and assent

Exclusion Criteria

• Female patients who are pregnant are not eligible
• Lactating females are not eligible unless they have agreed not to breastfeed their infants
• Active metastatic disease outside of the lungs including bone, central nervous system (CNS), or any extrapulmonary involvement
• > grade 1 pleural effusion
• Prior lung radiation
• Active autoimmune disorder that has required systemic treatment in the past 12 months, or a documented history of severe autoimmune disorder, or a syndrome that requires systemic steroids or immunosuppressive agents. Patients with type 1 diabetes mellitus, hypothyroidism only requiring hormone replacement, or skin disorders such as vitiligo, psoriasis, or alopecia not requiring systemic treatment may be permitted to enroll. Physiologic corticosteroid replacement for conditions such as adrenal or pituitary insufficiency is allowed
• Significant cardiovascular disease (such as New York Heart Association Class II or greater cardiac disease, myocardial infarction, or cerebrovascular accident) within 3 months prior to initiation of study treatment, unstable arrhythmia, or unstable angina
• Prior treatment with an immune checkpoint inhibitor is allowed provided it was not permanently discontinued due to toxicity and was not given with radiation
• Active tuberculosis
• Any medical condition or illness that would compromise the patient’s ability to undergo surgery, cause unacceptable safety risk, or compromise compliance with the protocol
• Chronic use of immunosuppressive therapies. Patient may not have received immunosuppressant medications, including corticosteroids, within 14 days of enrollment. However, patients who are currently or have previously been on any of the following steroid regimens are not excluded: * Physiologic steroid replacement for adrenal insufficiency * Topical, ocular, intra-articular, intranasal, or inhaled corticosteroid with minimal systemic absorption. * Short course (≤ 7 days) of corticosteroid prescribed prophylactically (e.g., for contrast dye allergy) or for the treatment of a non autoimmune condition (e.g., delayed-type hypersensitivity reaction caused by contact allergen)
• Patients with an uncontrolled infection
• Subjects who have received prior allogeneic stem cell transplant or solid organ transplant are not eligible
• Patients who, in the opinion of the investigator, may not be able to comply with the protocol required procedures
• Patients who are currently receiving any other investigational or anti-cancer agents
• Patients with a known history of HIV, hepatitis B, and/or hepatitis C (testing not required as part of screening)
• Current or prior pneumonitis
• Live/attenuated vaccine administered within 30 days of enrollment