Testing Atezolizumab With Selinexor in People ≥ 12 Years Old With Alveolar Soft Part Sarcoma, The AXIOM Trial

Inclusion Criteria:

• To be enrolled in the safety run-in, patients must have an advanced soft tissuesarcoma (not otherwise specified [NOS]). To be enrolled in the ASPS cohort, patientsmust have histologically or cytologically confirmed alveolar soft part sarcoma thatis not curable by surgery

• Patients must have measurable disease, defined as at least one lesion that canbe accurately measured in at least one dimension (longest diameter to berecorded for non-nodal lesions and short axis for nodal lesions) as ≥ 20 mm (≥ 2 cm) by chest x-ray or as ≥ 10 mm (≥ 1 cm) with CT scan, MRI, or calipers byclinical exam.

• Patients with unresectable, metastatic and measurable ASPS that isresistant/refractory to ICI treatment will be eligible for the ASPS cohort of thisstudy if they show clinical and/or radiological evidence of disease progressionafter receiving prior ICI therapy (including history and increasing physicalsymptoms). On-study documentation will include a physician's rationale that supportsevidence of clinical disease progression (i.e., increasing tumor pain)

• Age >= 12 years. Because no dosing or adverse event data are currently available onthe use of atezolizumab in combination with selinexor in patients ˂ 18 years of age,children < 12 years of age are excluded from this study

• Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 70%)

• Absolute neutrophil count >= 1,000/mcL

• Platelets >= 100,000/mcL

• Hemoglobin >= 9 g/dL

• Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (however,patients with known Gilbert disease who have serum bilirubin level =< 3 x ULN may beenrolled)

• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 2.5 x institutional ULN or =< 5 x ULN for patients with liver metastases

• Serum creatinine =< 1.5 x institutional ULN OR creatinine clearance >= 30mL/min/1.73 m^2 by Cockcroft-Gault

• Serum albumin >= 2.5 g/dL

• Baseline sodium (Na+) >= 130 mEq/L

• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviraltherapy with undetectable viral load within 28 days are eligible for this trial

• Administration of selinexor or atezolizumab may have an adverse effect on pregnancyand poses a risk to the human fetus, including embryo-lethality. Female patients ofchild-bearing potential and male patients must agree to use highly effectivecontraception (hormonal or barrier method of birth control; abstinence) prior tostudy entry, for the duration of study participation, for 90 days after the lastdose of selinexor, and for 150 days after the last dose of atezolizumab, whicheveris longer. Breastfeeding is not allowed while on selinexor or for 90 days after thelast dose of selinexor. Should a woman become pregnant or suspect she is pregnantwhile she or her partner is participating in this study, she should inform hertreating physician immediately

• Ability to understand and the willingness to sign a written informed consentdocument

• Willingness to provide biopsy samples for research purposes, except patientsenrolled on the safety run-in. Patients that cannot be safely biopsied may beconsidered for the study upon discussion with principal investigator

• Ability and willingness to swallow pills

• Vaccines intended to prevent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease 2019 (COVID-19) are allowed

Exclusion Criteria:

• Malabsorption syndrome or other conditions that would interfere with intestinalabsorption

• Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks fornitrosoureas or mitomycin C) prior to entering the study. However, the followingtherapies are allowed:

• Hormone-replacement therapy or oral contraceptives

• Herbal therapy > 1 week prior to cycle 1, day 1 (herbal therapy intended asanti-cancer therapy must be discontinued at least 1 week prior to cycle 1, day

• Palliative radiotherapy for bone metastases > 2 weeks prior to cycle 1, day 1

• Treatment with any other agent administered for the treatment of the patient'scancer, within five half-lives or 3 weeks prior to cycle 1, day 1, whichever isshorter

• History of malignancy other than ASPS prior to screening, with the exception ofmalignancies with a negligible risk of metastasis or death (e.g., 5-year overallsurvival [OS] rate > 90%), such as adequately treated carcinoma in situ of thecervix, non-melanoma skin carcinoma, localized prostate cancer, ductal carcinoma insitu, or stage I uterine cancer

• Treatment with systemic immunostimulatory agents (including, but not limited to,interferon and interleukin 2 [IL-2]) within 4 weeks or 5 half-lives of the drug (whichever is longer) prior to initiation of study treatment

• Treatment with systemic immunosuppressive medications (including, but not limitedto, prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, andanti-tumor necrosis factor [anti-TNF] agents) within 2 weeks prior to cycle 1, day 1or anticipation of need for systemic immunosuppressive medication during studytreatment, with the following exceptions:

• Patients who have received acute, low dose, systemic immunosuppressantmedications or one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of corticosteroids for a contrast allergy) are eligible afterPrincipal Investigator confirmation has been obtained

• Patients who have received mineralocorticoids (e.g., fludrocortisone),corticosteroids for chronic obstructive pulmonary disease (COPD) or asthma, orlow-dose corticosteroids for orthostatic hypotension or adrenocorticalinsufficiency are eligible

• Patients taking bisphosphonate therapy for symptomatic hypercalcemia. Use ofbisphosphonate therapy for other reasons (e.g., bone metastasis or osteoporosis) isallowed

• Patients with known primary central nervous system (CNS) malignancy or symptomaticCNS metastases are excluded, with the following exceptions:

• Patients with asymptomatic untreated CNS disease may be enrolled, provided allof the following criteria are met:

• Evaluable or measurable disease outside the CNS

• No metastases to brain stem, midbrain, pons, medulla, or cerebellum

• No history of intracranial hemorrhage or spinal cord hemorrhage

• No ongoing requirement for dexamethasone for CNS; patients on a stabledose of anticonvulsants are permitted.

• No neurosurgical resection or brain biopsy within 28 days prior to cycle 1, day 1

• Patients with asymptomatic treated CNS metastases may be enrolled, provided allthe criteria listed above are met as well as the following:

• Radiographic demonstration of improvement upon the completion ofCNS-directed therapy and no evidence of interim progression between thecompletion of CNS-directed therapy and radiographic screening for thecurrent study

• No stereotactic radiation or whole-brain radiation within 28 days prior tocycle 1, day 1

• Screening CNS radiographic study >= 4 weeks from completion ofradiotherapy and >= 2 weeks from discontinuation of corticosteroids

• History of severe allergic, anaphylactic, or other hypersensitivity reactions tochimeric antibodies, fusion proteins, or Chinese hamster ovary cell products or toany component of the atezolizumab formulation

• History of allergic reactions attributed to compounds of similar chemical orbiologic composition to atezolizumab or selinexor

• Patients with uncontrolled intercurrent illness, prior malignancy, any otherdisease, metabolic dysfunction, physical examination finding, or clinical laboratoryfinding that contraindicates the use of an investigational drug, may affect theinterpretation of the results, or may render the patient at high risk from treatmentcomplications

• Patients who are pregnant or breastfeeding, or are expecting to conceive or fatherchildren within the projected duration of the study, starting with the screeningvisit through 5 months after the last dose of atezolizumab or 3 months after thelast dose of selinexor, whichever is longer. A woman of childbearing potential (WOCBP) who has a positive urine pregnancy test (e.g., within 8 days) prior totreatment will be excluded from the study. If the urine test is positive or cannotbe confirmed as negative, a serum pregnancy test will be required. Women ofchildbearing potential must have a negative urine pregnancy test result within 8days prior to initiation of study treatment. Pregnant women are excluded from thisstudy because atezolizumab is a monoclonal antibody agent with the potential forteratogenic or abortifacient effects. Because there is an unknown but potential riskfor adverse events in nursing infants secondary to treatment of the mother withatezolizumab, breastfeeding should be discontinued if the mother is treated withatezolizumab. These potential risks may also apply to selinexor. Due to thepotential risks, WOCBPs and men must agree to use highly effective contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, forthe duration of study participation, and 5 months after completion of atezolizumabadministration or 3 months after completion of selinexor administration, whicheveris longer. Should a woman become pregnant or suspect she is pregnant while she orher partner is participating in this study, she should inform her treating physicianimmediately

• Patients with prior allogeneic bone marrow transplantation or prior solid organtransplantation

• Known clinically significant liver disease, including active viral, alcoholic, orother hepatitis; cirrhosis; fatty liver; and inherited liver disease

• Patients with past or resolved hepatitis B infection (defined as having anegative hepatitis B surface antigen [HBsAg] test and a positive anti-HBc [antibody to hepatitis B core antigen] antibody test) are eligible. For thesepatients, HBsAg and anti-HBc tests must be done within 28 days prior toenrollment

• Patients positive for hepatitis C virus (HCV) antibody are eligible only ifpolymerase chain reaction (PCR) is negative for HCV ribonucleic acid (RNA). Forthese patients, an HCV RNA test must be done within 28 days prior to enrollment

• History or risk of autoimmune disease, including, but not limited to, myastheniagravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoidarthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegenergranulomatosis, Sjogren syndrome, Guillain-Barre syndrome, or multiple sclerosis,with the following exceptions:

• Patients with a history of autoimmune-related hypothyroidism on a stable doseof thyroid replacement hormone may be eligible

• Patients with controlled Type 1 diabetes mellitus on a stable insulin regimenmay be eligible

• Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo withdermatologic manifestations only (e.g., patients with psoriatic arthritis wouldbe excluded) are permitted provided all of the following conditions are met:

• Rash must cover less than 10% of body surface area (BSA)

• Disease is well controlled at baseline and only requiring low potencytopical steroids

• No acute exacerbations of underlying condition within the last 12 months (not requiring psoralen plus ultraviolet A radiation [PUVA], methotrexate,retinoids, biologic agents, oral calcineurin inhibitors; high potency ororal steroids) within the previous 12 months

• History of idiopathic pulmonary fibrosis, pneumonitis (including drug induced),organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizingpneumonia, etc.), or evidence of active pneumonitis on screening chest computedtomography (CT) scan. History of radiation pneumonitis in the radiation field (fibrosis) is permitted

• Patients with significant cardiovascular disease (such as New York Heart Associationclass II or greater cardiac disease, myocardial infarction, or cerebrovascularaccident) within 3 months prior to initiation of study treatment, unstablearrhythmia, or unstable angina are ineligible

• Patients with known history or current symptoms of cardiac disease, or history oftreatment with cardiotoxic agents, should have a clinical risk assessment of cardiacfunction using the New York Heart Association Functional classification. To beeligible for this trial, patients should be class IIB or better

• Patients with active tuberculosis (TB) are excluded

• Patients with mild or moderate signs or symptoms of infection within 2 weeks priorto cycle 1, day 1 (including, but not limited to, receiving oral or intravenous [IV]antibiotics) are excluded. Patients with severe infections within 4 weeks prior tocycle 1, day 1 (including, but not limited to, hospitalization for complications ofinfection, bacteremia, or severe pneumonia) are excluded. Patients receivingprophylactic antibiotics (e.g., for prevention of a urinary tract infection orchronic obstructive pulmonary disease) are eligible

• Major surgical procedure within 28 days prior to cycle 1, day 1

• Administration of a live, attenuated vaccine within 4 weeks before cycle 1, day 1 oranticipation that such a live, attenuated vaccine will be required during the studyand up to 5 months after the last dose of atezolizumab

• Influenza vaccination should be given during influenza season only (approximately October to March). Patients must not receive live, attenuatedinfluenza vaccine within 4 weeks prior to cycle 1, day 1 or at any time duringthe study

• History of leptomeningeal disease

• Uncontrolled tumor-related pain. Patients requiring pain medication must be on astable regimen at study entry, with no changes to their pain regimen in the 4 weeksprior to enrollment

• Symptomatic lesions (e.g., bone metastases or metastases causing nerve impingement)amenable to palliative radiotherapy should be treated prior to enrollment. Patientsshould be recovered from the effects of radiation. There is no required minimumrecovery period

• Asymptomatic metastatic lesions that would likely cause functional deficits orintractable pain with further growth (e.g., epidural metastasis that is notcurrently associated with spinal cord compression) should be considered forloco-regional therapy if appropriate prior to enrollment

• Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrentdrainage procedures (once monthly or more frequently)

• Patients with indwelling catheters (e.g., PleurX [registered trademark]) are allowed

• Uncontrolled or symptomatic hypercalcemia (ionized calcium > 1.5 mmol/L, calcium > 12 mg/dL or corrected serum calcium > ULN)

• Any other disease, metabolic dysfunction, physical examination finding, or clinicallaboratory finding that contraindicates the use of an investigational drug, mayaffect the interpretation of the results, or may render the patient at high riskfrom treatment complications

• Current treatment with anti-viral therapy for HBV

• Treatment with investigational therapy within five half-lives or 28 days prior toinitiation of study treatment, whichever is shorter