| Eligibility |
Inclusion Criteria:
- To be enrolled in the safety run-in, patients must have an advanced soft tissue
sarcoma (not otherwise specified [NOS]). To be enrolled in the randomized arms,
patients must have histologically or cytologically confirmed alveolar soft part
sarcoma that is not curable by surgery
- Patients must have measurable disease, defined as at least one lesion that can be
accurately measured in at least one dimension (longest diameter to be recorded 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 by clinical exam
- Patients with unresectable, metastatic and measurable ASPS will be eligible for the
randomized portion of this study if they show clinical evidence of disease progression
(including history and increasing physical symptoms). On-study documentation will
include a physician's rationale that supports evidence of clinical disease progression
(i.e., increasing tumor pain)
- Age >= 18 years. Because no dosing or adverse event data are currently available on
the use of atezolizumab in combination with selinexor in patients ? 18 years of age,
children are excluded from this study
- Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 70%)
- Absolute neutrophil count >= 1,500/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 be enrolled)
- 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 >= 30 mL/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-retroviral
therapy with undetectable viral load within 28 days are eligible for this trial
- Administration of selinexor or atezolizumab may have an adverse effect on pregnancy
and poses a risk to the human fetus, including embryo-lethality. Female patients of
child-bearing potential and male patients must agree to use adequate contraception
(hormonal or barrier method of birth control; abstinence) prior to study entry, for
the duration of study participation, for 90 days after the last dose of selinexor, and
for 150 days after the last dose of atezolizumab, whichever is longer. Breastfeeding
is not allowed while on selinexor or for 90 days after the last dose of selinexor.
Should a woman become pregnant or suspect she is pregnant while she or her partner is
participating in this study, she should inform her treating physician immediately
- Ability to understand and the willingness to sign a written informed consent document
- Willingness to provide biopsy samples for research purposes, except patients enrolled
on the safety run-in. Patients that cannot be safely biopsied may be considered for
the randomized part of 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 intestinal
absorption
- Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for
nitrosoureas or mitomycin C) prior to entering the study. However, the following
therapies are allowed:
- Hormone-replacement therapy or oral contraceptives
- Herbal therapy > 1 week prior to cycle 1, day 1 (herbal therapy intended as
anti-cancer therapy must be discontinued at least 1 week prior to cycle 1, day 1)
- Palliative radiotherapy for bone metastases > 2 weeks prior to cycle 1, day 1
- Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including
anti-CTLA-1, anti-PD-1, or anti-PD-L1 therapeutic antibodies, for patients in the
randomized arms; these prior therapies are allowed for patients in the safety run-in
- Treatment with any other agent administered for the treatment of the patient's cancer,
within five half-lives or 4 weeks prior to cycle 1, day 1, whichever is shorter
- History of malignancy other than ASPS prior to screening, with the exception of
malignancies with a negligible risk of metastasis or death (e.g., 5-year overall
survival [OS] rate > 90%), such as adequately treated carcinoma in situ of the cervix,
non-melanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ, 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 limited to,
prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor
necrosis factor [anti-TNF] agents) within 2 weeks prior to cycle 1, day 1 or
anticipation of need for systemic immunosuppressive medication during study treatment,
with the following exceptions:
- Patients who have received acute, low dose, systemic immunosuppressant
medications or one-time pulse dose of systemic immunosuppressant medication
(e.g., 48 hours of corticosteroids for a contrast allergy) are eligible after
Principal Investigator confirmation has been obtained
- Patients who have received mineralocorticoids (e.g., fludrocortisone),
corticosteroids for chronic obstructive pulmonary disease (COPD) or asthma, or
low-dose corticosteroids for orthostatic hypotension or adrenocortical
insufficiency are eligible
- Patients taking bisphosphonate therapy for symptomatic hypercalcemia. Use of
bisphosphonate therapy for other reasons (e.g., bone metastasis or osteoporosis) is
allowed
- Patients with known primary central nervous system (CNS) malignancy or symptomatic CNS
metastases are excluded, with the following exceptions:
- Patients with asymptomatic untreated CNS disease may be enrolled, provided all of
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 stable dose
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 all
the criteria listed above are met as well as the following:
- Radiographic demonstration of improvement upon the completion of
CNS-directed therapy and no evidence of interim progression between the
completion of CNS-directed therapy and radiographic screening for the
current study
- No stereotactic radiation or whole-brain radiation within 28 days prior to
cycle 1, day 1
- Screening CNS radiographic study >= 4 weeks from completion of radiotherapy
and >= 2 weeks from discontinuation of corticosteroids
- History of severe allergic, anaphylactic, or other hypersensitivity reactions to
chimeric antibodies, fusion proteins, or Chinese hamster ovary cell products or to any
component of the atezolizumab formulation
- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to atezolizumab or selinexor
- Patients with uncontrolled intercurrent illness, prior malignancy, any other disease,
metabolic dysfunction, physical examination finding, or clinical laboratory finding
that contraindicates the use of an investigational drug, may affect the interpretation
of the results, or may render the patient at high risk from treatment complications
- Patients who are pregnant or breastfeeding, or are expecting to conceive or father
children within the projected duration of the study, starting with the screening visit
through 5 months after the last dose of atezolizumab or 3 months after the last 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 to treatment will be
excluded from the study. If the urine test is positive or cannot be confirmed as
negative, a serum pregnancy test will be required. Women of childbearing potential
must have a negative urine pregnancy test result within 8 days prior to initiation of
study treatment. Pregnant women are excluded from this study because atezolizumab is a
monoclonal antibody agent with the potential for teratogenic or abortifacient effects.
Because there is an unknown but potential risk for adverse events in nursing infants
secondary to treatment of the mother with atezolizumab, breastfeeding should be
discontinued if the mother is treated with atezolizumab. These potential risks may
also apply to selinexor. Due to the potential risks, WOCBPs and men must agree to use
adequate contraception (hormonal or barrier method of birth control; abstinence) prior
to study entry, for the duration of study participation, and 5 months after completion
of atezolizumab administration or 3 months after completion of selinexor
administration, whichever is longer. Should a woman become pregnant or suspect she is
pregnant while she or her partner is participating in this study, she should inform
her treating physician immediately
- Patients with prior allogeneic bone marrow transplantation or prior solid organ
transplantation
- Known clinically significant liver disease, including active viral, alcoholic, or
other hepatitis; cirrhosis; fatty liver; and inherited liver disease
- Patients with past or resolved hepatitis B infection (defined as having a
negative hepatitis B surface antigen [HBsAg] test and a positive anti-HBc
[antibody to hepatitis B core antigen] antibody test) are eligible. For these
patients, HBsAg and anti-HBc tests must be done within 28 days prior to
enrollment
- Patients positive for hepatitis C virus (HCV) antibody are eligible only if
polymerase chain reaction (PCR) is negative for HCV ribonucleic acid (RNA). For
these 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, myasthenia
gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid
arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener
granulomatosis, Sjogren syndrome, Guillain-Barre syndrome, or multiple sclerosis, with
the following exceptions:
- Patients with a history of autoimmune-related hypothyroidism on a stable dose of
thyroid replacement hormone may be eligible
- Patients with controlled Type 1 diabetes mellitus on a stable insulin regimen may
be eligible
- Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with
dermatologic manifestations only (e.g., patients with psoriatic arthritis would
be 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 potency
topical 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 or
oral steroids) within the previous 12 months
- History of idiopathic pulmonary fibrosis, pneumonitis (including drug induced),
organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing
pneumonia, etc.), or evidence of active pneumonitis on screening chest computed
tomography (CT) scan. History of radiation pneumonitis in the radiation field
(fibrosis) is permitted
- Patients with 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 are ineligible
- Patients with known history or current symptoms of cardiac disease, or history of
treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac
function using the New York Heart Association Functional classification. To be
eligible 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 prior to
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 to
cycle 1, day 1 (including, but not limited to, hospitalization for complications of
infection, bacteremia, or severe pneumonia) are excluded. Patients receiving
prophylactic antibiotics (e.g., for prevention of a urinary tract infection or chronic
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 or
anticipation that such a live, attenuated vaccine will be required during the study
and 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, attenuated influenza vaccine
within 4 weeks prior to cycle 1, day 1 or at any time during the study
- History of leptomeningeal disease
- Uncontrolled tumor-related pain. Patients requiring pain medication must be on a
stable regimen at study entry, with no changes to their pain regimen in the 4 weeks
prior to enrollment
- Symptomatic lesions (e.g., bone metastases or metastases causing nerve impingement)
amenable to palliative radiotherapy should be treated prior to enrollment. Patients
should be recovered from the effects of radiation. There is no required minimum
recovery period
- Asymptomatic metastatic lesions that would likely cause functional deficits or
intractable pain with further growth (e.g., epidural metastasis that is not currently
associated with spinal cord compression) should be considered for loco-regional
therapy if appropriate prior to enrollment
- Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent
drainage 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 clinical
laboratory finding that contraindicates the use of an investigational drug, may affect
the interpretation of the results, or may render the patient at high risk from
treatment complications
- Current treatment with anti-viral therapy for HBV
- Treatment with investigational therapy within five half-lives or 28 days prior to
initiation of study treatment, whichever is shorter
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