Stereotactic Body Radiation Therapy, Tremelimumab and Durvalumab in Treating Participants With Recurrent or Metastatic Cervical, Vaginal, or Vulvar Cancers

Written informed consent obtained from subject prior to any protocol related procedures

Performance status Eastern Cooperative Oncology Group (ECOG) 0-2.

Body weight \> 30 kg

Must have an average life expectancy of 6 months

Patient is able and willing to comply with protocol and study procedures for the duration of the study including undergoing treatment and scheduled visits and examinations including follow-up visits

Histological diagnosis of recurrent or metastatic cervical, vaginal, or vulvar cancer or an unknown pelvic malignancy most likely to have arisen from these sites as determined clinically by the treating physicians (i.e. squamous cell carcinoma or adenocarcinoma that is high risk \[HR\] human papillomavirus positive \[HPV\]+, but not limited to this example)

Metastatic disease in at least two distinct lesions (including the index lesion to be treated) with at least one site outside of the radiation field and evaluable by Response Evaluation Criteria in Solid Tumors (RECIST) criteria for evaluation of response

At least one index lesion to be treated measuring 1 cm amenable to hypofractionated radiation therapy

Staging computed tomography (CT) scans done prior to enrollment

Have had at least one line of prior platinum-based systemic chemotherapy once diagnosed with recurrence or metastatic disease if primary cervical cancer. If a patient has primary vulvar or vaginal cancer, there is not a requirement.

May have received 1 prior biologic regimen (i.e. avastin) but not within 4 weeks of enrollment

Full recovery from the acute effects of prior treatments, defined as effects having resolved to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v) 4.03 grade 0 or 1 with the exception of alopecia and certain laboratory values as outlined below; subjects with irreversible toxicity that is not reasonably expected to be exacerbated by durvalumab and tremelimumab may be included (e.g., hearing loss, neuropathy) upon approval of the principal investigator (PI)

In patients with central nervous system (CNS) metastases, metastases must be asymptomatic at the time of day 1 of the study and meet the following criteria:

* Brain metastases should have been treated with either whole brain radiation therapy (WBRT), stereotactic radiosurgery (SRS)/gamma-knife, or surgical resection;

* At least 28 days without progression of CNS metastases as evidenced by magnetic resonance imaging (MRI) or CT from last day of treatment with radiation to the CNS metastases;

* At least 3 months from surgical resection (if had surgery) with stability on MRI brain at enrollment;

* At least 14 days since last dose of corticosteroids;

* Must not have leptomeningeal disease or cord compression

Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =\< 2.5 x upper limit of normal (ULN); for subjects with liver metastasis, ALT and AST =\< 5 x ULN within 3 weeks prior to initial treatment

Total bilirubin =\< 1.5 x ULN except in patients with documented Gilbert's syndrome or liver metastasis, who must have a baseline total bilirubin =\< 3.0 mg/dl within 3 weeks prior to initial treatment

Serum creatinine clearance (CL) \> 40 mL/min by the Cockcroft-Gault formula or by 24-hour urine collection for determination of creatinine clearance within 3 weeks prior to initial treatment

Negative screening test results for hepatitis B, hepatitis C, and human immunodeficiency virus

Absolute neutrophil count (ANC) \>= 1,500 cells/ul without growth factor support prior to initial treatment

Hemoglobin \>= 9 g/dL prior to initial treatment

Platelet count \>= 100,000 platelets/ul prior to initial treatment

Subjects must either be of non-reproductive potential (ie, post-menopausal by history; OR history of hysterectomy, OR history of bilateral tubal ligation, OR history of bilateral oophorectomy) or must have a negative serum or urine pregnancy test upon study entry; women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause; the following age-specific requirements apply:

* Women \< 50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy); they would also be considered had radiation-induced or chemotherapy-induced menopause with last menses \> 1 year ago

* Women \>= 50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses \> 1 year ago, had chemotherapy-induced menopause with last menses \> 1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy)

* Women of any age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced or chemotherapy-induced menopause

Females of childbearing potential who are sexually active with a nonsterilized male partner must use highly effective method of contraception from the time of screening, and must agree to continue using such precautions for 180 days after the final dose of durvalumab and tremelimumab; cessation of contraception after this point should be discussed with a responsible physician; they must also refrain from egg cell donation for 180 days after the final dose of durvalumab and tremelimumab

* Note: A highly effective method of contraception is defined as one that results in a low failure rate (i.e., less than 1% per year) when used consistently and correctly; the acceptable methods of contraception include barrier methods (male condom plus spermicide, copper T intrauterine device, levonorgesterel-releasing intrauterine system) or hormonal methods (implants, hormone shot or injection, combined pill, minipill, patch)

What this study is about