A Study of Several Radiation Doses for Patients With Progression on Immunotherapy/Checkpoint Inhibitors

Inclusion Criteria:

* Subjects must have signed and dated an IRB approved written informed consent form in accordance with regulatory and institutional guidelines.
* Subjects must be willing and able to comply with scheduled visits, treatment schedule, laboratory testing, and other study obligations.
* Males and females ≥ 18 years of age.
* Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
* Histologically confirmed metastatic cancer of any histology for which there is an FDA indication for an immune checkpoint inhibitor including melanoma, lung, bladder, renal and head/neck cancers.
* Patient has been receiving treatment with an immune checkpoint inhibitor including but not limited to ipilimumab, nivolumab, avelumab, durvalumab, pembrolizumab, atezolizumab, and tremelimumab for at least 2 months. A combination of these therapies is also permitted. No max prior lines of therapy.
* Patient has evidence of limited progression (up to 5 lesions either new or increase in at least 25% in the cross-sectional diameter of a known lesion) on most recent systemic imaging as determined by the treating physician. Patients with greater than 5 lesions can be included after discussion with the study investigators.
* Patient must be eligible to continue to receive an immune checkpoint inhibitor after radiotherapy.
* Subjects must have at least two lesions:

  * One lesion must be safely amenable to irradiation in the opinion of the treating radiation oncologist. This can be a lesion that was previously irradiated if it is deemed appropriate by the treating physician and principal investigator. Standard MSKCC re-irradiation dose constraints must be met.
  * At least one, not-to-be-irradiated lesion measurable by CT or MRI per RECIST 1.1 criteria.
* Prior palliative or curative radiotherapy must be completed at least 14 days prior to treatment.
* Immunosuppressive doses of systemic medication, such as steroids or absorbed topical steroids (doses \>10mg/day prednisone or equivalent) must be discontinued at least 14 days prior to radiotherapy administration.
* Women of childbearing potential must have a negative serum within 7 days prior to treatment, or urine pregnancy test (within 24 hours) (minimum sensitivity 25 IU/L or equivalent units of HCG). Women of childbearing potential must agree to follow instructions for method(s) of contraception from time of enrollment for the duration of treatment.
* Men who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year.

Notes:

* Women who are not of childbearing potential i.e., who are postmenopausal or surgically sterile as well as azoospermia men do not require contraception.
* Azoospermic males, and women of childbearing potential who are continuously not heterosexually active, are exempt from contraceptive requirements. However, they still must have a pregnancy test.
* Exclusion Criteria:

  * Active brain metastases (untreated brain metastases or growth on imaging as defined below) or leptomeningeal disease are not allowed. Subjects with brain metastases are eligible if these have been treated and there is no MRI (or CT if MRI contraindicated) evidence of progression for at least 8 weeks after treatment for these metastases is complete and within 28 days prior to first study treatment.
  * Any medical disorder that, in the opinion of the investigator, might increase the risk associated with study participation or interferes with the interpretation of study results.
  * Prior active malignancy within the previous 3 years except for locally curable cancers such as basal or squamous skin cancer, superficial bladder, low risk prostate cancer, breast, or cervix cancer. If other prior malignancy was active within prior 3 years, enrollment requires approval of a principal investigator.
  * Patients should be excluded if they have an active, known or suspected autoimmune disease. Subjects are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger
  * Subjects requiring systemic treatment with either corticosteroids (\> 10 mg daily prednisone equivalents for greater than 5 days) or other immunosuppressive medications within 14 days of study drug administration should be excluded. Inhaled or topical steroids and adrenal replacement doses \>10mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
  * Treatment with any other chemotherapy, radiation therapy, biologics for cancer, or investigational therapy concurrently or within 14 days of enrollment
  * History of allergy to checkpoint inhibitors
  * History of severe hypersensitivity reaction to any monoclonal antibody.
  * Women must not be breastfeeding.