Radiation Therapy for the Treatment of Metastatic Gastrointestinal Cancers
Radiation Therapy for the Treatment of Metastatic Gastrointestinal Cancers
This phase II trial studies how well radiation therapy works for the treatment of
 gastrointestinal cancer that are spreading to other places in the body (metastatic).
 Radiation therapy uses high energy x-rays to kill cancer cells and shrink tumors. This trial
 is being done to determine if giving radiation therapy to patients who are being treated with
 immunotherapy and whose cancers are progressing (getting worse) can slow or stop the growth
 of their cancers. It may also help researchers determine if giving radiation therapy to one
 tumor can stimulate the immune system to attack other tumors in the body that are not
 targeted by the radiation therapy.
PRIMARY OBJECTIVE:

 I. To determine whether radiation therapy can convert overall response rates from progressive
 disease to stable or responsive disease as measured by Response Evaluation Criteria in Solid
 Tumors (RECIST) version (v.) 1.1.

 SECONDARY OBJECTIVES:

 I. To define overall response rate by immune-Modified Response Evaluation Criteria in Solid
 Tumors (iRECIST) criteria.

 II. To determine time to progression. III. To determine overall survival. IV. To determine
 local control in radiated lesion(s). V. To characterize the effect of distant radiation on
 unirradiated target lesions.

 VI. To describe the incidence of new metastatic lesions. VII. To determine treatment safety
 by Common Terminology Criteria for Adverse Events (CTCAE) v. 5.0.

 VIII. To describe time to new systemic therapy.

 EXPLORATORY OBJECTIVES:

 I. To define radiation-induced effects on circulating immune cells. II. To describe
 remodeling of the circulating T cell repertoire by deep sequencing of variable, diversity and
 joining (VDJ) regions of T cell receptors (TCRs).

 III. To describe changes in circulating tumor deoxyribonucleic acid (DNA) (ctDNA).

 OUTLINE:

 Patients undergo radiation therapy for a total of 5 treatments over 5-9 calendar days in the
 absence of disease progression or unacceptable toxicity.

 After completion of study treatment, patients are followed up at 14 day, 6 months, and then
 up to 36 months.
Inclusion Criteria:

 -  Patients must have a histologically, cytologically, or radiographically confirmed
 metastatic gastrointestinal (GI) malignancy (esophageal, gastroesophageal, gastric,
 small intestine, hepatocellular, pancreaticobiliary, colorectal, or anal cancer)

 -  Patients must be receiving immunotherapy (checkpoint inhibitor or CTLA4 inhibitor)
 with overall response of progressive disease by RECIST criteria

 -  Patients must have at least two metastases which are individually progressing as per
 RECIST criteria, one of which can be safely unirradiated as adjudicated by the
 treating radiation oncologist (e.g. lesions for which small increases in dimensions
 are unlikely to precipitate significant symptoms)

 -  Patients must have 1-5 sites of disease meeting standard-of-care indications for
 palliative radiation therapy as adjudicated by the treating radiation oncologist. For
 example:

 -  Symptomatic disease causing pain, bleeding, dyspnea, dysphagia, or nausea

 -  At-risk for neurologic, respiratory, cardiovascular, gastrointestinal,
 musculoskeletal, or hepatobiliary compromise

 -  Evaluation by a radiation oncologist within 28 days of study registration

 -  Absolute neutrophil count at least 1,200/microliter (mcL)

 -  Platelets at least 75,000/mcL

 -  Hemoglobin at least 9 g/dL (unless documented bleeding where at least 8 g/dL is
 permitted)

 -  Total bilirubin less than 2 mg/dL or 1.5 X upper limit of normal (ULN)

 -  Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) less than 5 X ULN

 -  International normalized ratio (INR) less than 1.5 X ULN unless on anticoagulation
 therapy

 -  Albumin at least 2.8 g/dL

 -  Creatinine less than 1.5 X ULN and/or creatinine clearance >= 60 mL/min

 -  Life expectancy exceeding 6 months

 -  Eastern Cooperative Oncology Group (ECOG) 0-2 or Karnofsky performance status >= 50

 -  Radiation therapy is known to be teratogenic and therefore women of child-bearing
 potential and men must agree to use adequate contraception (hormonal or barrier method
 of birth control) prior to study entry and for the duration of radiation therapy.
 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. Men
 treated or enrolled on this protocol must also agree to use adequate contraception
 prior to the study and for 3 months after completion of radiation therapy.
 Contraception requirements during the follow-up period of 6 months will be according
 to standard of care for immunotherapy administration.

 -  If a woman is of child-bearing potential, a negative pregnancy test within 28
 days prior to study enrollment is required

 -  Ability to understand a written informed consent document, and the willingness to sign
 it

 Exclusion Criteria:

 -  Enrollment on immunotherapy clinical trial for which radiation therapy is not
 permitted

 -  Administration of radiation therapy within 4 weeks prior to study enrollment

 -  Treatment with systemic corticosteroids or other immunosuppressive medications
 (including but not limited to prednisone, dexamethasone, cyclophosphamide,
 methotrexate, anti-tumor necrosis factor (TNF) agents, etc) within 2 weeks of
 enrollment

 -  Systemic corticosteroids for adrenal insufficiency is not excluded

 -  Systemic corticosteroids for acute asthma, bronchitis, or chronic obstructive
 pulmonary disease exacerbation (less than 2 weeks in duration) is not excluded

 -  Systemic corticosteroids used for short-term purposes (e.g. nausea,
 anti-inflammatory indications for brain/spinal metastases or radiation-induced
 pain flares) are not excluded

 -  Radiation therapy is contraindicated as adjudicated by the radiation oncologist