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Patients undergo radiation therapy for a total of 5 treatments over 5-9 calendar days in the absence of disease progression or unacceptable toxicity. Target prescription dose will be 30 Gy in 5 fractions and each treatment site (up to 5) will undergo standard Department-approved treatment planning, quality-assurance, and delivery protocols

Radiation Therapy (RT)

Hewitt Chang

Mary Feng, MD

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.

Radiation Therapy for the Treatment of Metastatic Gastrointestinal Cancers

Phase II Study of Hypofractionated Radiation Therapy to Augment Immune Response in Patients With Metastatic GastroIntestinal Malignancies Progressing on Immune Therapy (ARM-GI)

Proportion of patients who achieve as their best overall response according to Response Evaluation Criteria in Solid Tumors (RECIST) v. 1.1 criteria: Stable disease (SD), partial response (PR), confirmed Complete Response (CR), or progressive disease (PD). Corresponding exact confidence intervals will be reported for the entire cohort and stratified by histologic subtype, programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) status, microsatellite instability (MSI), and organs treated if sample size allows. Patients with unevaluable or unknown response status will be considered nonresponders.

Will be determined by immune-Modified Response Evaluation Criteria in Solid Tumors (iRECIST). Immune Complete Response (iCR), Partial Response (iPR), or Stable Disease (iSD) per definitions of CR, PR, and SD, but occurring after initial immune unconfirmed progressive disease (iUPD). The same definition will be used for per lesion analysis. PD will be designated for all patients with PD determination by RECIST v1.1 or immune-confirmed progressive disease (iCPD) by iRECIST. Unconfirmed response for all patients designated as iUPD. Will be reported as proportion of response and corresponding exact confidence intervals. Patients with unevaluable or unknown response status will be considered nonresponders.

PFS is defined as the duration of time from start of radiation treatment to time of progression or death a proportion with exact confidence intervals and will be reported for the entire cohort and stratified by histologic subtype, PD1/PDL1 status, MSI, and organs treated if sample size allows. Time to local progression will be described using the cumulative incidence method and comparisons between strata via Gray's test, if sample size allows; Otherwise, Kaplan-Meier methodology will be used and comparisons will be made via log-rank test; and Cox proportional hazards analysis, if possible.

OS will be measured from the date of initiation of RT. OS is defined as the time from the date of initiation of RT to the date of death due to any cause. Censoring will be performed using the date of last known contact for those who are alive at the time of analysis. OS will be reported for the entire cohort and stratified by histologic subtype, PD1/PDL1 status, MSI, and organs treated if sample size allows.

Local control will be defined as absence of per-lesion PD in an irradiated lesion (as defined above, a 20% increase in the longest diameter since the treatment started or a 5 mm increase over the nadir longest diameter from initiation of radiation therapy to time of progression of radiated lesion(s)

Abscopal response rate is defined as present for all patients for whom an unirradiated target or non-target lesion previously determined to be a progressing lesion is designated as SD, CR/iCR or PR/iPR on per-lesion analysis will be described as a proportion with exact confidence intervals and will be reported for the entire cohort, reported for RECIST and iRECIST definitions, and stratified by histologic subtype, PD1/PDL1 status, MSI, and organs treated if sample size allows

From initiation of radiation therapy to first imaging scan after radiation therapy completion, time to new metastatic lesions will be described using the cumulative incidence method and comparisons between strata via Gray's test, if sample size allows; Kaplan-Meier methodology will be used and comparisons will be made via log-rank test; and Cox proportional hazards analysis, if possible.

Common Terminology Criteria for Adverse Events (CTCAE v.5.0) will be used to determine frequency of grade 3 or higher adverse events reported as a proportion with corresponding exact confidence intervals.

Time to new systemic therapy from initiation of radiation therapy to initiation of new systemic therapy will be described using Kaplan-Meier product limit estimators, and Cox proportional hazards analysis, if possible.

Spots Global Cancer Trial Database for stage iv adenocarcinoma of the gastroesophageal junction