Pembrolizumab and Palliative Radiation Therapy in Treating Patients With Metastatic Esophagus, Stomach, or Gastroesophageal Junction Cancer

Phase 2

Completed

Conditions: Gastric Adenocarcinoma
Stage IV Esophageal Squamous Cell Carcinoma AJCC v7
Metastatic Malignant Neoplasm in the Stomach
Stage IV Esophageal Adenocarcinoma AJCC v7
Gastroesophageal Junction Adenocarcinoma
Gastric Squamous Cell Carcinoma

Interventions: Radiation: External Beam Radiation Therapy
Other: Laboratory Biomarker Analysis
Biological: Pembrolizumab

Registration Number: NCT02830594

Lead Sponsor: City of Hope Medical Center

Brief Summary: This phase II trial studies how well pembrolizumab and palliative radiation therapy works in treating patients with esophagus, stomach, or gastroesophageal junction cancer that has spread to other parts of the body. Monoclonal antibodies, such as pembrolizumab, may interfere with the ability of tumor cells to grow and spread. Palliative radiation therapy, such as external beam radiation therapy, uses high energy beams to treat symptoms that are caused by tumors. Giving pembrolizumab together with palliative radiation therapy may work better in treating patients with esophagus, stomach, or gastroesophageal junction cancer that has spread to other parts of the body.

Detailed Description: PRIMARY OBJECTIVE:

I. To establish that the combination of pembrolizumab and traditional external beam multifractionated radiation therapy (RT) to the primary tumor or a single target metastatic site of patients with metastatic gastric, esophageal, and/or gastroesophageal junction (GEJ) cancers will lead to an increase in tumor infiltrating cytotoxic T-cells and circulating cytotoxic T cells and a reduction in immunosuppressive regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) in metastatic sites.

SECONDARY OBJECTIVES:

I. To establish that the combination of pembrolizumab and RT is feasible in the patient population and evaluate toxicities per National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE) version (ver.) 4.03.

II. To evaluate overall response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and immune related (ir)RECIST in this treatment population and correlate with tumor T-cell response.

III. To evaluate progression-free (PFS) and overall survival (OS) in this treatment population.

EXPLORATORY OBJECTIVES:

I. To measure changes in whole genome serum micro ribonucleic acid (miRNA) signature before and after protocol therapy and correlate with tumor/immune/stromal cell miRNA expression profiling determined by deep sequencing.

II. To measures changes in fecal and oral microbiomic diversity and correlative with ORR, PFS, and OS.

III. To assess germline mutations in a panel of miRNA regulatory genes using the MiraDx assay as predictors of response and toxicity to pembrolizumab and RT.

OUTLINE:

INITIAL TREATMENT: Patients undergo palliative external beam RT daily. On day 1, patients undergo the first RT fraction and then receive pembrolizumab intravenously (IV) over 30 minutes. Cycles repeat every 3 weeks for up to 35 cycles in the absence of disease progression or unacceptable toxicity.

SECOND PHASE: Patients who achieve a complete response, stop study treatment, and then experience radiographic disease progression may be eligible for the second phase at the discretion of the investigator if no cancer treatment was administered since the last dose of pembrolizumab and trial eligibility safety parameters are met. Patients receive pembrolizumab IV over 30 minutes on day 1. Cycles repeat every 3 weeks for up to 17 cycles in the absence of disease progression or unacceptable toxicity.

After completion of treatment, patients are followed up at 30 days, every 6 weeks for 1 year, and then every 9 and 12 weeks for up to 2 years.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 14

Inclusion Criteria

Documented informed consent of the participant
Willing to provide tumor tissue amenable to ultrasound or computed tomography (CT)-guided biopsy for biomarker analyses
- Patients with malignant ascites are permitted to participate and provide ascites samples for biomarker analyses
- Patents receiving radiation to a single metastatic site in which only the primary tumor is accessible for biopsy by endoscopy will also be eligible
Eastern Cooperative Oncology Group (ECOG) performance status of =< 1
Life expectancy of >= 3 months
Diagnosis of metastatic squamous cell carcinoma and/or adenocarcinoma of the esophagus, gastroesophageal junction, or stomach in need of palliative radiotherapy to the primary tumor or a single metastatic site for symptoms such as pain, dysphagia, and/or gastrointestinal bleeding
- Patients with adenocarcinoma histology and known human epidermal growth factor receptor 2 (HER2) overexpressing disease are permitted to participate if the progressed or are intolerant of prior trastuzumab-containing therapy
Measurable metastatic sites of disease outside of the target lesion undergoing palliative radiation based on RECIST 1.1 as assessed by the investigator
Have no limits on prior lines of therapy or may be treatment-naive if in need of palliative RT provided the patient has not received prior anti-programmed cell death protein 1(PD-1), anti-programmed cell death 1 ligand 1 (PD-L1), or anti-programmed cell death 1 ligand 2 (PD-L2) therapy
Absolute neutrophil count (ANC) >= 1,500/mm^3
Platelets >= 100,000/mm^3
Hemoglobin >= 9 g/dL
- May receive transfusion to meet this goal
Total serum bilirubin =< 1.5 x upper limit of normal (ULN) OR direct bilirubin =< ULN if total bilirubin levels > 1.5 x ULN
Albumin >= 2.5 mg/dL
Aspartate aminotransaminase (AST) and alanine aminotransferase (ALT) =< 2.5 x ULN OR =< 5.0 x ULN if liver metastases present
Serum creatinine =< 1.5 x ULN OR creatinine clearance (if measured or calculated per institutional standard) >= 60 mL/min if creatinine levels > 1.5 x ULN
- Glomerular filtration rate (GFR) can also be used in place of creatinine or creatinine clearance (CrCl)
If not receiving anticoagulants: international normalized ratio (INR) OR prothrombin (PT) =< 1.5 x ULN; if on anticoagulant therapy: PT must be within therapeutic range of intended use of anticoagulants
If not receiving anticoagulants: activated partial thromboplastin time (aPTT) =< 1.5 x ULN; if on anticoagulant therapy: aPTT must be within therapeutic range of intended use of anticoagulants
Negative urine or serum pregnancy test (female of childbearing potential only)
- If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
Female of childbearing potential: willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication
- Childbearing potential defined as not being surgically sterilized or have not been free from menses for > 1 year
Male: use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy

Exclusion Criteria

Anti-PD-1, anti-PD-L1, or anti-PD-L2 agents
Prior radiation therapy within the field of the target lesion that in the opinion of the treating radiation oncologist would preclude further palliative radiation to a dose of 30 gray (Gy)
Anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier
Chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to a previously administered agent
- Note: Subjects with =< grade 2 neuropathy are an exception to this criterion and may qualify for the study
- Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy
Live vaccine within 30 days of planned start of study therapy
- Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist) are live attenuated vaccines, and are not allowed
Immunosuppressive therapy within 7 days prior to the first dose of trial treatment
Investigational device within 4 weeks of the first dose of treatment
Currently receiving an investigational agent
About to undergo palliative radiation for a symptomatic central nervous system (CNS) metastasis
Systemic steroid therapy
Hypersensitivity to pembrolizumab or any of its excipients
Diagnosis of immunodeficiency
Active autoimmune disease that has required systemic treatment in the past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs)
- Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment
Known history of, or any evidence of active, non-infectious pneumonitis
Current active infection requiring systemic therapy
Known history of active tuberculosis (TB), human immunodeficiency virus (HIV) 1/2, hepatitis B or hepatitis C
Known additional malignancy that is progressing or requires active treatment
- Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer
Known active central nervous system (CNS) metastases and/or carcinomatous meningitis
- Subjects with previously treated brain metastases may participate provided they are stable, have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment; this exception does not include carcinomatous meningitis which is excluded regardless of clinical stability
History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator
Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
Pregnant or breastfeeding (female only)

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (pembrolizumab, RT)	Laboratory Biomarker Analysis	INITIAL TREATMENT: Patients undergo palliative external beam RT daily. On day 1, patients undergo the first RT fraction and then receive pembrolizumab intravenously (IV) over 30 minutes. Cycles repeat every 3 weeks for up to 35 cycles in the absence of disease progression or unacceptable toxicity. SECOND PHASE: Patients who achieve a complete response, stop study treatment, and then experience radiographic disease progression may be eligible for the second phase at the discretion of the investigator if no cancer treatment was administered since the last dose of pembrolizumab and trial eligibility safety parameters are met. Patients receive pembrolizumab IV over 30 minutes on day 1. Cycles repeat every 3 weeks for up to 17 cycles in the absence of disease progression or unacceptable toxicity.
Treatment (pembrolizumab, RT)	Pembrolizumab	INITIAL TREATMENT: Patients undergo palliative external beam RT daily. On day 1, patients undergo the first RT fraction and then receive pembrolizumab intravenously (IV) over 30 minutes. Cycles repeat every 3 weeks for up to 35 cycles in the absence of disease progression or unacceptable toxicity. SECOND PHASE: Patients who achieve a complete response, stop study treatment, and then experience radiographic disease progression may be eligible for the second phase at the discretion of the investigator if no cancer treatment was administered since the last dose of pembrolizumab and trial eligibility safety parameters are met. Patients receive pembrolizumab IV over 30 minutes on day 1. Cycles repeat every 3 weeks for up to 17 cycles in the absence of disease progression or unacceptable toxicity.
Treatment (pembrolizumab, RT)	External Beam Radiation Therapy	INITIAL TREATMENT: Patients undergo palliative external beam RT daily. On day 1, patients undergo the first RT fraction and then receive pembrolizumab intravenously (IV) over 30 minutes. Cycles repeat every 3 weeks for up to 35 cycles in the absence of disease progression or unacceptable toxicity. SECOND PHASE: Patients who achieve a complete response, stop study treatment, and then experience radiographic disease progression may be eligible for the second phase at the discretion of the investigator if no cancer treatment was administered since the last dose of pembrolizumab and trial eligibility safety parameters are met. Patients receive pembrolizumab IV over 30 minutes on day 1. Cycles repeat every 3 weeks for up to 17 cycles in the absence of disease progression or unacceptable toxicity.

Primary Outcome Measures

Name	Time	Method
Changes in Tumor Proportion Scores (TPS) in Non-irradiated Sites Assessed by Flow Cytometry	Baseline to 105 weeks	Multicolor immunofluorescence was performed to quantitate analogous TPS expression in pre- and posttreatment biopsies. Difference in MIDS expression between pre- and posttreatment was tested using a Paired T-test.
Changes in Myeloid-derived Suppressor Cells (MDSC) in Non-irradiated Sites Assessed by Flow Cytometry	Baseline to 105 weeks	Multicolor immunofluorescence was performed to quantitate analogous MIDS expression in pre- and posttreatment biopsies. Difference in MIDS expression between pre- and posttreatment was tested using a Paired T-test.
Changes in Combined Positive Scoring (CPS) in Non-irradiated Sites Assessed by Flow Cytometry	Baseline to 105 weeks	Multicolor immunofluorescence was performed to quantitate analogous CPS expression in pre- and posttreatment biopsies. Difference in MIDS expression between pre- and posttreatment was tested using a Paired T-test.

Secondary Outcome Measures

Name	Time	Method
Overall Response Rate (ORR)	Up to 36 months	Response was assessed using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and immune related (ir)RECIST. Overall Response (OR) = CR + PR.
Overall Survival (OS)	Up to 36 months	Estimated using the product-limit method of Kaplan and Meier. Event defined as death from any cause.
Incidence of Treatment Related Adverse Events of Pembrolizumab	Up to 36 months	Graded per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Adverse events with incidence greater than 10%. An adverse event is any untoward medical experience or change of an existing condition that occurs during or after treatment, whether or not it is considered to be related to the protocol intervention. Serious Adverse Events as: Death; Is life-threatening experience (places the subject at immediate risk of death from the event as it occurred); Unplanned hospitalization (equal to or greater than 24 hours) or prolongation of existing hospitalization; A persistent or significant disability/incapacity; A congenital anomaly/birth defect; Secondary malignancy; Any other adverse event that, based upon appropriate medical judgment, may jeopardize the subject's health and may require medical or surgical intervention to prevent one of the outcomes listed above.
Progression-free Survival (PFS)	Up to 36 months	Estimated using the product-limit method of Kaplan and Meier. Event defined as progression or death from any cause. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. irPD defined as a minimum 20% increase and minimum 5 mm absolute increase in TMTB compared to nadir, or irPD for non-target or new non-measurable lesions. Confirmation of progression is recommended minimum 4 weeks after the first irPD assessment.