Cancer of the Esophagus, Esophageal Cancer
Conditions
Brief summary
The investigators propose to treat patients with metastatic esophageal cancers and dysphagia with two fractions of brachytherapy followed by pembrolizumab. The brachytherapy is hypofractionated and will provide a radiation dose of sufficient intensity to induce the release of tumor-derived antigens and trigger an antitumor immune response. The simplicity of the design should maximize the chance to examine the hypothesis that radiotherapy can induce an immune response, which can then be augmented by pembrolizumab treatment. Success in this study would provide the impetus to conduct further trials aimed at developing this unique strategy as a more broadly applicable therapeutic option in the treatment of patients suffering from these deadly cancers, and will provide important mechanistic insights into the relationship between radiation treatment and immune therapy augmentation.
Interventions
DRUGPembrolizumab
Provided by Merck.
RADIATIONBrachytherapy
It will be delivered using a high-dose-rate Ir-192 afterloader via a dedicated esophageal applicator.
Sponsors
Washington University School of Medicine
Merck Sharp & Dohme LLC
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Any patient with metastatic esophageal cancer that is deemed a candidate for brachytherapy for local control or treatment of dysphagia as determined by treating physician * Presence of an evaluable metastatic lesion (locoregional lymph nodes are acceptable) * At least 18 years of age. * ECOG performance status 0-2 * Adequate bone marrow and organ function as defined below: * Absolute neutrophil count ≥ 1,500/mcL * Platelets ≥ 100,000/mcL * Hemoglobin ≥ 9 g/dL * Total bilirubin ≤ 1.5 x IULN OR Direct bilirubin ≤ IULN for patients with total bilirubin \> 1.5 x IULN * AST(SGOT)/ALT(SGPT) ≤ 2.5 x IULN (or ≤ 5 x IULN for patients with liver metastases) * Serum creatinine ≤ 1.5 x IULN OR Creatinine clearance by Cockcroft-Gault ≥ 60 mL/min/1.73 m2 for patients with creatinine levels \> 1.5 x IULN * INR or PT ≤ 1.5 x IULN unless patient is receiving anticoagulant therapy as long as INR or PTT is within therapeutic range of intended use of anticoagulants * aPTT ≤ 1.5 x IULN unless patient is receiving anticoagulant therapy as long as INR or PTT is within therapeutic range of intended use of a anticoagulants * Sexually active women of childbearing potential and men must agree to use contraceptive methods prior to study entry, for the duration of study participation, and for 120 days after the last dose of pembrolizumab. Should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately. * Either enrolled in HRPO# 201107221 ("Tissue and Blood Acquisition for Genomic Analysis and Collection of Health Information for Patients with Gastrointestinal Cancers"), which facilitates the collection of specimens for correlative studies, or consenting to collection of blood and tissue as part of this protocol for research testing. * Ability to understand and willingness to sign an IRB approved written informed consent document (or that of legally authorized representative, if applicable).
Exclusion criteria
* Prior treatment with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent * Received a live vaccine within 30 days prior to the first dose of pembrolizumab. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g. FluMist) are live attenuated vaccines and are not allowed. * Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of pembrolizumab. * Currently receiving any other investigational agents, has participated in a study of an investigational agent, or use of an investigational device within 4 weeks of the first dose of pembrolizumab. * Has received systemic therapy within 4 weeks of the first dose of pembrolizumab. * Known active central nervous system metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least 4 weeks prior to the first dose of MK-3475 and any neurologic symptoms have returned to baseline), 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. * A history of allergic reactions attributed to compounds of similar chemical or biologic composition to pembrolizumab or other agents used in the study. * Uncontrolled intercurrent illness that would limit compliance with study requirements. This would include, but is not limited to: ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, immunosuppression, autoimmune conditions, underlying pulmonary disease, or psychiatric illness/social situations. * Has an active autoimmune disease requiring systemic treatment within 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. * History of (non-infectious) pneumonitis that required steroids or current pneumonitis * Pregnant and/or breastfeeding. Women of childbearing potential must have a negative pregnancy test within 72 hours of study entry. * Known history of hepatitis B (defined as hepatitis B surface antigen \[HBsAg\] reactive) or known active hepatitis C virus (defined as HCV RNA \[qualitative\] is detected). * Known history of active TB. * Known history of HIV (HIV 1/2 antibodies).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety as Measured by Number of Participants With Grade 3 or Higher Treatment Related Adverse Events | Through 30 days after completion of treatment (median length of adverse event follow-up 106 days, full range 42-1023 days) | The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 will be utilized for all toxicity reporting. In general, CTCAE version 4.03 has the following definitions for the grading scale: Grade 3: severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL. Grade 4: life-threatening consequences; urgent intervention indicated. Grade 5: Death related to AE. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Percent Change in Esophageal Tumor Length as Measured by Endoscopy | Prior to brachytherapy and once anytime between 2-6 months after start of pembrolizumab (up to approximately 7 months post-baseline) | — |
| Change in Esophageal Lumen Size as Measured by Endoscopy | Prior to brachytherapy, at 1-2 weeks after initiation of brachytherapy (optional), and 2-6 months after start of pembrolizumab | — |
| Worst Grade of Dysphagia Experienced by Participant | From start of treatment through 8 weeks post-pembrolizumab (median length of dysphagia follow-up 132 days, full range 42-1049 days) | The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 will be utilized for all toxicity reporting. Grade 1: symptomatic, able to eat regular diet; Grade 2: symptomatic and altered eating/swallowing; Grade 3: severely altered eating/swallowing; tube feeding or TPN or hospitalization indicated; Grade 4: life-threatening consequences; urgent intervention indicated; Grade 5: death. |
| Overall Response as Measured by Immune-Related Response Criteria (irRC) | Through completion of treatment (median length of treatment 76 days, full range 25-993 days) | \- Response and progression will be evaluated in this study using Immune-Related Response Criteria. * irCR, complete disappearance of all lesions (whether measurable or not, and no new lesions) - confirmation by a repeat, consecutive assessment no less than 4 weeks from the date first documented * irPR, decrease in tumor burden ≥ 50% relative to baseline - confirmed by a consecutive assessment at least 4 weeks after first documentation * irSD, not meeting criteria for irCR or irPR, in absence of irPD * irPD, increase in tumor burden ≥ 25% relative to nadir (minimum recorded tumor burden) - confirmation by a repeat, consecutive assessment no less than 4 weeks from the date first documented * Patients are considered to have irPR or irSD even if new lesions are present as long as they meet the respective thresholds of response as described above. Furthermore, patients are not considered to have irPD if new lesions are present and the tumor burden of all lesions. |
| Median Progression-free Survival (PFS) | Up to 1 year after completion of treatment (median length of treatment 76 days, full range 25-993 days) | PFS was defined as the duration from the first infusion of pembrolizumab until disease progression or death (whichever occurred first). |
| Median Overall Survival (OS) | Up to 1 year after completion of treatment (median length of treatment 76 days, full range 25-993 days) | OS was defined as the duration from the first infusion of pembrolizumab until death. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORCliff Robinson, M.D.
Washington University School of Medicine
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 64 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 16 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 15 Participants |
| Region of Enrollment United States | 16 participants |
| Sex: Female, Male Female | 3 Participants |
| Sex: Female, Male Male | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 13 / 16 |
| other Total, other adverse events | 16 / 16 |
| serious Total, serious adverse events | 12 / 16 |
Outcome results
None listed