Metabolomic and BH3 Profiling of Esophageal Cancers: Identification of Novel Assessment Methods of Treatment Response for Precision Therapy

Phase 2

Terminated

Conditions: Esophageal Neoplasms
Squamous Cell Carcinoma
Esophageal Cancer
Esophageal Squamous Cell Cancer
Esophageal Adenocarcinoma

Interventions: Other: Chemoradiotherapy
Procedure: Esophagectomy

Registration Number: NCT03223662

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: Background:

The number of patients with esophageal cancer keeps rising. For many patients, a combination of surgery, chemotherapy, and radiation is necessary to completely treat the disease. Usually, patients receive chemotherapy and radiation at the same time followed by surgery to remove the part of the esophagus with the tumor (Neoadjuvant chemoradiotherapy (nCRT)). Researchers want to learn how to make this treatment more effective.

Objective:

To see if biopsies before treatment can show which patients will do the best with a combination of chemotherapy, radiation, and surgery.

Eligibility:

Adults at least 18 years old with esophageal adenocarcinoma or squamous cell carcinoma who should be treated with chemotherapy, radiation, and surgery.

Design:

Patients will undergo standard testing that is routine for all patients with this disease. These tests include:

Medical history

Physical exam with activity and nutritional assessment

Standard lab tests

Imaging studies including a computerized axial tomography (CAT) scan and positron-emission tomography (PET) scan

Breathing test into a machine to measure size and function of lungs.

Biopsy for a small sample of tumor is removed by esophagogastroduodenoscopy (EGD): A tube inserted into the mouth under anesthesia

Endoscopic ultrasound is performed in some but not all patients.

Patients will have nCRT at the clinic or with their local doctor.

In 6 -12 weeks after nCRT, patients will undergo surgery with:

1. A robotically-assisted, minimally-invasive esophagectomy

2. Or, a traditional, open approach.

After surgery, patients are usually in the hospital for 2 weeks and have a feeding tube for at least 2 weeks and potentially longer until they are eating enough to not lose weight.

Patients will return for follow-up visits with labs and CAT scans every 6 months for the first two years then every year afterwards.

Detailed Description: Background:

* The incidence of esophageal cancer continues to increase with an estimated 16,900 new cases and 15,700 deaths in 2016. Esophageal adenocarcinoma (EAC) is the dominant histology in the United States and accounts for the rising incidence; the incidence of esophageal squamous cell cancer (ESCC) remains stable.

* Neoadjuvant chemoradiotherapy (nCRT) followed by esophagectomy is now a standard approach for locally advanced, operable esophageal cancer.

* A survival advantage compared to surgery alone was demonstrated in the phase III Chemo

Radiotherapy for Oesophageal cancer followed by Surgery Study (CROSS) trial.

* Patients who experience a pathological complete response (pCR) following neoadjuvant therapy are most likely to have long-term survival.

* Presently, accurate assessment of pathologic response requires esophagectomy. Positron-emissions tomography (fludeoxyglucose (FDG-PET)) and endoscopic evaluation with biopsies fail to detect cancer in a significant percentage of patients with residual disease following neoadjuvant therapy.

* Currently there are no validated tissue or serologic biomarkers which can be used to guide surgical management of esophageal cancer patients based on response to nCRT.

Primary Objective:

-To determine whether a metabolomic signature in tumor, blood, or urine or whether BH3 profiling of pre-neoadjuvant tumor biopsies correlates with the outcome of pathological complete response after neoadjuvant chemoradiotherapy for patients with esophageal adenocarcinoma or squamous cell carcinoma.

Eligibility:

-Patients with locally-advanced, histologically confirmed EAC or ESCC who are candidates for nCRT and esophagectomy.

Design:

* Patients will receive standard of care nCRT either at the National Cancer Institute (NCI) or at referring institutions.

* Specimens of plasma, urine, and esophageal tumor with matched normal esophagus will be obtained before neoadjuvant therapy for metabolomic profiling and BH3 profiling.

Blood, urine, normal esophagus, and tumor (if present) will be obtained after neoadjuvant therapy.

* Patients will undergo an esophagectomy as a robotically-assisted, minimally-invasive esophagectomy (RAMIE) or a traditional open approach for contraindications to minimally-invasive approaches or based on institutional expertise.

* Analysis will be performed to determine if pathological complete response (pCR) after chemoradiotherapy (CRT) correlates with pretreatment metabolomic signatures or BH3 profiling in tumor, blood or urine.

* Patients with EAC and ESCC will be evaluated independently.

* The accrual ceiling will be set to 120 patients for the entire study - 80 patients for EAC and 40 patients for ESCC to allow for unevaluable patients. The accrual is expected to be completed in 4 years.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 2

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Neoadjuvant Chemoradiotherapy and esophagectomy	Esophagectomy	Standard of care neoadjuvant chemoradiotherapy (nCRT) and esophagectomy
Neoadjuvant Chemoradiotherapy and esophagectomy	Chemoradiotherapy	Standard of care neoadjuvant chemoradiotherapy (nCRT) and esophagectomy

Primary Outcome Measures

Name	Time	Method
BH3 Profiling of Pre-neoadjuvant Tumor Biopsy and Outcome of Pathological Complete Response After Neoadjuvant Chemoradiotherapy in Patients With Esophageal Adenocarcinoma or Squamous Cell Carcinoma	Pre-neoadjuvant therapy within 4 weeks, and after neoadjuvant therapy >4 weeks but prior to surgery	Two tumor samples and two normal esophagus samples will be obtained for BH3 profiling of pre-neoadjuvant tumor biopsy and outcome of pathological complete response after neoadjuvant chemoradiotherapy in patients with esophageal adenocarcinoma or squamous cell carcinoma. Response will be defined by the Mandard Score. Major response with no viable tumor (Grade 1) and \<10% viable tumor (Grade 2) versus non major response of \>10% viable tumor (Grade 3-5) as assessed by final pathology. Grade 1-2 is better survival than Grade 3-5.
Metabolomic Signature in Tumor, Blood, or Urine and Outcome of Pathological Complete Response After Neoadjuvant Chemoradiotherapy in Patients With Esophageal Adenocarcinoma or Squamous Cell Carcinoma	After neoadjuvant therapy >4 weeks but prior to surgery	Specimens of normal esophagus, esophageal tumors, blood, or urine will be analyzed to determine specific signatures and outcome of pathological complete response after neoadjuvant chemoradiotherapy in patients with esophageal adenocarcinoma or squamous cell carcinoma. Response will be defined by the Mandard Score. Major response with no viable tumor (Grade 1) and \<10% viable tumor (Grade 2) versus non major response of \>10% viable tumor (Grade 3-5) as assessed by final pathology. Grade 1-2 is better survival than Grade 3-5.

Secondary Outcome Measures

Name	Time	Method
Overall Survival (OS) in Esophageal Adenocarcinoma (EAC) and Esophageal Squamous Cell Carcinoma (ESCC) Patients Undergoing Neoadjuvant Chemoradiotherapy (nCRT) and Esophagectomy	From treatment start date until date of death or date last known alive.	Overall survival is defined as the time from treatment start date until date of death or date last known alive.
Metabolomic Profiles and B-cell Lymphoma (Bcl-2) Homology Domain-3 (BH-3) Profiling in Resectable Esophageal Adenocarcinomas (EAC) and Esophageal Squamous Cell Carcinoma (ESCC) Treated With Neoadjuvant Chemoradiotherapy (nCRT)	Pre-neoadjuvant therapy within 4 weeks, and after neoadjuvant therapy >4 weeks but prior to surgery	Evaluation of metabolomic profiles and Bcl-2 homology domain-3 (BH-3) profiling in resectable esophageal adenocarcinomas (EAC) and esophageal squamous cell carcinoma (ESCC) treated with neoadjuvant chemoradiotherapy (nCRT)
Tumor Protein 53 (p53) Mutational Status and the Metabolomic Profiles	Pre-neoadjuvant therapy within 4 weeks, and after neoadjuvant therapy >4 weeks but prior to surgery	One tumor sample and one normal esophagus sample will be obtained. p53 mutational analysis will be performed to determine mutational status and the metabolomic profiles .
Metabolomic Signatures or BH3 Profiling in Tumor, Blood, or Urine of Esophageal Adenocarcinoma (EAC) and Esophageal Squamous Cell Carcinoma (ESCC) With Major Responses (Mandard Score of 1 and 2) Versus Minimal Response (Mandard Score 3-5)	Pre-neoadjuvant therapy within 4 weeks, and after neoadjuvant therapy >4 weeks but prior to surgery	Specimens of tumor, blood, or urine will be obtained to determine metabolomic signatures or BH3 profiling in tumor, blood, or urine of EAC and ESCC with major responses (Mandard score of 1 and 2) versus minimal response (Mandard score 3-5). Grade 1-2 is better survival than Grade 3-5.
Disease-free Survival in Esophageal Adenocarcinoma (EAC) and Esophageal Squamous Cell Carcinoma (ESCC) Patients Undergoing Neoadjuvant Chemoradiotherapy (nCRT) and Esophagectomy	From the time of esophagectomy until development of metastatic disease or death, whichever comes first	Disease-free survival is defined as the appearance of any new lesion that is likely metastatic or locally-recurrent esophageal cancer and will be assessed from the time of esophagectomy until development of metastatic disease or death, whichever comes first