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

NCT03223662 | Terminated Phase 2 Results

• 2 other identifiers: 17013517-C-0135
• Study Type: interventional
• Target: 2
• Locations: 1 country
• Sites: 1

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. 1.A robotically-assisted, minimally-invasive esophagectomy
2. 2.Or, a traditional, open approach.

Conditions

Esophageal Cancer; Esophageal Adenocarcinoma; Esophageal Squamous Cell Cancer; Esophageal Neoplasms; Squamous Cell Carcinoma

Keywords

Neoadjuvant Chemoradiotherapy (nCRT); Esophagectomy; Tissue or serologic biomarkers

Outcome Measures

Primary Outcomes (2)

• 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

  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.

  After neoadjuvant therapy >4 weeks but prior to surgery

• 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

  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.

  Pre-neoadjuvant therapy within 4 weeks, and after neoadjuvant therapy >4 weeks but prior to surgery

Secondary Outcomes (5)

• 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

• 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

• 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

• 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

• 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.

Study Arms (1)

Neoadjuvant Chemoradiotherapy and esophagectomy

OTHER

Standard of care neoadjuvant chemoradiotherapy (nCRT) and esophagectomy

Other: Chemoradiotherapy; Procedure: Esophagectomy

Interventions

Chemoradiotherapy OTHER

Chemotherapy: Carboplatin (AUC=2)x5 and Paclitaxel (50 mg/m(2))x5 for two cycles. Radiation: a total dose of 40.4 Gray (Gy) will be given in 23 fractions of 1.8 Gy, 5 fractions per week, starting the first day of the first cycle of chemotherapy.

Neoadjuvant Chemoradiotherapy and esophagectomy

Esophagectomy PROCEDURE

Minimally-invasive esophagectomy (RAMIE) or traditional open approach if necessary.

Neoadjuvant Chemoradiotherapy and esophagectomy

Eligibility Criteria

• Age: 18 Years - 99 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients must have histologically confirmed esophageal adenocarcinoma (EAC) or esophageal squamous cell carcinoma (ESCC).
• Disease should be deemed resectable by pre-operative computed tomography (CT) and/or positron-emission tomography (PET) scans and the patient should be operable based on surgeon assessment.
• Patients willing to complete neoadjuvant chemoradiotherapy (nCRT) per standard of care followed by esophagectomy. Patients will be treated under protocol 04-C0165.
• years of age or older.
• Able to understand and sign the Informed Consent Document.
• Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2.
• Patients must have organ and marrow function that is not prohibitive of surgical resection as defined below:
• leukocytes greater than or equal to 3,000/mcL
• absolute neutrophil count greater than or equal to 1,500/mcL
• platelets greater than or equal to 50,000/mcL
• nCRT used in this study is potentially dangerous for developing human fetus. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration and 6 months post chemoradiotherapy. 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.
• Women must have a negative urine pregnancy test OR be post-menopausal for at least 2 years OR patient has had a hysterectomy

You may not qualify if:

• Patients in which nCRT followed by surgery is not the appropriate management:
• Early stage disease that requires local therapy without chemoradiotherapy (CRT).
• Patients with metastatic disease.
• Patients in which biopsy prior to starting nCRT is not obtainable.
• Patients who previously received neoadjuvant chemotherapy
• Concomitant medical problems in the opinion of physician that would place the patient at unacceptable risk for a major surgical procedure.
• Active systemic infections, coagulation disorders or other major medical illnesses of the cardiovascular, respiratory or immune system, myocardial infarction, heart failure, hepatic disease that prohibits administration of neoadjuvant therapy or surgery.
• Women who are pregnant or breastfeeding because of the potentially dangerous effects of the chemotherapy on the fetus or infant.
• Patients with a diagnosis of another malignancy that is either active or in remission less than five years. Basal cell and squamous cell carcinoma of the skin are not contraindications to this protocol

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

Location

Related Publications (4)

• Piessen G, Messager M, Mirabel X, Briez N, Robb WB, Adenis A, Mariette C. Is there a role for surgery for patients with a complete clinical response after chemoradiation for esophageal cancer? An intention-to-treat case-control study. Ann Surg. 2013 Nov;258(5):793-9; discussion 799-800. doi: 10.1097/SLA.0000000000000228.

  PMID: 24096755 BACKGROUND

• Stiles BM, Salzler G, Jorgensen A, Nasar A, Paul S, Lee PC, Port JL, Altorki NK. Complete metabolic response is not uniformly predictive of complete pathologic response after induction therapy for esophageal cancer. Ann Thorac Surg. 2013 Nov;96(5):1820-5. doi: 10.1016/j.athoracsur.2013.05.027. Epub 2013 Jul 26.

  PMID: 23895888 BACKGROUND

• Shaikh T, Ruth K, Scott WJ, Burtness BA, Cohen SJ, Konski AA, Cooper HS, Astsaturov I, Meyer JE. Increased time from neoadjuvant chemoradiation to surgery is associated with higher pathologic complete response rates in esophageal cancer. Ann Thorac Surg. 2015 Jan;99(1):270-6. doi: 10.1016/j.athoracsur.2014.08.033. Epub 2014 Nov 18.

  PMID: 25440267 BACKGROUND

• Taylor Ripley R, Surman DR, Diggs LP, Trepel JB, Lee MJ, Ryan J, Davis JL, Steinberg SM, Hernandez JM, Hoang C, Kenney CM, Bond CD, Kunst TF, Letai A, Schrump DS. Metabolomic and BH3 profiling of esophageal cancers: novel assessment methods for precision therapy. BMC Gastroenterol. 2018 Jun 22;18(1):94. doi: 10.1186/s12876-018-0823-x.

  PMID: 29933761 DERIVED

MeSH Terms

Conditions

Esophageal Neoplasms; Adenocarcinoma Of Esophagus; Esophageal Squamous Cell Carcinoma; Carcinoma, Squamous Cell

Interventions

Chemoradiotherapy; Esophagectomy

Condition Hierarchy (Ancestors)

Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Head and Neck Neoplasms; Digestive System Diseases; Esophageal Diseases; Gastrointestinal Diseases; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms, Squamous Cell

Intervention Hierarchy (Ancestors)

Combined Modality Therapy; Therapeutics; Drug Therapy; Radiotherapy; Digestive System Surgical Procedures; Surgical Procedures, Operative

Results Point of Contact

• Title: Caryn Steakley
• Organization: National Cancer Institute

steaklec@nih.gov

240-858-3749

Study Officials

• Robert T Ripley

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Deputy Clinical Director

Study Record Dates

• First Submitted: July 19, 2017
• First Posted: July 21, 2017
• Study Start: October 31, 2017
• Primary Completion: July 27, 2018
• Study Completion: July 27, 2018
• Last Updated: October 30, 2018
• Results First Posted: October 30, 2018

Record last verified: 2018-10

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)