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

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ClinicalTrials.gov Identifier: NCT03223662
Recruitment Status : Recruiting
First Posted : July 21, 2017
Last Update Posted : April 25, 2018
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( 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 CAT scan and PET scan

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

Biopsy for a small sample of tumor is removed by 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.


Condition or disease Intervention/treatment Phase
Esophageal Cancer Esophageal Adenocarcinoma Esophageal Squamous Cell Cancer Esophageal Neoplasms Squamous Cell Carcinoma Other: Chemoradiotherapy Procedure: Esophagectomy Phase 2

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. Positronemissions tomography (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 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 pCR after 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.

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 120 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Metabolomic and BH3 Profiling of Esophageal Cancers: Identification of Novel Assessment Methods of Treatment Response for Precision Therapy
Actual Study Start Date : October 31, 2017
Estimated Primary Completion Date : December 31, 2021
Estimated Study Completion Date : December 31, 2027

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
1/Arm 1
Standard of care nCRT and esophagectomy
Other: Chemoradiotherapy
Chemotherapy: Carboplatin (AUC=2)x5 and Paclitaxel (50 mg/m2)x5 for two cycles. Radiation: a total dose of 40.4 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.

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




Primary Outcome Measures :
  1. Correlation between a 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 [ Time Frame: 10 years ]
    Correlation between a metabolomic signature in tumor, blood, or urine and outcome of pathological complete response afterneoadjuvant chemoradiotherapy in patients with esophagealadenocarcinoma or squamous cell carcinoma

  2. Correlation between 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 [ Time Frame: 10 years ]
    Correlation between BH3 profiling of pre-neoadjuvant tumor biopsy and outcome of pathological complete response after neoadjuvantchemoradiotherapy in patients with esophageal adenocarcinoma or squamous cell carcinoma


Secondary Outcome Measures :
  1. 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) [ Time Frame: 10 years ]
    Evaluation of metabolomic profiles and Bcl-2 homology domain-3 (BH-3) profiling in resectable esophageal adenocarcinomas (EAC) andesophageal squamous cell carcinoma (ESCC) treated with neoadjuvant chemoradiotherapy (nCRT)

  2. Correlation (if any) between 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) [ Time Frame: 10 years ]
    Correlation (if any) between 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 (Mandardscore 3-5

  3. Correlation between tumor and systemic metabolomic signatures and disease-free survival (DFS) or Overall survival (OS) in EAC and ESCC patients undergoing nCRT and esophagectomy [ Time Frame: 10 years ]
    Correlation between tumor and systemic metabolomic signatures and disease-free survival (DFS) or Overall survival (OS) in EAC andESCC patients undergoing nCRT and esophagectomy

  4. Correlation between p53 mutational status and the metabolomic profiles [ Time Frame: 10 years ]


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Ages Eligible for Study:   18 Years to 99 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA:
  • Patients must have histologically confirmed EAC or ESCC.
  • Disease should be deemed resectable by pre-operative CT and/or PET scans and the patient should be operable based on surgeon assessment.
  • Patients willing to complete nCRT per standard of care followed by esophagectomy. Patients will be treated under protocol 04-C0165.
  • 18 years of age or older.
  • Able to understand and sign the Informed Consent Document.
  • 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

EXCLUSION CRITERIA:

  • Patients in which nCRT followed by surgery is not the appropriate management:

    • Early stage disease that requires local therapy without 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03223662


Contacts
Contact: Cara M Kenney, R.N. (240) 760-6233 kenneycara@mail.nih.gov

Locations
United States, Maryland
National Institutes of Health Clinical Center Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office    888-624-1937      
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
Principal Investigator: Robert T Ripley, M.D. National Cancer Institute (NCI)

Additional Information:
Publications:
Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT03223662     History of Changes
Other Study ID Numbers: 170135
17-C-0135
First Posted: July 21, 2017    Key Record Dates
Last Update Posted: April 25, 2018
Last Verified: April 13, 2018

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) ):
Neoadjuvant Chemoradiotherapy (nCRT)
Esophagectomy
Tissue or serologic biomarkers

Additional relevant MeSH terms:
Carcinoma, Squamous Cell
Adenocarcinoma
Esophageal Neoplasms
Neoplasms, Squamous Cell
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Head and Neck Neoplasms
Digestive System Diseases
Esophageal Diseases
Gastrointestinal Diseases