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Molecular Phenotyping in Predicting Response in Patients With Stage IB-III Esophageal Cancer Receiving Combination Chemotherapy

Primary Purpose

Stage IB Esophageal Adenocarcinoma, Stage IIA Esophageal Adenocarcinoma, Stage IIB Esophageal Adenocarcinoma

Status

Terminated

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

Paclitaxel

Carboplatin

Oxaliplatin

Leucovorin Calcium

Fluorouracil

Radiation Therapy

Therapeutic Conventional Surgery

Laboratory Biomarker Analysis

About this trial

This is an interventional treatment trial for Stage IB Esophageal Adenocarcinoma

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Patients must have histologically or cytologically confirmed localized (T1N1-3M0 or T2-4NanyM0, stage IB-III) Siewert type 1 or type 2 esophageal adenocarcinoma that is amenable to surgical resection as determined by a thoracic surgeon and for which all disease (primary tumor and involved lymph nodes) can be treated with radiation, as determined by a radiation oncologist
Patients may not have received any prior chemotherapy, biologic therapy or radiation therapy for management of their disease; chemotherapy or biologic therapy administered for treatment of another primary malignancy are permitted if treatment was greater than 5 years ago
Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status =< 2
Patients must have a life expectancy of > 3 months, in the opinion of and as documented by the investigator
Hemoglobin >= 10.0 g/dl
Absolute neutrophil count >= 1,500/mcL
Platelet count >= 100,000/mcL
Total bilirubin within normal institutional limits
Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) =< 2.5 X institutional upper limit of normal
Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X institutional upper limit of normal
Serum creatinine within normal institutional limits OR creatinine clearance >= 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal (as calculated by Cockcroft-Gault)
Patients must have an avid primary tumor with an standardized uptake value (SUV) of >= 5 on baseline (18F) FDG-PET/computed tomography (CT) imaging
Men must agree to use adequate contraception (double barrier method of birth control or abstinence) 1 week prior to study entry, for the duration of study participation and for 1 month after completing combined modality treatment with chemotherapy and radiation; should a male patient's female partner become pregnant or suspect that she is pregnant while her partner is participating in this study, the treating physician should be informed immediately
Patients must have the ability to understand and the willingness to sign a written informed consent document
This study will be limited to enrollment of Caucasian males only

Exclusion Criteria:

Patients who are receiving any chemotherapy, biologic therapy, radiation therapy or any investigational agent
Patients with metastatic disease
Patients with a history of allergic reactions attributed to compounds of similar chemical or biologic composition to platinums, taxanes or fluoropyrimidines
Patients who have previously received radiation therapy to the chest or abdomen such that there would be overlap between the previous and current radiation field
Patients with uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
Patients with human immunodeficiency virus (HIV) whom are not receiving antiretroviral therapy
Patients with another malignancy within the past 5 years

Sites / Locations

Case Comprehensive Cancer Center

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Arm Label

Arm I (paclitaxel, carboplatin, radiation therapy, surgery)

Arm II (combination chemotherapy, radiation therapy, surgery)

Arm Description

INDUCTION: Patients receive chemotherapy with carboplatin and paclitaxel. Patients receive carboplatin (AUC=2) and paclitaxel (90 mg/m2) intravenously on days 1 and 8 of a 21 day treatment cycle for two cycles (total of 6 weeks). CHEMORADIATION THERAPY: Patients receive carboplatin (AUC=2) and paclitaxel (50 mg/m2) intravenously once weekly for five weeks throughout the duration of their radiation which is daily (Monday through Friday). SURGERY: Approximately 4-10 weeks after completion of chemoradiation therapy, patients undergo esophagectomy at the discretion of the treating team.

INDUCTION: Patients receive mFOLFOX6 where they get oxaliplatin 85 mg/m2 intravenously on day 1, leucovorin 400 mg/m2 IV on day 1, 5-FU 400 mg/m2 IV on day 1 and then 5FU at 2400 mg/m2 IV to be administered over a 46 hour period. This is repeated every 2 weeks for 3 cycles (total of 6 weeks). CHEMORADIATION THERAPY: Patients receive oxaliplatin 85 mg/m2 IV on day 1 every 2 weeks for a total of 3 cycles (6 weeks) as well as 5FU 300 mg/m2/day over 96 hours via continuous infusion each week of radiation for a total of 6 weeks. SURGERY: Approximately 4-10 weeks after completion of chemoradiation therapy, patients undergo esophagectomy at the discretion of the treating team.

Outcomes

Primary Outcome Measures

Relative Expression Differences in Individual Genes and Gene Profiles Between Patients Responding and Not Responding to Treatment, as Assessed by (18F) FDG-PET

Baseline gene profiles will be compared for 10 (18F) FDG-PET responders vs. 15 (18F) FDG-PET non-responders per treatment regimen using a t-test and p-values will be corrected for multiple comparisons by calculating the false discovery rate (FDR) p-value (filtering on a FDR p-value < 0.05). Top genes identified will be tested in combination for their sensitivity and specificity using logistic regression models.

Relative Expression Differences in Individual microRNAs and microRNA Profiles Between Patients Responding and Not Responding to Treatment, Assessed by (18F) FDG-PET

Baseline microRNA profiles will be compared for 10 (18F) FDG-PET responders vs. 15 (18F) FDG-PET non-responders per treatment regimen using a t-test and p-values will be corrected for multiple comparisons by calculating the FDR p-value (filtering on a FDR p-value < 0.05). Top microRNAs identified will be tested in combination for their sensitivity and specificity using logistic regression models.

Biological Pathway Perturbation Upon Exposure to Chemotherapy

Predefined signatures of biological pathway activities will be evaluated in order to identify pathway perturbation upon exposure to chemotherapy. Significant pathway modulations upon brief exposure will then be evaluated for association with clinical response using non-parametric tests such as the Wilcoxon signed-rank test. In all cases, statistical correction to account for multiple hypothesis testing will be employed and pathways with a false discovery rate of 10% or lower will be considered as significant.

Secondary Outcome Measures

Relative Expression Differences Between Baseline and Post-induction Chemotherapy Specimens of Individual Genes and Gene Expression Profiles

Changes in baseline and post-treatment gene expression levels will be calculated between (18F) FDG-PET responders and non-responders, filtering for expression level changes of >= 0.20. Differences in expression level change per treatment regimen will be calculated using a t-test and p-values will be corrected for multiple comparisons by calculating FDR p-value (filtering on a FDR p-value < 0.05). Top genes identified will be tested in combination for their sensitivity and specificity using logistic regression models to predict responsiveness or resistance to each individual treatment regimen.

Relative Expression Differences Between Baseline and Post-induction Chemotherapy Specimens of Individual microRNAs and microRNA Profiles

Changes in baseline and post-treatment microRNA levels will be calculated between (18F) FDG-PET responders and non-responders, filtering for expression level changes of >= 0.20. Differences in expression level change per treatment regimen will be calculated using a t-test and p-values will be corrected for multiple comparisons by calculating FDR p-value (filtering on a FDR p-value < 0.05). Top microRNAs identified will be tested in combination for their sensitivity and specificity using logistic regression models to predict responsiveness or resistance to each individual treatment regimen.

Relative Expression Differences in Baseline Individual Genes and Gene Expression Profiles Between Patients Achieving and Not Achieving a Pathologic Complete Response Following Treatment

Baseline gene expression profiles for 8 pathologic complete responders vs. 17 patients not achieving a pathologic complete response per treatment regimen using a t-test will be compared. Top genes will be tested in combination for their sensitivity and specificity using logistic regression models to predict achievement of a pathologic complete response vs. patients not achieving a pathologic complete response.

Relative Expression Differences in Baseline Individual microRNAs and microRNA Profiles Between Patients Achieving and Not Achieving a Pathologic Complete Response Following Treatment

Baseline microRNA profiles for 8 pathologic complete responders vs. 17 patients not achieving a pathologic complete response per treatment regimen using a t-test will be compared. Top microRNAs will be tested in combination for their sensitivity and specificity using logistic regression models to predict achievement of a pathologic complete response vs. patients not achieving a pathologic complete response.

Relative Expression Differences Between Baseline and Post-induction Gene Expression Levels/Profiles Between Patients Achieving and Not Achieving a Pathologic Complete Response Following Treatment

Changes in baseline and post-treatment gene expression level/profiles will be compared between 8 pathologic responders vs. 17 patients not achieving a pathologic complete response per treatment regimen, filtering for expression levels changes of 0.20 and above. Differences in expression level changes per treatment regimen will be calculated using a t-test. Top genes will be tested in combination for their sensitivity and specificity using logistic regression models to predict achievement of a pathologic complete response vs. patients not achieving a pathologic complete response.

Relative Expression Differences Between Baseline and Post-induction microRNA Levels/Profiles Between Patients Achieving and Not Achieving a Pathologic Complete Response Following Treatment

Changes in baseline and post-treatment microRNA level/profiles will be compared between 8 pathologic responders vs. 17 patients not achieving a pathologic complete response per treatment regimen, filtering for expression levels changes of 0.20 and above. Differences in expression level changes per treatment regimen will be calculated using a t-test. Top microRNAs will be tested in combination for their sensitivity and specificity using logistic regression models to predict achievement of a pathologic complete response vs. patients not achieving a pathologic complete response.

Occurrence of Grade 3 or 4 Toxicity Per the National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE) Version 4.0

Toxicities will be summarized as the percentage of patients experiencing each type and grade of event according to treatment group. Patients who receive at least one dose of treatment will be included in the analysis.

Full Information

NCT ID

NCT02392377

First Posted

March 13, 2015

Last Updated

January 16, 2018

Sponsor

Case Comprehensive Cancer Center

Collaborators

National Cancer Institute (NCI)

1. Study Identification

Unique Protocol Identification Number

NCT02392377

Brief Title

Molecular Phenotyping in Predicting Response in Patients With Stage IB-III Esophageal Cancer Receiving Combination Chemotherapy

Official Title

Pilot Study of Correlation Between Molecular Phenotype and Response to Two Independent Treatment Regimens, Carboplatin and Paclitaxel vs. 5-Fluorouracil and Oxaliplatin Chemotherapy in Patients With Localized Esophageal Adenocarcinoma

Study Type

Interventional

2. Study Status

Record Verification Date

January 2018

Overall Recruitment Status

Terminated

Why Stopped

Slow accrual

Study Start Date

February 2015 (undefined)

Primary Completion Date

December 2015 (Actual)

Study Completion Date

December 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Case Comprehensive Cancer Center

Collaborators

National Cancer Institute (NCI)

4. Oversight

Data Monitoring Committee

5. Study Description

Brief Summary

This randomized pilot phase II trial studies how well molecular phenotyping works in predicting response in patients with stage IB-III esophageal cancer who are receiving carboplatin and paclitaxel or oxaliplatin, leucovorin calcium, and fluorouracil. Studying the genes in a patients tumor cells before and after chemotherapy may help in understanding if there are specific features of the tumor cells that make a person more or less likely to respond to treatment and how these features may be affected by treatment.

Detailed Description

PRIMARY OBJECTIVES: I. To evaluate gene and micro ribonucleic acid (miRNA) expression levels in patients with esophageal adenocarcinoma prior to receiving chemotherapy and identify relative expression differences between patients responding and not responding to treatment with carboplatin and paclitaxel or 5-fluorouracil (fluorouracil) and oxaliplatin as measured by fluorodeoxyglucose F-18 ([18F] FDG)-positron emission tomography (PET). SECONDARY OBJECTIVES: I. To evaluate the impact of treatment on expression patterns of both genes and miRNAs in patients with esophageal adenocarcinoma following treatment with either carboplatin and paclitaxel or 5-fluorouracil and oxaliplatin, and identify expression patterns associated with treatment response and resistance as assessed by (18F) FDG-PET. II. To evaluate the expression patterns of genes and miRNAs in patients with esophageal adenocarcinoma prior to and following a full neoadjuvant combined-modality treatment program with either carboplatin and paclitaxel or 5-fluorouracil and oxaliplatin chemotherapy plus radiation, and identify relative expression differences between patients achieving a pathologic complete response and patients not achieving a pathologic complete response. OUTLINE: Patients are randomized to 1 of 2 treatment arms. ARM I: INDUCTION: Patients receive carboplatin (IV) and paclitaxel intravenously (IV) on days 1 and 8 of a 21 day cycle for two cycles (total of 6 weeks). CHEMORADIATION THERAPY: Patients receive carboplatin (AUC=2) and paclitaxel (50 mg/m2) intravenously once weekly for five weeks throughout the duration of their radiation which is daily (Monday through Friday). This will be given in combination with radiation therapy to a total of 50.4Gy using 180cGy fractions. ARM II: INDUCTION: Patients receive mFOLFOX6 where they get oxaliplatin 85 mg/m2 intravenously on day 1, leucovorin 400 mg/m2 IV on day 1, 5-FU 400 mg/m2 IV on day 1 and then 5FU at 2400 mg/m2 IV to be administered over a 46 hour period. This is repeated every 2 weeks for 3 cycles (total of 6 weeks). CHEMORADIATION THERAPY: Patients receive chemoradiation with oxaliplatin 85 mg/m2 IV on day 1 every 2 weeks for a total of 3 cycles (6 weeks) as well as 5FU 300 mg/m2/day over 96 hours via continuous infusion each week of radiation for a total of 6 weeks. This will be given in combination with radiation therapy to a total of 50.4Gy using 180cGy fractions. SURGERY: In both arms, approximately 4-10 weeks after completion of chemoradiation therapy, patients undergo esophagectomy at the discretion of the treating team. After completion of study treatment, patients are followed up at 30 days and then periodically thereafter.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Stage IB Esophageal Adenocarcinoma, Stage IIA Esophageal Adenocarcinoma, Stage IIB Esophageal Adenocarcinoma, Stage IIIA Esophageal Adenocarcinoma, Stage IIIB Esophageal Adenocarcinoma, Stage IIIC Esophageal Adenocarcinoma

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

1 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Arm I (paclitaxel, carboplatin, radiation therapy, surgery)

Arm Type

Experimental

Arm Description

Arm Title

Arm II (combination chemotherapy, radiation therapy, surgery)

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Paclitaxel

Other Intervention Name(s)

Anzatax, TAX

Intervention Description

Given IV or IVPB

Intervention Type

Drug

Intervention Name(s)

Carboplatin

Intervention Description

Given IV or IVPB

Intervention Type

Drug

Intervention Name(s)

Oxaliplatin

Intervention Description

Given IV

Intervention Type

Drug

Intervention Name(s)

Leucovorin Calcium

Other Intervention Name(s)

Intervention Description

Given IV

Intervention Type

Drug

Intervention Name(s)

Fluorouracil

Intervention Description

Given IV

Intervention Type

Radiation

Intervention Name(s)

Radiation Therapy

Other Intervention Name(s)

Cancer Radiotherapy, Irradiate, Irradiated, Irradiation, RT

Intervention Description

Undergo radiation therapy

Intervention Type

Procedure

Intervention Name(s)

Therapeutic Conventional Surgery

Intervention Description

Undergo esophagectomy

Intervention Type

Other

Intervention Name(s)

Laboratory Biomarker Analysis

Intervention Description

Correlative studies

Primary Outcome Measure Information:

Title

Relative Expression Differences in Individual Genes and Gene Profiles Between Patients Responding and Not Responding to Treatment, as Assessed by (18F) FDG-PET

Description

Time Frame

Baseline

Title

Relative Expression Differences in Individual microRNAs and microRNA Profiles Between Patients Responding and Not Responding to Treatment, Assessed by (18F) FDG-PET

Description

Time Frame

Baseline

Title

Biological Pathway Perturbation Upon Exposure to Chemotherapy

Description

Time Frame

Up to 6 weeks

Secondary Outcome Measure Information:

Title

Relative Expression Differences Between Baseline and Post-induction Chemotherapy Specimens of Individual Genes and Gene Expression Profiles

Description

Time Frame

Baseline to post-induction (36-43 days)

Title

Relative Expression Differences Between Baseline and Post-induction Chemotherapy Specimens of Individual microRNAs and microRNA Profiles

Description

Time Frame

Baseline to post-induction (36-43 days)

Title

Relative Expression Differences in Baseline Individual Genes and Gene Expression Profiles Between Patients Achieving and Not Achieving a Pathologic Complete Response Following Treatment

Description

Time Frame

Baseline

Title

Relative Expression Differences in Baseline Individual microRNAs and microRNA Profiles Between Patients Achieving and Not Achieving a Pathologic Complete Response Following Treatment

Description

Time Frame

Baseline

Title

Relative Expression Differences Between Baseline and Post-induction Gene Expression Levels/Profiles Between Patients Achieving and Not Achieving a Pathologic Complete Response Following Treatment

Description

Time Frame

Baseline to post-induction (36-43 days)

Title

Relative Expression Differences Between Baseline and Post-induction microRNA Levels/Profiles Between Patients Achieving and Not Achieving a Pathologic Complete Response Following Treatment

Description

Time Frame

Baseline to post-induction (36-43 days)

Title

Occurrence of Grade 3 or 4 Toxicity Per the National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE) Version 4.0

Description

Time Frame

Up to 30 days after the end of treatment

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Patients must have histologically or cytologically confirmed localized (T1N1-3M0 or T2-4NanyM0, stage IB-III) Siewert type 1 or type 2 esophageal adenocarcinoma that is amenable to surgical resection as determined by a thoracic surgeon and for which all disease (primary tumor and involved lymph nodes) can be treated with radiation, as determined by a radiation oncologist Patients may not have received any prior chemotherapy, biologic therapy or radiation therapy for management of their disease; chemotherapy or biologic therapy administered for treatment of another primary malignancy are permitted if treatment was greater than 5 years ago Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status =< 2 Patients must have a life expectancy of > 3 months, in the opinion of and as documented by the investigator Hemoglobin >= 10.0 g/dl Absolute neutrophil count >= 1,500/mcL Platelet count >= 100,000/mcL Total bilirubin within normal institutional limits Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) =< 2.5 X institutional upper limit of normal Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X institutional upper limit of normal Serum creatinine within normal institutional limits OR creatinine clearance >= 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal (as calculated by Cockcroft-Gault) Patients must have an avid primary tumor with an standardized uptake value (SUV) of >= 5 on baseline (18F) FDG-PET/computed tomography (CT) imaging Men must agree to use adequate contraception (double barrier method of birth control or abstinence) 1 week prior to study entry, for the duration of study participation and for 1 month after completing combined modality treatment with chemotherapy and radiation; should a male patient's female partner become pregnant or suspect that she is pregnant while her partner is participating in this study, the treating physician should be informed immediately Patients must have the ability to understand and the willingness to sign a written informed consent document This study will be limited to enrollment of Caucasian males only Exclusion Criteria: Patients who are receiving any chemotherapy, biologic therapy, radiation therapy or any investigational agent Patients with metastatic disease Patients with a history of allergic reactions attributed to compounds of similar chemical or biologic composition to platinums, taxanes or fluoropyrimidines Patients who have previously received radiation therapy to the chest or abdomen such that there would be overlap between the previous and current radiation field Patients with uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements Patients with human immunodeficiency virus (HIV) whom are not receiving antiretroviral therapy Patients with another malignancy within the past 5 years

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Jennifer Eads

Organizational Affiliation

Case Comprehensive Cancer Center

Official's Role

Principal Investigator

Facility Information:

Facility Name

Case Comprehensive Cancer Center

City

Cleveland

State/Province

Ohio

ZIP/Postal Code

44106-5065

Country

United States

12. IPD Sharing Statement

Learn more about this trial

Molecular Phenotyping in Predicting Response in Patients With Stage IB-III Esophageal Cancer Receiving Combination Chemotherapy

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