Personalized Therapy for Esophagogastric Cancer Using Thymidylate Synthase Genetic Markers

March 7, 2016 updated by: Washington University School of Medicine

In this study the investigators aim to: 1) confirm the objective response rate (ORR) observed in the investigators initial study for patients with the TSER*2/*2 genotype 2) determine whether PEMOX regimen is more worthy of future development for this patient genotype selected population than FOLFOX based on the data indicating that pemetrexed may be a better TS targeted agent than 5-FU.

Patients who are homozygous for the TSER*2 allele (TSER*2/*2) will be able to continue in the study and will be randomized. Patients with other TSER genotypes will not be included and will be considered screen fails.

The first 8 patients with the TSER*2/*2 genotype will be randomized 1:1 to receive treatment with either PEMOX or FOLFOX (4 in each group).

Analysis of the objective response rate (ORR) in each treatment arm will occur after the first 8 patients are enrolled. Using the proposed Bayesian design, subsequent patients will be preferentially assigned to the "better performing" treatment arm based on continuous real-time reassessments of ORR results.

Study Overview

Status

Withdrawn

Conditions

Intervention / Treatment

Study Type

Interventional

Phase

  • Phase 2

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

Pre-Registration Inclusion Criteria

  • Histologically or cytologically confirmed unresectable or metastatic esophagogastric adenocarcinoma.
  • Measurable disease defined as lesions that can be accurately measured in at least one dimension (longest diameter to be recorded) as >10 mm with CT scan, as >20 mm by chest x-ray, or >10 mm with calipers by clinical exam. PET/CT scan is acceptable as a substitute for a CT scan if the CT portion of the PET/CT is of identical diagnostic quality to a diagnostic CT scan.
  • At least 18 years of age.
  • ECOG performance status < 2
  • Able to understand and willing to sign an IRB approved written informed consent document (or that of legally authorized representative, if applicable).

Registration Inclusion Criteria

  • TSER genotype *2/*2
  • ECOG performance status < 2

  • Normal bone marrow and organ function as defined below:

    • Absolute neutrophil count ≥ 1,500 cells/mm3
    • Platelets ≥ 100,000 cells/mm3
    • Total bilirubin < 1.5 x IULN
    • AST(SGOT)/ALT(SGPT) < 3.0 x IULN
    • Creatinine within normal institutional limits OR Creatinine clearance ≥ 45 mL/min/1.73 m2 for patients with creatinine levels above institutional normal
  • Women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control, abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately.

Exclusion Criteria:

Pre-Registration Exclusion Criteria

  • Prior therapy for this cancer.
  • A history of other malignancy ≤ 5 years previous with the exception of basal cell or squamous cell carcinoma of the skin which were treated with local resection only or carcinoma in situ of the cervix.
  • 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.
  • Known HIV-positivity on combination antiretroviral therapy because of the potential for pharmacokinetic interactions with pemetrexed and/or oxaliplatin. In addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated.

Registration Exclusion Criteria

  • Currently receiving any other investigational agents.
  • Known brain metastases. Patients with known brain metastases must be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.
  • A history of allergic reactions attributed to compounds of similar chemical or biologic composition to pemetrexed, 5-FU, leucovorin or oxaliplatin, or other agents used for premedication in the study.
  • Pregnant and/or breastfeeding. Patient must have a negative pregnancy test within 14 days of study entry.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: PEMOX

Pemetrexed will be given intravenously (IV) on an outpatient basis on Day 1 of each 14-day cycle over 10 minutes. Oxaliplatin will be given (IV) on an outpatient basis on Day 1 of each 14-day cycle at a dose over 120 minutes. Drugs may be given in either order.

-Oxaliplatin will be administered on Day 2 for Cycle 1 only. **
Drug: Oxaliplatin
Other Names:
  • Eloxatin®
Drug: Pemetrexed
Other Names:
  • Alimta®
Genetic: Germline genotyping analyses for TSER
Experimental: FOLFOX

The modified FOLFOX-6 regimen is the following drugs given every 14 days:

  • Oxaliplatin on Day 1 of each cycle
  • Leucovorin over 120 minutes on Day 1 of each cycle

  • 5-FU bolus and continuous infusion over 46 hours beginning on Day 1 of each cycle

    • Oxaliplatin will be administered on Day 2 for Cycle 1 only and the 5-FU infusion will be interrupted at 20 hours so that the FLT-PET scan can be performed (only for FLT-PET scan eligible patients).
Drug: Oxaliplatin
Other Names:
  • Eloxatin®
Drug: Pemetrexed
Other Names:
  • Alimta®
Drug: Leucovorin
Other Names:
  • Wellcovorin
Genetic: Germline genotyping analyses for TSER
Drug: Fluorouracil
Other Names:
  • 5-Fluorouracil
  • 5FU
  • Adrucil®

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Objective response rate (ORR)
Time Frame: Baseline, end of every 4th cycle, and end of treatment (estimated average of 6 months)

ORR=complete response + partial response by RECIST criteria

Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm.

Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.
Baseline, end of every 4th cycle, and end of treatment (estimated average of 6 months)

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Overall survival (OS)
Time Frame: Every 3 months for up to 4 years from the date of study registration or until death, whichever occurs first
OS = The length of time from the start of treatment to time of death.
Every 3 months for up to 4 years from the date of study registration or until death, whichever occurs first
Quality of life
Time Frame: Baseline and Day 1 of each cycle through Cycle 5 Day 1 (approximately Day 70)
Quality of life will be assessed by the EORTC QLQ-C30 and the EORTC QLQ-STO22
Baseline and Day 1 of each cycle through Cycle 5 Day 1 (approximately Day 70)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Washington University School of Medicine

Collaborators

Gateway for Cancer Research

Investigators

  • Principal Investigator: A. Craig Lockhart, M.D., Washington University School of Medicine

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

February 1, 2015

Primary Completion (Anticipated)

September 1, 2018

Study Completion (Anticipated)

February 1, 2022

Study Registration Dates

First Submitted

November 18, 2014

First Submitted That Met QC Criteria

November 19, 2014

First Posted (Estimate)

November 20, 2014

Study Record Updates

Last Update Posted (Estimate)

March 8, 2016

Last Update Submitted That Met QC Criteria

March 7, 2016

Last Verified

March 1, 2016

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 201412051

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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