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Genetic Analysis-Guided Irinotecan Hydrochloride Dosing of mFOLFIRINOX in Treating Patients With Locally Advanced Gastroesophageal or Stomach Cancer

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ClinicalTrials.gov Identifier: NCT02366819
Recruitment Status : Recruiting
First Posted : February 19, 2015
Last Update Posted : February 7, 2018
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
University of Chicago

Brief Summary:
This pilot clinical trial studies genetic analysis-guided irontecan hydrochloride dosing of modified fluorouracil, irinotecan hydrochloride, leucovorin calcium, oxaliplatin (mFOLFIRINOX) in treating patients with gastroesophageal or stomach cancer that has spread from where it started to nearby tissue or lymph nodes. Drugs used in chemotherapy, such as fluorouracil, irinotecan hydrochloride, leucovorin calcium, and oxaliplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Leucovorin calcium may also help fluorouracil work better. Genetic analysis may help doctors determine what dose of irinotecan hydrochloride patients can tolerate.

Condition or disease Intervention/treatment Phase
Esophageal Adenocarcinoma Gastric Adenocarcinoma Stage IIB Gastric Cancer Stage IIIA Esophageal Adenocarcinoma Stage IIIA Gastric Cancer Stage IIIB Esophageal Adenocarcinoma Stage IIIB Gastric Cancer Stage IIIC Esophageal Adenocarcinoma Stage IIIC Gastric Cancer Drug: Oxaliplatin Drug: Leucovorin Calcium Drug: Irinotecan Hydrochloride Drug: Fluorouracil Procedure: Conventional Surgery Phase 4

Detailed Description:

PRIMARY OBJECTIVES:

I. To determine the residual tumor (R) 0 resection rate. II. To determine the pathologic complete response (pCR) rate of up to 36 patients treated with 4 cycles of neoadjuvant mFOLFIRINOX (UGTA1A1 genotype-dosed irinotecan [irinotecan hydrochloride]) regimen.

SECONDARY OBJECTIVES:

I. Response rate (radiographic [computed tomography (CT)], and metabolic (positron emission tomography [PET] maximum standardized uptake value [SUVmax]) to chemotherapy.

II. Chemotherapy-related toxicity. III. Surgical morbidity. IV. Overall survival (OS) measured from the time of histologic diagnosis. V. Disease-free survival measured from the time of histologic diagnosis. VI. Pattern of recurrence (distant, locoregional, both). VII. Human epidermal growth factor receptor 2 positive (HER2+) vs HER2 negative (-) difference in clinical outcomes.

OUTLINE:

PREOPERATIVE THERAPY: Patients receive oxaliplatin intravenously (IV) over 2 hours, leucovorin calcium IV over 2 hours, irinotecan hydrochloride IV over 90 minutes, and fluorouracil IV over 46 hours continuously on day 1. Courses repeat every 2 weeks for 4 courses in the absence of disease progression or unacceptable toxicity.

SURGERY: Patients undergo surgery.

POST-OPERATIVE THERAPY: Beginning 5-10 weeks after surgery, patients receive oxaliplatin IV over 2 hours, leucovorin calcium IV over 2 hours, irinotecan hydrochloride IV over 90 minutes, and fluorouracil IV over 46 hours continuously on day 1. Courses repeat every 2 weeks for 4 more courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years and then every 6 months for 3 years.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 36 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Pilot Trial of Perioperative Genotype-Guided Irinotecan Dosing of mFOLFIRINOX for Locally Advanced Gastroesophageal Adenocarcinoma
Study Start Date : December 2014
Estimated Primary Completion Date : January 2019
Estimated Study Completion Date : January 2019


Arm Intervention/treatment
Experimental: Treatment (mFOLFIRINOX, surgery)

PREOPERATIVE THERAPY: Patients receive oxaliplatin IV over 2 hours, leucovorin calcium IV over 2 hours, irinotecan hydrochloride IV over 90 minutes, and fluorouracil IV over 46 hours continuously on day 1. Courses repeat every 2 weeks for 4 courses in the absence of disease progression or unacceptable toxicity.

SURGERY: Patients undergo conventional surgery.

POST-OPERATIVE THERAPY: Beginning 5-10 weeks after surgery, patients receive oxaliplatin IV over 2 hours, leucovorin calcium IV over 2 hours, irinotecan hydrochloride IV over 90 minutes, and fluorouracil IV over 46 hours continuously on day 1. Courses repeat every 2 weeks for 4 more courses in the absence of disease progression or unacceptable toxicity.

Drug: Oxaliplatin
Given IV

Drug: Leucovorin Calcium
Given IV
Other Name: CF

Drug: Irinotecan Hydrochloride
Given IV

Drug: Fluorouracil
Given IV

Procedure: Conventional Surgery
Undergo surgery
Other Name: surgery, conventional




Primary Outcome Measures :
  1. R0 (analysis will be performed evaluating the R0 rate) [ Time Frame: During surgery ]
    Intention-to-treat analysis will be performed, and patients with tumor progression during/after neoadjuvant chemotherapy that precludes surgery will be included as non-R0 resection. A subset analysis will be performed evaluating the R0 rate for those patients actually undergoing surgery.


Secondary Outcome Measures :
  1. Response rate [ Time Frame: Up to 5 years ]
    Will be evaluated by reporting event rates along with exact (binomial distribution-based) 95% confidence intervals.

  2. Surgical morbidity [ Time Frame: Up to 5 years ]
    Will be evaluated by reporting event rates along with exact (binomial distribution-based) 95% confidence intervals.

  3. Pattern of recurrence [ Time Frame: Up to 5 years ]
    Will be evaluated by reporting event rates along with exact (binomial distribution-based) 95% confidence intervals.

  4. Incidence of toxicity based on NCI-CTCAE v 4.0 [ Time Frame: Up to 5 years ]
    Toxicities will be summarized by type, grade, and attribution.

  5. OS (estimated using the Kaplan-Meier procedure and compared in the subgroups of patients with and without pCR (grade 1a) using the log-rank test) [ Time Frame: Time from enrollment/registration to the time of death, of any cause, assessed up to 5 years ]
    Will be estimated using the Kaplan-Meier procedure and compared in the subgroups of patients with and without pCR (grade 1a) using the log-rank test.

  6. Progression free survival [ Time Frame: Time from enrollment/registration to time of progression or death from any cause, assessed up to 5 years ]
    Will be estimated using the Kaplan-Meier procedure and compared in the subgroups of patients with and without pCR (grade 1a) using the log-rank test.


Other Outcome Measures:
  1. Circulating tumor cell (CTC) numbers derived from portal and peripheral blood samples [ Time Frame: Up to 5 years ]
    Pearson or Spearman rank correlation coefficients will be calculated between CTC numbers derived from portal and peripheral blood samples.

  2. Change in SUVmax for PET/CT studies [ Time Frame: Baseline to after 8 weeks of chemotherapy ]
    Will be analyzed lesion-by-lesion using paired t-tests or Wilcoxon, signed rank tests.

  3. Change in SUVmax for the primary esophageal tumor [ Time Frame: Baseline to up to 5 years ]
    Will be correlated with clinical and histopathological response rates by logistic regression, and with progression-free and overall survival by Cox regression analysis.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Histologically confirmed locally advanced gastric (primary endpoint includes proximal and mid-body stomach) or esophagogastric adenocarcinoma; distal gastric (antral) adenocarcinomas are eligible for enrolment but will not be included in the primary analysis
  • Locally advanced disease as determined by endoscopic ultrasound (EUS) stage > primary tumor (T) 3 and/or any T, lymph nodes (N)+ disease without metastatic disease (Mx)
  • All patients must have diagnostic laparoscopy with diagnostic washings for cytology; both cytology positive and negative patients are eligible for enrolment, but only cytology negative patients will be included in the primary analyses; gross peritoneal disease is not eligible
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 1
  • Eligible for surgery with curative intent
  • Absolute neutrophil count (ANC) >= 1250/ul
  • Hemoglobin >= 9 g/dL
  • Platelets >= 100,000/ul
  • Total bilirubin < 1.5 x upper limit of normal
  • Serum glutamic oxaloacetic transaminase (SGOT) and serum glutamate pyruvate transaminase (SGPT) < 2.5 x upper limit of normal for patients without liver metastases OR SGOT and SGPT < 5 x upper limit of normal for patients with liver metastases
  • Creatinine =< 1.5 x upper limit of normal
  • Measurable or non-measurable disease by Response Evaluation Criteria in Solid Tumor (RECIST) 1.1 will be allowed
  • 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 and for the duration of study participation, up until 30 days after final study treatment; should a woman become pregnant or suspect that she is pregnant while participating in this study, she should inform her treating physician immediately
  • Patients taking substrates, inhibitors, or inducers of cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) should be encouraged to switch to alternative drugs whenever possible, given the potential for drug-drug interactions with irinotecan
  • Signed informed consent

Exclusion Criteria:

  • Previous or concurrent malignancy, except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or any other cancer for which the patient has been previously treated and the lifetime recurrence risk is less than 30%
  • Inflammatory bowel disease that is uncontrolled or on active treatment (Crohn's disease, ulcerative colitis)
  • Diarrhea, grade 1 or greater by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE, version [v] 4.0)
  • Neuropathy, grade 2 or greater by NCI-CTCAE, v 4.0
  • Serious underlying medical or psychiatric illnesses that would, in the opinion of the treating physician, substantially increase the risk for complications related to treatment
  • Active uncontrolled bleeding
  • Pregnancy or breastfeeding
  • Major surgery within 4 weeks
  • Patients with any polymorphism in UGT1A1 other than *1 or *28 (e.g, *6) will be allowed and treated as in the *28/*28 dosing group

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): NCT02366819


Locations
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United States, Illinois
University of Chicago Comprehensive Cancer Center Recruiting
Chicago, Illinois, United States, 60637
Contact: Daniel V. Catenacci    773-702-7596    dcatenac@medicine.bsd.uchicago.edu   
Principal Investigator: Daniel V. Catenacci         
Kellogg Cancer Center - Evanston Hospital Recruiting
Evanston, Illinois, United States, 60201
Contact: Robert d. Marsh    847-570-2112    rmarsh@northshore.org   
Principal Investigator: Robert d. Marsh         
NorthShore University HealthSystem Recruiting
Evanston, Illinois, United States, 60201
Contact: Mark S. Talamonti    847-570-2560    mtalamonti@northshore.org   
Principal Investigator: Mark S. Talamonti         
Sponsors and Collaborators
University of Chicago
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Daniel Catenacci University of Chicago Comprehensive Cancer Center

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Responsible Party: University of Chicago
ClinicalTrials.gov Identifier: NCT02366819     History of Changes
Other Study ID Numbers: IRB14-0594
NCI-2014-02574 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
IRB14-0594 ( Other Identifier: University of Chicago )
P30CA014599 ( U.S. NIH Grant/Contract )
First Posted: February 19, 2015    Key Record Dates
Last Update Posted: February 7, 2018
Last Verified: February 2018
Additional relevant MeSH terms:
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Adenocarcinoma
Stomach Neoplasms
Esophageal Neoplasms
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Gastrointestinal Diseases
Stomach Diseases
Head and Neck Neoplasms
Esophageal Diseases
Oxaliplatin
Irinotecan
Fluorouracil
Calcium
Levoleucovorin
Calcium-Regulating Hormones and Agents
Physiological Effects of Drugs
Antineoplastic Agents
Topoisomerase I Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antimetabolites
Antimetabolites, Antineoplastic
Immunosuppressive Agents