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

Primary Purpose

Esophageal Adenocarcinoma, Gastric Adenocarcinoma, Stage IIB Gastric Cancer

Status
Recruiting
Phase
Phase 4
Locations
United States
Study Type
Interventional
Intervention
Oxaliplatin
Leucovorin Calcium
Irinotecan Hydrochloride
Fluorouracil
Conventional Surgery
Sponsored by
University of Chicago
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Esophageal Adenocarcinoma

Eligibility Criteria

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

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

Sites / Locations

  • University of Chicago Comprehensive Cancer CenterRecruiting
  • Kellogg Cancer Center - Evanston HospitalRecruiting
  • NorthShore University HealthSystemRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment (mFOLFIRINOX, surgery)

Arm Description

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.

Outcomes

Primary Outcome Measures

R0 (analysis will be performed evaluating the R0 rate)
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

Response rate
Will be evaluated by reporting event rates along with exact (binomial distribution-based) 95% confidence intervals.
Surgical morbidity
Will be evaluated by reporting event rates along with exact (binomial distribution-based) 95% confidence intervals.
Pattern of recurrence
Will be evaluated by reporting event rates along with exact (binomial distribution-based) 95% confidence intervals.
Incidence of toxicity based on NCI-CTCAE v 4.0
Toxicities will be summarized by type, grade, and attribution.
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)
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.
Progression free survival
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.

Full Information

First Posted
January 27, 2015
Last Updated
April 27, 2023
Sponsor
University of Chicago
Collaborators
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT02366819
Brief Title
Genetic Analysis-Guided Irinotecan Hydrochloride Dosing of mFOLFIRINOX in Treating Patients With Locally Advanced Gastroesophageal or Stomach Cancer
Official Title
PERIOP-FOLFIRINOX: A Pilot Trial of Perioperative Genotype-guided Irinotecan Dosing of gFOLFIRINOX for Locally Advanced Gastroesophageal Adenocarcinoma
Study Type
Interventional

2. Study Status

Record Verification Date
April 2023
Overall Recruitment Status
Recruiting
Study Start Date
December 11, 2014 (Actual)
Primary Completion Date
March 20, 2024 (Anticipated)
Study Completion Date
March 8, 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of Chicago
Collaborators
National Cancer Institute (NCI)

4. Oversight

Data Monitoring Committee
No

5. Study Description

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.
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.

6. Conditions and Keywords

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

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
36 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Treatment (mFOLFIRINOX, surgery)
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Oxaliplatin
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
Leucovorin Calcium
Other Intervention Name(s)
CF
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
Irinotecan Hydrochloride
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
Fluorouracil
Intervention Description
Given IV
Intervention Type
Procedure
Intervention Name(s)
Conventional Surgery
Other Intervention Name(s)
surgery, conventional
Intervention Description
Undergo surgery
Primary Outcome Measure Information:
Title
R0 (analysis will be performed evaluating the R0 rate)
Description
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.
Time Frame
During surgery
Secondary Outcome Measure Information:
Title
Response rate
Description
Will be evaluated by reporting event rates along with exact (binomial distribution-based) 95% confidence intervals.
Time Frame
Up to 5 years
Title
Surgical morbidity
Description
Will be evaluated by reporting event rates along with exact (binomial distribution-based) 95% confidence intervals.
Time Frame
Up to 5 years
Title
Pattern of recurrence
Description
Will be evaluated by reporting event rates along with exact (binomial distribution-based) 95% confidence intervals.
Time Frame
Up to 5 years
Title
Incidence of toxicity based on NCI-CTCAE v 4.0
Description
Toxicities will be summarized by type, grade, and attribution.
Time Frame
Up to 5 years
Title
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)
Description
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.
Time Frame
Time from enrollment/registration to the time of death, of any cause, assessed up to 5 years
Title
Progression free survival
Description
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.
Time Frame
Time from enrollment/registration to time of progression or death from any cause, assessed up to 5 years
Other Pre-specified Outcome Measures:
Title
Circulating tumor cell (CTC) numbers derived from portal and peripheral blood samples
Description
Pearson or Spearman rank correlation coefficients will be calculated between CTC numbers derived from portal and peripheral blood samples.
Time Frame
Up to 5 years
Title
Change in SUVmax for PET/CT studies
Description
Will be analyzed lesion-by-lesion using paired t-tests or Wilcoxon, signed rank tests.
Time Frame
Baseline to after 8 weeks of chemotherapy
Title
Change in SUVmax for the primary esophageal tumor
Description
Will be correlated with clinical and histopathological response rates by logistic regression, and with progression-free and overall survival by Cox regression analysis.
Time Frame
Baseline to up to 5 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Daniel Catenacci
Organizational Affiliation
University of Chicago Comprehensive Cancer Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Chicago Comprehensive Cancer Center
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60637
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Daniel V. Catenacci
Phone
773-702-7596
Email
dcatenac@medicine.bsd.uchicago.edu
First Name & Middle Initial & Last Name & Degree
Daniel V. Catenacci
Facility Name
Kellogg Cancer Center - Evanston Hospital
City
Evanston
State/Province
Illinois
ZIP/Postal Code
60201
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Robert d. Marsh
Phone
847-570-2112
Email
rmarsh@northshore.org
First Name & Middle Initial & Last Name & Degree
Robert d. Marsh
Facility Name
NorthShore University HealthSystem
City
Evanston
State/Province
Illinois
ZIP/Postal Code
60201
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Mark S. Talamonti
Phone
847-570-2560
Email
mtalamonti@northshore.org
First Name & Middle Initial & Last Name & Degree
Mark S. Talamonti

12. IPD Sharing Statement

Citations:
PubMed Identifier
32058557
Citation
Catenacci DVT, Chase L, Lomnicki S, Karrison T, de Wilton Marsh R, Rampurwala MM, Narula S, Alpert L, Setia N, Xiao SY, Hart J, Siddiqui UD, Peterson B, Moore K, Kipping-Johnson K, Markevicius U, Gordon B, Allen K, Racette C, Maron SB, Liao CY, Polite BN, Kindler HL, Turaga K, Prachand VN, Roggin KK, Ferguson MK, Posner MC. Evaluation of the Association of Perioperative UGT1A1 Genotype-Dosed gFOLFIRINOX With Margin-Negative Resection Rates and Pathologic Response Grades Among Patients With Locally Advanced Gastroesophageal Adenocarcinoma: A Phase 2 Clinical Trial. JAMA Netw Open. 2020 Feb 5;3(2):e1921290. doi: 10.1001/jamanetworkopen.2019.21290.
Results Reference
derived

Learn more about this trial

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

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