Irinotecan and Cisplatin in Treating Patients Who Are Undergoing Surgery For Locally Advanced Cancer of the Stomach or Gastroesophageal Junction

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00062374
• Collaborator: (none)
• Enrollment: 55
• Location: 1
• Arm: 1
• Duration (Months): 96
• Patients Per Site Per Month: 0.6

Study Details

Study Description

Brief Summary

This phase II trial is studying how well giving irinotecan together with cisplatin works in treating patients who are undergoing surgical resection for locally advanced cancer of the stomach or gastroesophageal junction. Drugs used in chemotherapy, such as irinotecan and cisplatin, work in different ways to stop tumor cells from dividing so they stop growing or die. Combining more than one chemotherapy drug and giving them before surgery may shrink the tumor so that it can be removed during surgery.

Condition or Disease	Intervention/Treatment	Phase
Gastric Adenocarcinoma; Stage II Gastric Cancer; Stage III Gastric Cancer; Stage IV Gastric Cancer	Drug: Cisplatin; Procedure: Computed Tomography; Radiation: Fludeoxyglucose F-18; Other: Fluorothymidine F-18; Drug: Irinotecan Hydrochloride; Procedure: Positron Emission Tomography; Procedure: Therapeutic Conventional Surgery	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. To evaluate the correlation of fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) imaging early in the preoperative treatment program of locally advanced gastric cancer with histologic response assessment and patient outcome, defined as overall and progression-free survival.

SECONDARY OBJECTIVES:

1. To evaluate the efficacy and safety of preoperative chemotherapy with irinotecan and cisplatin in the treatment of locally advanced gastric cancer.

2. To examine the biology of locally advanced gastric cancer and the response to chemotherapy by DNA microarray technology and by histopathology.

3. To obtain preliminary data on biodistribution, dosimetry and explore the potential clinical usefulness of fluorodeoxythymidine (FLT) PET in patients with locally advanced gastric cancer undergoing a novel combination neoadjuvant chemotherapy.

OUTLINE: This is an open-label, nonrandomized, multicenter study.

Neoadjuvant chemotherapy: Patients receive cisplatin intravenously (IV) over 30 minutes followed by irinotecan IV over 30 minutes on days 1, 8, 22, and 29. Treatment repeats every 6 weeks for 2 courses in the absence of disease progression or unacceptable toxicity.

Surgery: Within 4 weeks after completion of neoadjuvant chemotherapy, patients undergo radical subtotal or total gastrectomy with lymph node dissection.

Patients undergo fluorodeoxyglucose FDG-PET/CT at baseline. Some patients undergo additional FDG-PET/CT scans in weeks 3 and 6. Approximately 5 patients undergo fluorothymidine FLT-PET/CT at baseline, during week 3, and/or before surgical resection.

Patients are followed up every 3 months for 2 years, every 6 months for 2 years, and then annually thereafter.

Study Design

• Study Type: Interventional
• Actual Enrollment: 55 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Evaluation of Preoperative Chemotherapy With Irinotecan and Cisplatin for Advanced, But Resectable Gastric Cancer: A Coordinated Multidisciplinary, Multicenter Study Linking Functional Imaging, Genomic Expression Profiles and Histopathology
• Study Start Date: Jun 1, 2003
• Actual Primary Completion Date: Jun 1, 2011
• Actual Study Completion Date: Jun 1, 2011

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Treatment (preoperative chemotherapy) Neoadjuvant chemotherapy: Patients receive cisplatin IV over 30 minutes followed by irinotecan IV over 30 minutes on days 1, 8, 22, and 29. Treatment repeats every 6 weeks for 2 courses in the absence of disease progression or unacceptable toxicity. Surgery: Within 4 weeks after completion of neoadjuvant chemotherapy, patients undergo radical subtotal or total gastrectomy with lymph node dissection.

Drug: Cisplatin; Given IV; Other Names: Abiplatin Blastolem Briplatin CDDP Cis-diammine-dichloroplatinum Cis-diamminedichloridoplatinum Cis-diamminedichloro Platinum (II) Cis-diamminedichloroplatinum Cis-dichloroammine Platinum (II) Cis-platinous Diamine Dichloride Cis-platinum Cis-platinum II Cis-platinum II Diamine Dichloride Cismaplat Cisplatina Cisplatinum Cisplatyl Citoplatino Citosin Cysplatyna DDP Lederplatin Metaplatin Neoplatin Peyrone's Chloride Peyrone's Salt Placis Plastistil Platamine Platiblastin Platiblastin-S Platinex Platinol Platinol- AQ Platinol-AQ Platinol-AQ VHA Plus Platinoxan Platinum Platinum Diamminodichloride Platiran Platistin Platosin ; Procedure: Computed Tomography; Undergo FDG and FLT PET/CT; Other Names: CAT CAT Scan Computerized Axial Tomography Computerized Tomography CT CT SCAN tomography ; Radiation: Fludeoxyglucose F-18; Undergo FDG-PET/CT; Other Names: 18FDG FDG fludeoxyglucose F 18 Fludeoxyglucose F18 Fluorine-18 2-Fluoro-2-deoxy-D-Glucose Fluorodeoxyglucose F18 ; Other: Fluorothymidine F-18; Undergo FLT-PET/CT; Other Names: 18F-FLT 3'-Deoxy-3'-(18F) Fluorothymidine 3'-deoxy-3'-[18F]fluorothymidine Fluorothymidine F 18 ; Drug: Irinotecan Hydrochloride; Given IV; Other Names: Campto Camptosar Camptothecin 11 Camptothecin-11 CPT 11 CPT-11 Irinomedac U-101440E ; Procedure: Positron Emission Tomography; Undergo FDG and FLT PET/CT; Other Names: Medical Imaging, Positron Emission Tomography PET PET SCAN Positron Emission Tomography Scan Positron-Emission Tomography proton magnetic resonance spectroscopic imaging ; Procedure: Therapeutic Conventional Surgery; Undergo radical subtotal or total gastrectomy with lymph node dissection

Outcome Measures

Primary Outcome Measures

1. Histological Response Determined by FDG Uptake Correlates [Day 15]

   The primary objective was to demonstrate that a decrease in FDG-SUV discriminates treatment response. Response was defined pathologically based on microscopic inspection for residual cancer cells and fibrosis. Using a two sample t-test, we would be able to adequately test that the decrease in SUV early in the treatment plan is significantly different between responders and non responders. Data adjudication was invalid, and needs to be re-adjudicated Non-Responder= Tumor Regression Grade 3 or higher Responder=Tumor Regression Grade 1 (CR) or Grade 2 (PR)

Other Outcome Measures

1. Disease Free Survival (DFS) [Every 3 mos for the first 2 yrs, then every 6 mos for 2 years and once a year afterwards, up to 5 years]

   Overall Survival (OS) and Disease Free Survival (DFS) are the secondary endpoints. Technical problems with measurement of OS leading to unreliable or uniterpretable data. Data adjudication was invalid, and needs to be re-adjudicated. Therefore, only DFS data is being reported.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• All patients must have microscopically confirmed adenocarcinoma of the stomach or gastroesophageal (GE) junction with material reviewed by the Department of Pathology of the participating Institution; tumors involving the GE junction must have the bulk of their disease in the stomach; tumors of the distal esophagus that extend less than 2cm into the stomach are ineligible for this study; using the Siewert's classification for the GE junction, tumors designated as Types II and III are indeed considered eligible for this clinical trial

• All patients must have localized cancer potentially curable by surgery; the tumor stage should be Tany N+ M0 or T3-T4 Nany M0, by staging that includes a computed tomography (CT) scan and either laparoscopy-assisted pancreatobiliary (LAP) or endoscopic ultrasound (EUS); patients with T1-2N0M0 tumors, confirmed by LAP ("good risk") are ineligible; any sites of suspected M1 disease by these criteria must be proven to be M0 prior to entrance into a neoadjuvant trial

• Patients must have a Karnofsky Performance Status >= 60% (Eastern Cooperative Oncology Group [ECOG] =< 2) and be able to tolerate the proposed surgical procedure and chemotherapy regimen

• Patients may not have received prior chemotherapy or radiation for this disease

• Absolute neutrophil count (ANC) >= 1,500 cells/mm^3

• Platelets >= 100,000/mm^3

• Serum creatinine =< 1.5 mg/dL

• Total serum bilirubin =< 1.5 mg/dL

• Patients must have signed informed consent indicating that they are aware of the investigational nature of the study and that participation is voluntary

• No clinically significant auditory impairment

• No clinically significant peripheral neuropathy

• New York Heart Association (NYHA) class I-II

• Patients must not have a prior history of cancer within the last five years except for non-melanoma skin cancer, non-metastatic prostate cancer or carcinoma in situ of the uterine cervix

Exclusion Criteria:

• Any metastatic disease

• NYHA Class III or IV heart disease; history of active angina or myocardial infarction within 6 months; history of significant ventricular arrhythmia requiring medication with antiarrhythmics or a history of a clinically significant conduction system abnormality

• Pregnant or lactating women are ineligible; fertile men and women, unless using effective contraception, are ineligible; a pregnancy test will be performed on sexually active women of childbearing potential prior to entry into the study; treatment may not begin until the results of the pregnancy test are ascertained

• Serious intercurrent infections, or nonmalignant medical illnesses that are uncontrolled or whose control may be jeopardized by the complications of this therapy

• Grade 2 or greater pre-existing peripheral neuropathy

• Psychiatric disorders rendering patients incapable of complying with the requirements of the protocol

• Any concurrent active malignancy other than non-melanoma skin cancers, non-metastatic prostate cancer or carcinoma-in-situ of the uterine cervix; patients with previous malignancies but without evidence of disease for > 5 years will be allowed to enter the trial

• Clinically significant hearing loss

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Memorial Sloan-Kettering Cancer Center	New York	New York	United States	10065

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Manisha Shah, Memorial Sloan Kettering Cancer Center

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT00062374
• Other Study ID Numbers: NCI-2012-01438; NCI-2012-01438; NCI-5917; CDR0000304738; MSKCC-03032; 03-032; 5917; P30CA008748
• First Posted: Jun 6, 2003
• Last Update Posted: Jul 6, 2017
• Last Verified: Jun 1, 2017

• Additional relevant MeSH terms: Stomach Neoplasms; Deoxyglucose; Alovudine; Cisplatin; Irinotecan; Camptothecin; Fluorodeoxyglucose F18

Study Results

Participant Flow

Recruitment Details	Date Opened to Accrual: 6/5/2003 Date Closed to Accrual: 8/8/2006 Date Closed: 6/28/2011 Recruitment location is the medical clinic

Arm/Group Title	Arm I
Arm/Group Description	Cisplatin + Irinotecan
Period Title: Overall Study
STARTED	55
COMPLETED	43
NOT COMPLETED	12

Baseline Characteristics

Arm/Group Title	Arm I
Arm/Group Description	Neoadjuvant chemotherapy: Patients receive cisplatin IV over 30 minutes followed by irinotecan IV over 30 minutes on days 1, 8, 22, and 29. Treatment repeats every 6 weeks for 2 courses in the absence of disease progression or unacceptable toxicity. Surgery: Within 4 weeks after completion of neoadjuvant chemotherapy, patients undergo radical subtotal or total gastrectomy with lymph node dissection. irinotecan hydrochloride: Given IV cisplatin: Given IV conventional surgery: Undergo radical subtotal or total gastrectomy with lymph node dissection positron emission tomography/computed tomography: Undergo FDG-PET/CT fludeoxyglucose F 18: Undergo FDG-PET/CT positron emission tomography/computed tomography: Undergo FLT-PET/CT fluorine F 18 fluorothymidine: Undergo FLT-PET/CT
Overall Participants	55
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	35 63.6%
>=65 years	20 36.4%
Sex: Female, Male (Count of Participants)
Female	23 41.8%
Male	32 58.2%
Region of Enrollment (participants) [Number]
United States	55 100%

Outcome Measures

1. Primary Outcome

Title	Histological Response Determined by FDG Uptake Correlates
Description	The primary objective was to demonstrate that a decrease in FDG-SUV discriminates treatment response. Response was defined pathologically based on microscopic inspection for residual cancer cells and fibrosis. Using a two sample t-test, we would be able to adequately test that the decrease in SUV early in the treatment plan is significantly different between responders and non responders. Data adjudication was invalid, and needs to be re-adjudicated Non-Responder= Tumor Regression Grade 3 or higher Responder=Tumor Regression Grade 1 (CR) or Grade 2 (PR)
Time Frame	Day 15

Outcome Measure Data

Analysis Population Description

Technical problems with measurement of FDG-SUV data leading to unreliable or uninterpretable data. Data adjudication was invalid, and needs to be re-adjudicated. Therefore, only histological response is reported.

Arm/Group Title	Arm I
Arm/Group Description	Neoadjuvant chemotherapy: Patients receive cisplatin IV over 30 minutes followed by irinotecan IV over 30 minutes on days 1, 8, 22, and 29. Treatment repeats every 6 weeks for 2 courses in the absence of disease progression or unacceptable toxicity. Surgery: Within 4 weeks after completion of neoadjuvant chemotherapy, patients undergo radical subtotal or total gastrectomy with lymph node dissection. irinotecan hydrochloride: Given IV cisplatin: Given IV conventional surgery: Undergo radical subtotal or total gastrectomy with lymph node dissection positron emission tomography/computed tomography: Undergo FDG-PET/CT fludeoxyglucose F 18: Undergo FDG-PET/CT positron emission tomography/computed tomography: Undergo FLT-PET/CT fluorine F 18 fluorothymidine: Undergo FLT-PET/CT
Measure Participants	43
Progression of Disease	2 3.6%
Responders	3 5.5%
Non-Responders	38 69.1%

2. Other Pre-specified Outcome

Title	Disease Free Survival (DFS)
Description	Overall Survival (OS) and Disease Free Survival (DFS) are the secondary endpoints. Technical problems with measurement of OS leading to unreliable or uniterpretable data. Data adjudication was invalid, and needs to be re-adjudicated. Therefore, only DFS data is being reported.
Time Frame	Every 3 mos for the first 2 yrs, then every 6 mos for 2 years and once a year afterwards, up to 5 years

Outcome Measure Data

Analysis Population Description

Technical problems with measurement leading to unreliable or uninterpretable data. Data adjudication was invalid, and needs to be re-adjudicated.

Arm/Group Title	Arm I
Arm/Group Description	Neoadjuvant chemotherapy: Patients receive cisplatin IV over 30 minutes followed by irinotecan IV over 30 minutes on days 1, 8, 22, and 29. Treatment repeats every 6 weeks for 2 courses in the absence of disease progression or unacceptable toxicity. Surgery: Within 4 weeks after completion of neoadjuvant chemotherapy, patients undergo radical subtotal or total gastrectomy with lymph node dissection. irinotecan hydrochloride: Given IV cisplatin: Given IV conventional surgery: Undergo radical subtotal or total gastrectomy with lymph node dissection positron emission tomography/computed tomography: Undergo FDG-PET/CT fludeoxyglucose F 18: Undergo FDG-PET/CT positron emission tomography/computed tomography: Undergo FLT-PET/CT fluorine F 18 fluorothymidine: Undergo FLT-PET/CT
Measure Participants	43
Median (95% Confidence Interval) [months]	23.8

Adverse Events

Adverse Event Reporting Description	Number of participants at risk is the same as the total number of participants that were treated.
Arm/Group Title	Arm I
Arm/Group Description	Neoadjuvant chemotherapy: Patients receive cisplatin IV over 30 minutes followed by irinotecan IV over 30 minutes on days 1, 8, 22, and 29. Treatment repeats every 6 weeks for 2 courses in the absence of disease progression or unacceptable toxicity. Surgery: Within 4 weeks after completion of neoadjuvant chemotherapy, patients undergo radical subtotal or total gastrectomy with lymph node dissection. irinotecan hydrochloride: Given IV cisplatin: Given IV conventional surgery: Undergo radical subtotal or total gastrectomy with lymph node dissection positron emission tomography/computed tomography: Undergo FDG-PET/CT fludeoxyglucose F 18: Undergo FDG-PET/CT positron emission tomography/computed tomography: Undergo FLT-PET/CT fluorine F 18 fluorothymidine: Undergo FLT-PET/CT
All Cause Mortality
	Arm I
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Arm I
	Affected / at Risk (%)	# Events
Total	14/55 (25.5%)
Blood and lymphatic system disorders
Febrile neutropenia	3/55 (5.5%)	3
Hemorrhage, NOS	2/55 (3.6%)	3
Hemoglobin decrease	1/55 (1.8%)	1
Cardiac disorders
Cardiovascular, other	1/55 (1.8%)	1
Gastrointestinal disorders
Abdominal pain/cramping	1/55 (1.8%)	1
Diarrhea	2/55 (3.6%)	2
Fatigue	1/55 (1.8%)	1
Gastrointestinal disorder	1/55 (1.8%)	1
Nausea	1/55 (1.8%)	1
Vomiting	1/55 (1.8%)	1
General disorders
Chest pain	2/55 (3.6%)	2
Investigations
Creatinine increased	1/55 (1.8%)	1
Neutrophil count decrease	2/55 (3.6%)	2
Metabolism and nutrition disorders
Dehydration	1/55 (1.8%)	1
Hyperglycemia	1/55 (1.8%)	1
Musculoskeletal and connective tissue disorders
Muscle weakness	1/55 (1.8%)	1
Nervous system disorders
CNS/cerebrovascular ischemia	2/55 (3.6%)	2
Seizure	1/55 (1.8%)	1
Vascular disorders
Hypotension	1/55 (1.8%)	1
Thrombosis	5/55 (9.1%)	6
Other (Not Including Serious) Adverse Events
	Arm I
	Affected / at Risk (%)	# Events
Total	44/55 (80%)
Blood and lymphatic system disorders
Hemoglobin decrease	30/55 (54.5%)	54
Ear and labyrinth disorders
Hearing impaired	4/55 (7.3%)	4
Gastrointestinal disorders
Abdominal pain/cramping	15/55 (27.3%)	24
Constipation	4/55 (7.3%)	5
Diarrhea	25/55 (45.5%)	41
Dyspepsia	4/55 (7.3%)	4
Dysphagia	3/55 (5.5%)	3
Nausea	33/55 (60%)	64
Vomiting	12/55 (21.8%)	23
General disorders
Edema	6/55 (10.9%)	6
Fatigue	36/55 (65.5%)	83
Pain, other	3/55 (5.5%)	3
Investigations
Creatinine	6/55 (10.9%)	43
White blood cell count decrease	32/55 (58.2%)	148
Lymphocyte count decrease	11/55 (20%)	37
Neutrophil count decrease	31/55 (56.4%)	112
Platelet count decreased	21/55 (38.2%)	81
Aspartate aminotransferase increase	7/55 (12.7%)	14
Alanine aminotransferase increase	10/55 (18.2%)	31
Weight loss	5/55 (9.1%)	6
Metabolism and nutrition disorders
Anorexia	16/55 (29.1%)	18
Dehydration	6/55 (10.9%)	8
Hyperglycemia	11/55 (20%)	20
Hyperkalemia	11/55 (20%)	12
Hypernatremia	5/55 (9.1%)	5
Hypoalbuminemia	11/55 (20%)	27
Hypocalcemia	35/55 (63.6%)	219
Hypoglycemia	3/55 (5.5%)	3
Hypokalemia	16/55 (29.1%)	31
Hypomagnesemia	12/55 (21.8%)	41
Hyponatremia	20/55 (36.4%)	60
Hypophosphatemia	17/55 (30.9%)	31
Nervous system disorders
Dizziness	6/55 (10.9%)	7
Neuropathy-sensory	11/55 (20%)	12
Taste disturbance	4/55 (7.3%)	6
Psychiatric disorders
Mood alteration/anxiety	4/55 (7.3%)	5
Respiratory, thoracic and mediastinal disorders
Dyspnea	7/55 (12.7%)	7
Pharyngeal mucositis	3/55 (5.5%)	4
Skin and subcutaneous tissue disorders
Alopecia	5/55 (9.1%)	6
Vascular disorders
Thrombosis	5/55 (9.1%)	5

Limitations/Caveats

Technical problems with measurement leading to unreliable or uninterpretable data. Data adjudication was invalid, and needs to be re-adjudicated.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.