Adenocarcinoma of the Gastroesophageal Junction, Esophageal Cancer, Gastric Cancer
Conditions
Keywords
recurrent esophageal cancer, stage IV esophageal cancer, recurrent gastric cancer, stage IV gastric cancer, adenocarcinoma of the gastroesophageal junction, stage IIIB gastric cancer, stage IIIC gastric cancer, stage IIIB esophageal cancer, stage IIIC esophageal cancer, adenocarcinoma of the esophagus, adenocarcinoma of the stomach
Brief summary
RATIONALE: Drugs used in chemotherapy, such as oxaliplatin, leucovorin calcium, fluorouracil, irinotecan hydrochloride, and docetaxel, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Combining more than one drug may kill more tumor cells. It is not yet known which regimen of combination chemotherapy is more effective in treating tumor cells. PURPOSE: This randomized phase II trial studies how well oxaliplatin, leucovorin calcium, and fluorouracil work compared to irinotecan hydrochloride and docetaxel in treating patients with esophageal cancer, gastric cancer, or gastroesophageal junction cancer.
Detailed description
OBJECTIVES: * To assess progression-free survival of high-excision repair cross-complementing 1(ERCC1) patients with advanced or metastatic cancer of the esophagus, stomach, or gastroesophageal junction (GEJ) treated with FOLFOX comprising oxaliplatin, leucovorin calcium, and fluorouracil compared to those treated with irinotecan hydrochloride plus docetaxel. * To assess progression-free survival of low-ERCC1 patients with advanced or metastatic cancer of the esophagus, stomach, or GEJ treated with FOLFOX compared to those treated with irinotecan hydrochloride plus docetaxel. * To assess progression-free survival of low-ERCC1 patients with advanced or metastatic cancer of the esophagus, stomach, or GEJ treated with FOLFOX compared to high-ERCC1 patients treated with FOLFOX. * To assess overall survival of and toxicities in each of the two treatment arms in this group of patients. * To assess the response probability (confirmed and unconfirmed, complete and partial responses) in the subset of patients with measurable disease in each of the two treatment arms. * To explore whether there is evidence of interaction between treatment arm and ERCC1 expression in this group of patients. (Exploratory) * To bank tissue and blood for future translational medicine studies; a) To explore the relationship of ERCC-1 and ERCC-2 single nucleotide polymorphism (SNP) genotypes with clinical outcome in these patients; and b) To explore the association between germline variations in these SNPs and ERCC-1 mRNA expression in these patients. (Exploratory) OUTLINE: This is a multicenter study. Patients are stratified according to ERCC1 expression (high \[≥ 1.7\] vs low \[\< 1.7\]), and disease site (esophageal vs gastric/gastroesophageal junction). Patients are randomized to 1 of 2 treatment arms. * Arm I (FOLFOX): Patients receive oxaliplatin IV over 2 hours and leucovorin calcium IV over 2 hours on day 1, and fluorouracil IV over 46-48 hours on days 1-2. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity. * Arm II: Patients receive irinotecan hydrochloride IV over 90 minutes and docetaxel IV over 30-60 minutes on days 1 and 8. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Blood and tumor tissue samples may be collected for ERCC1 expression analysis and future research studies. After completion of study treatment, patients are followed up every 3 months for up to 3 years.
Interventions
DRUGFOLFOX regimen
Given IV. Fluorouracil, oxaliplatin, & leucovorin calcium.
DRUGdocetaxel
30 mg/m\^2, IV over 30 minutes on Day 1,8 of each 21 day cycle.
DRUGfluorouracil
400 mg/m\^2, IV bolus on Day 1 of each 14 day cycle; 2400 mg/m\^2 IV over 46-48 hours on Days 1-2 of each 14 day cycle.
DRUGirinotecan hydrochloride
65 mg/m\^2, IV over 90 minutes on Days 1 & 8 of every 21 day cycle.
DRUGleucovorin calcium
400 mg/m\^2, IV over 2 hours on Day 1 of every 14 day cycle.
DRUGoxaliplatin
85 mg/m\^2, IV over 2 hours on Day 1 of every 14 day cycle.
Sponsors
National Cancer Institute (NCI)
SWOG Cancer Research Network
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 120 Years
Healthy volunteers
No
Inclusion criteria
DISEASE CHARACTERISTICS: * Patients must have unresectable advanced or metastatic histologically or cytologically confirmed adenocarcinoma of the esophagus, stomach, or gastroesophageal junction (GEJ) * Patients must not have received treatment for metastatic or unresectable disease * Patients must not have brain metastases * Patients must have measurable and/or non-measurable disease * Patients who have had HER-2 expression testing prior to patient consent to this study must be HER-2 negative; if HER-2 expression has not been tested prior to patient consent to this study, a second specimen must be submitted for HER-2 expression; if the specimen is HER-2 positive (or if HER-2 could not be evaluated), the patient will not be randomized * Patients must have completed any prior neoadjuvant and adjuvant therapy for resectable disease at least 180 days prior to registration PATIENT CHARACTERISTICS: * Zubrod performance status of 0-1 * Hemoglobin ≥ 9 g/dL * Absolute neutrophil count (ANC) ≥ 1,500/mcL * Platelets ≥ 100,000/mcL * Total bilirubin ≤ 1.5 mg/dL regardless of whether patients have liver involvement secondary to tumor * AST and ALT both ≤ 3 times institutional upper limit of normal (IULN) unless the liver is involved with tumor, in which case both AST and ALT must be ≤ 5 times IULN * Serum creatinine \< 1.5 mg/dL within 28 days prior to registration AND/OR calculated creatinine clearance \> 60 mL/min * Patients must not have motor or sensory neuropathy \> Grade 1 using CTCAE version 4.0 * Patients must not be pregnant or nursing; women and men of reproductive potential must have agreed to use an effective contraceptive method * No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease-free for five years PRIOR CONCURRENT THERAPY: * See Disease Characteristics * All palliative radiation therapy alone must be completed at least 14 days prior to registration * Patient must have no plans to receive concurrent chemotherapy, hormonal therapy, radiotherapy, immunotherapy, or any other type of therapy for treatment of cancer while on this protocol treatment
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | Up to 3 years after registration | OS is the length of time between protocol registration and patient death |
| Progression-free Survival (PFS) in High-ERCC1 Patients | Up to 3 years after registration | Progression-free survival is the length of time between protocol registration and disease progression or death, whichever occurs first. |
| PFS in Low-ERCC1 Participants | Up to 3 years after registration | Progression-free survival is the length of time between protocol registration and disease progression or death, whichever occurs first. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) | Up to 3 years after registration | ORR (complete response, unconfirmed complete response, partial response, unconfirmed partial response) in patients with measurable disease were assessed in each arm and compared between arms using Chi-squared test. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. |
| PFS Variation by ERCC1 | up to 3 years after registration | Progression-free survival is the length of time between protocol registration and disease progression or death, whichever occurs first. Participants were divided into subgroups according to ERCC1 quartiles to assess whether the differences in PFS between the two treatment arms varied by ERCC1 levels. |
| Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Duration of treatment and follow up until death or 3 years post registration | Adverse Events (AEs) are reported by CTCAE Version 4.0. Only adverse events that are possibly, probably or definitely related to study drug are reported. |
Countries
United States
Participant flow
Pre-assignment details
213 participants were randomized, but six were ineligible and 5 were excluded from analysis due to death or withdrawal prior to randomization. Therefore 202 were deemed eligible and analyzable for the primary analysis.
Participants by arm
| Arm | Count |
|---|---|
| Arm I FOLFOX regimen: Participants receive oxaliplatin IV over 2 hours and leucovorin calcium IV over 2 hours on day 1, and fluorouracil IV over 46-48 hours on days 1-2. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.
FOLFOX regimen: Given IV. Fluorouracil, oxaliplatin, & leucovorin calcium.
fluorouracil: 400 mg/m\^2, IV bolus on Day 1 of each 14 day cycle; 2400 mg/m\^2 IV over 46-48 hours on Days 1-2 of each 14 day cycle.
leucovorin calcium: 400 mg/m\^2, IV over 2 hours on Day 1 of every 14 day cycle.
oxaliplatin: 85 mg/m\^2, IV over 2 hours on Day 1 of every 14 day cycle. | 98 |
| Arm II Participants receive irinotecan hydrochloride IV over 90 minutes and docetaxel IV over 30-60 minutes on days 1 and 8. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
docetaxel: 30 mg/m\^2, IV over 30 minutes on Day 1,8 of each 21 day cycle.
irinotecan hydrochloride: 65 mg/m\^2, IV over 90 minutes on Days 1 & 8 of every 21 day cycle. | 104 |
| Total | 202 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 16 | 18 |
| Overall Study | Death | 6 | 8 |
| Overall Study | Not protocol specified | 7 | 2 |
| Overall Study | Progression/relapse | 53 | 59 |
| Overall Study | Reason under review | 0 | 1 |
| Overall Study | Withdrawal unrelated to AE | 16 | 16 |
Baseline characteristics
| Characteristic | Arm II | Total | Arm I |
|---|---|---|---|
| Age, Continuous | 62.4 years | 62.5 years | 62.5 years |
| ERCC1 High (>=1.7) | 15 Participants | 28 Participants | 13 Participants |
| ERCC1 Low (<1.7) | 89 Participants | 174 Participants | 85 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 19 Participants | 31 Participants | 12 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 83 Participants | 166 Participants | 83 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants | 5 Participants | 3 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 8 Participants | 13 Participants | 5 Participants |
| Race (NIH/OMB) Black or African American | 6 Participants | 13 Participants | 7 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 10 Participants | 12 Participants | 2 Participants |
| Race (NIH/OMB) White | 80 Participants | 163 Participants | 83 Participants |
| Sex: Female, Male Female | 21 Participants | 41 Participants | 20 Participants |
| Sex: Female, Male Male | 83 Participants | 161 Participants | 78 Participants |
| Site of Disease Esophageal | 36 Participants | 69 Participants | 33 Participants |
| Site of Disease Gastric/GEJ | 68 Participants | 133 Participants | 65 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 89 / 98 | 94 / 104 |
| other Total, other adverse events | 88 / 91 | 95 / 98 |
| serious Total, serious adverse events | 7 / 91 | 17 / 98 |
Outcome results
Primary
Overall Survival (OS)
OS is the length of time between protocol registration and patient death
Time frame: Up to 3 years after registration
Population: Eligible and analyzable participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm I FOLFOX | Overall Survival (OS) | 11.4 months |
| Arm II IT | Overall Survival (OS) | 8.7 months |
p-value: 0.295% CI: [0.61, 1.11]Regression, Cox
Primary
PFS in Low-ERCC1 Participants
Progression-free survival is the length of time between protocol registration and disease progression or death, whichever occurs first.
Time frame: Up to 3 years after registration
Population: Eligible and analyzable participants with ERCC1 level \< 1.7
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm I FOLFOX | PFS in Low-ERCC1 Participants | 5.9 months |
| Arm II IT | PFS in Low-ERCC1 Participants | 2.8 months |
p-value: 0.0295% CI: [0.5, 0.93]Regression, Cox
Primary
Progression-free Survival (PFS) in High-ERCC1 Patients
Progression-free survival is the length of time between protocol registration and disease progression or death, whichever occurs first.
Time frame: Up to 3 years after registration
Population: Eligible and analyzable participants with ERCC1 level \>= 1.7
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm I FOLFOX | Progression-free Survival (PFS) in High-ERCC1 Patients | 4.7 months |
| Arm II IT | Progression-free Survival (PFS) in High-ERCC1 Patients | 5.3 months |
p-value: 0.8395% CI: [0.41, 2.05]Regression, Cox
Secondary
Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs
Adverse Events (AEs) are reported by CTCAE Version 4.0. Only adverse events that are possibly, probably or definitely related to study drug are reported.
Time frame: Duration of treatment and follow up until death or 3 years post registration
Population: Participants who received at least one dose of protocol treatment and were thus eligible for AE assessment
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm I FOLFOX | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Dysphagia | 1 Participants |
| Arm I FOLFOX | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Vomiting | 5 Participants |
| Arm I FOLFOX | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Edema limbs | 0 Participants |
| Arm I FOLFOX | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Infections and infestations - Other, specify | 0 Participants |
| Arm I FOLFOX | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Esophageal hemorrhage | 0 Participants |
| Arm I FOLFOX | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Weight loss | 0 Participants |
| Arm I FOLFOX | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Esophagitis | 0 Participants |
| Arm I FOLFOX | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Allergic reaction | 1 Participants |
| Arm I FOLFOX | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Fatigue | 7 Participants |
| Arm I FOLFOX | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Infusion related reaction | 1 Participants |
| Arm I FOLFOX | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Febrile neutropenia | 1 Participants |
| Arm I FOLFOX | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Activated partial thromboplastin time prolonged | 0 Participants |
| Arm I FOLFOX | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Gastrointestinal pain | 0 Participants |
| Arm I FOLFOX | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Diarrhea | 4 Participants |
| Arm I FOLFOX | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Generalized muscle weakness | 2 Participants |
| Arm I FOLFOX | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Acute kidney injury | 0 Participants |
| Arm I FOLFOX | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Headache | 0 Participants |
| Arm I FOLFOX | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Alkaline phosphatase increased | 1 Participants |
| Arm I FOLFOX | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Heart failure | 0 Participants |
| Arm I FOLFOX | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Pneumonitis | 0 Participants |
| Arm I FOLFOX | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Hyperglycemia | 1 Participants |
| Arm I FOLFOX | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Anemia | 6 Participants |
| Arm I FOLFOX | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Hypertension | 1 Participants |
| Arm I FOLFOX | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Hyponatremia | 2 Participants |
| Arm I FOLFOX | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Hypoalbuminemia | 1 Participants |
| Arm I FOLFOX | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Anorexia | 0 Participants |
| Arm I FOLFOX | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Hypocalcemia | 0 Participants |
| Arm I FOLFOX | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Respiratory failure | 0 Participants |
| Arm I FOLFOX | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Hypokalemia | 2 Participants |
| Arm I FOLFOX | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Aspartate aminotransferase increased | 2 Participants |
| Arm I FOLFOX | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Hypomagnesemia | 0 Participants |
| Arm I FOLFOX | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Dehydration | 2 Participants |
| Arm I FOLFOX | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Leukocytosis | 0 Participants |
| Arm I FOLFOX | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Back pain | 0 Participants |
| Arm I FOLFOX | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Lung infection | 1 Participants |
| Arm I FOLFOX | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Hypotension | 1 Participants |
| Arm I FOLFOX | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Lymphocyte count decreased | 9 Participants |
| Arm I FOLFOX | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Bladder infection | 0 Participants |
| Arm I FOLFOX | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Mucositis oral | 2 Participants |
| Arm I FOLFOX | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Upper gastrointestinal hemorrhage | 0 Participants |
| Arm I FOLFOX | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Multi-organ failure | 0 Participants |
| Arm I FOLFOX | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Blood bilirubin increased | 1 Participants |
| Arm I FOLFOX | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Nausea | 7 Participants |
| Arm I FOLFOX | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Alanine aminotransferase increased | 2 Participants |
| Arm I FOLFOX | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Neutrophil count decreased | 29 Participants |
| Arm I FOLFOX | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Bone pain | 1 Participants |
| Arm I FOLFOX | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Non-cardiac chest pain | 0 Participants |
| Arm I FOLFOX | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Urinary tract infection | 0 Participants |
| Arm I FOLFOX | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Obstruction gastric | 1 Participants |
| Arm I FOLFOX | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | CD4 lymphocytes decreased | 0 Participants |
| Arm I FOLFOX | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Palmar-plantar erythrodysesthesia syndrome | 1 Participants |
| Arm I FOLFOX | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | INR increased | 0 Participants |
| Arm I FOLFOX | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Peripheral motor neuropathy | 1 Participants |
| Arm I FOLFOX | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Confusion | 1 Participants |
| Arm I FOLFOX | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Peripheral sensory neuropathy | 10 Participants |
| Arm I FOLFOX | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Vascular access complication | 0 Participants |
| Arm I FOLFOX | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Platelet count decreased | 5 Participants |
| Arm I FOLFOX | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Sepsis | 1 Participants |
| Arm I FOLFOX | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Death NOS | 1 Participants |
| Arm I FOLFOX | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Stomach pain | 0 Participants |
| Arm I FOLFOX | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Dry mouth | 1 Participants |
| Arm I FOLFOX | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Syncope | 1 Participants |
| Arm I FOLFOX | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Depression | 1 Participants |
| Arm I FOLFOX | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Thromboembolic event | 1 Participants |
| Arm I FOLFOX | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | White blood cell decreased | 9 Participants |
| Arm I FOLFOX | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Abdominal pain | 1 Participants |
| Arm II IT | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | White blood cell decreased | 14 Participants |
| Arm II IT | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Alanine aminotransferase increased | 1 Participants |
| Arm II IT | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Alkaline phosphatase increased | 1 Participants |
| Arm II IT | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Death NOS | 0 Participants |
| Arm II IT | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Dehydration | 19 Participants |
| Arm II IT | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Depression | 0 Participants |
| Arm II IT | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Diarrhea | 28 Participants |
| Arm II IT | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Hyponatremia | 5 Participants |
| Arm II IT | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Hypotension | 3 Participants |
| Arm II IT | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | INR increased | 1 Participants |
| Arm II IT | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Infections and infestations - Other, specify | 1 Participants |
| Arm II IT | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Infusion related reaction | 0 Participants |
| Arm II IT | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Platelet count decreased | 1 Participants |
| Arm II IT | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Pneumonitis | 1 Participants |
| Arm II IT | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Respiratory failure | 2 Participants |
| Arm II IT | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Thromboembolic event | 0 Participants |
| Arm II IT | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Upper gastrointestinal hemorrhage | 1 Participants |
| Arm II IT | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Urinary tract infection | 1 Participants |
| Arm II IT | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Vascular access complication | 1 Participants |
| Arm II IT | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Vomiting | 8 Participants |
| Arm II IT | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Weight loss | 2 Participants |
| Arm II IT | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Abdominal pain | 0 Participants |
| Arm II IT | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Activated partial thromboplastin time prolonged | 1 Participants |
| Arm II IT | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Acute kidney injury | 1 Participants |
| Arm II IT | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Allergic reaction | 0 Participants |
| Arm II IT | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Anemia | 14 Participants |
| Arm II IT | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Anorexia | 7 Participants |
| Arm II IT | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Aspartate aminotransferase increased | 5 Participants |
| Arm II IT | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Back pain | 1 Participants |
| Arm II IT | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Bladder infection | 1 Participants |
| Arm II IT | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Blood bilirubin increased | 1 Participants |
| Arm II IT | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Bone pain | 0 Participants |
| Arm II IT | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | CD4 lymphocytes decreased | 3 Participants |
| Arm II IT | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Confusion | 0 Participants |
| Arm II IT | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Dry mouth | 0 Participants |
| Arm II IT | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Dysphagia | 1 Participants |
| Arm II IT | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Edema limbs | 1 Participants |
| Arm II IT | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Esophageal hemorrhage | 1 Participants |
| Arm II IT | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Esophagitis | 1 Participants |
| Arm II IT | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Fatigue | 14 Participants |
| Arm II IT | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Febrile neutropenia | 6 Participants |
| Arm II IT | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Gastrointestinal pain | 1 Participants |
| Arm II IT | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Generalized muscle weakness | 2 Participants |
| Arm II IT | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Headache | 1 Participants |
| Arm II IT | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Heart failure | 1 Participants |
| Arm II IT | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Hyperglycemia | 1 Participants |
| Arm II IT | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Hypertension | 1 Participants |
| Arm II IT | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Hypoalbuminemia | 4 Participants |
| Arm II IT | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Hypocalcemia | 2 Participants |
| Arm II IT | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Hypokalemia | 8 Participants |
| Arm II IT | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Hypomagnesemia | 2 Participants |
| Arm II IT | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Leukocytosis | 1 Participants |
| Arm II IT | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Lung infection | 1 Participants |
| Arm II IT | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Lymphocyte count decreased | 7 Participants |
| Arm II IT | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Mucositis oral | 1 Participants |
| Arm II IT | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Multi-organ failure | 2 Participants |
| Arm II IT | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Nausea | 12 Participants |
| Arm II IT | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Neutrophil count decreased | 19 Participants |
| Arm II IT | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Non-cardiac chest pain | 1 Participants |
| Arm II IT | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Obstruction gastric | 0 Participants |
| Arm II IT | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Palmar-plantar erythrodysesthesia syndrome | 0 Participants |
| Arm II IT | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Peripheral motor neuropathy | 0 Participants |
| Arm II IT | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Peripheral sensory neuropathy | 1 Participants |
| Arm II IT | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Sepsis | 6 Participants |
| Arm II IT | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Stomach pain | 2 Participants |
| Arm II IT | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Syncope | 2 Participants |
Secondary
Overall Response Rate (ORR)
ORR (complete response, unconfirmed complete response, partial response, unconfirmed partial response) in patients with measurable disease were assessed in each arm and compared between arms using Chi-squared test. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
Time frame: Up to 3 years after registration
Population: Participants with measurable disease
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm I FOLFOX | Overall Response Rate (ORR) | 42 percentage of evaluable participants |
| Arm II IT | Overall Response Rate (ORR) | 30 percentage of evaluable participants |
p-value: 0.1Chi-squared
Secondary
PFS Variation by ERCC1
Progression-free survival is the length of time between protocol registration and disease progression or death, whichever occurs first. Participants were divided into subgroups according to ERCC1 quartiles to assess whether the differences in PFS between the two treatment arms varied by ERCC1 levels.
Time frame: up to 3 years after registration
Population: Eligible and analyzable participants were divided into quartiles based on ERCC1 levels.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Arm I FOLFOX | PFS Variation by ERCC1 | Q1 ERCC1 (0.20-0.80) | 5.6 months |
| Arm I FOLFOX | PFS Variation by ERCC1 | Q2 ERCC1 (0.81-1.10) | 7.4 months |
| Arm I FOLFOX | PFS Variation by ERCC1 | Q3 ERCC1 (1.11-1.42) | 5.6 months |
| Arm I FOLFOX | PFS Variation by ERCC1 | Q4 ERCC1 (1.43-5.71) | 4.6 months |
| Arm II IT | PFS Variation by ERCC1 | Q4 ERCC1 (1.43-5.71) | 2.6 months |
| Arm II IT | PFS Variation by ERCC1 | Q1 ERCC1 (0.20-0.80) | 2.8 months |
| Arm II IT | PFS Variation by ERCC1 | Q3 ERCC1 (1.11-1.42) | 2.9 months |
| Arm II IT | PFS Variation by ERCC1 | Q2 ERCC1 (0.81-1.10) | 3.0 months |
Comparison: Statistical analysis for Q1 ERCC1p-value: 0.4195% CI: [0.44, 1.4]Regression, Cox
Comparison: Statistical analysis for Q2 ERCC1p-value: 0.0695% CI: [0.32, 1.02]Regression, Cox
Comparison: Statistical analysis for Q3 ERCC1p-value: 0.6695% CI: [0.49, 1.58]Regression, Cox
Comparison: Statistical analysis for Q4 ERCC1p-value: 0.395% CI: [0.42, 1.31]Regression, Cox