FOLFOX Followed by FOLFIRI or Reverse Sequence Treatment in Advanced Gastric Cancer (AGC)

Randomized Phase II Study of FOLFOX Followed by FOLFIRI or Reverse Sequence Treatment in Patients With Advanced or Relapsed Gastric Cancer

FOLFOX* followed by FOLFIRI** or reverse sequence treatment regimen have been used as a standard treatment modality in metastatic colorectal cancer.Oxaliplatin and Irinotecan were used for advanced gastric cancer also. The investigators study was designed to evaluate the safety and efficacy of FOLFOX followed by FOLFIRI or reverse sequence treatment regimen as a first-line and second line therapy for patients with relapsed or metastatic gastric cancer similar with colorectal cancer.

*FOLFOX: oxaliplatin followed by leucovorin before bolus 5-FU followed by continuous infusion 5-FU

**FOLFIRI: irinotecan followed by leucovorin before bolus 5-FU followed by continuous infusion 5-FU

Study Overview

• Status: Completed
• Conditions: Gastric Cancer
• Intervention / Treatment: Drug: irinotecan, oxaliplatin; Drug: oxaliplatin, irinotecan

Detailed Description

Gastric cancer remains a major public health issue, and is the fourth most common cancer and the second leading cause of cancer deaths worldwide. In Korea, gastric cancer is the most common cancer in men, the second most common cancer in women, and the second leading cause of cancer death. Despite the development of early gastric cancer detection programs, more than two-thirds of patients diagnosed with gastric cancer will develop unresectable disease. Even patients with operable tumors evidence high rates of both local and distant recurrence. In cases of advanced gastric cancer, the median survival rate is 9 to 10 months. Additionally, the overall 5-year survival rate is less than 25% in Korea and Japan.

Several combination regimens of chemotherapy for gastric cancer have been developed, but the survival advantage appears to be marginal, and no worldwide standard regimens have yet been established. Recently, a meta-analysis has been conducted to evaluate the efficacy and tolerability of chemotherapy in patients with advanced gastric cancer. The analysis of chemotherapy versus best supportive care (Hazard Ratio/HR = 0.39, confidence interval (CI) 95% 0.28-0.52) and combination versus single agent, mainly 5-Fluorouracil (5-FU), (HR = 0.83, 95% CI 0.74-0.93) demonstrated significant OS results in favour of chemotherapy and combination chemotherapy. Several chemotherapeutic drugs, including 5-fluorouracil (5-FU), mitomycin C, nitrosoureas, and doxorubicin have evidenced some level of efficacy against advanced gastric cancer. However, the majority of combination chemotherapy regimens for advanced gastric cancer have evidenced overall response rates in a range of 30 to 50% in phase II studies. Furthermore, no new regimens including the use of taxanes or irinotecan have improved either response or survivals in phase II or III trials other than docetaxel, cisplatina and infusional 5-FU (DCF) combination.

Oxaliplatin, a third-generation platinum analogue, is a diaminocyclohexane platinum which forms interstrand DNA adducts, which differ from those formed by cisplatin or carboplatin in terms of their capability to overcome resistance mechanisms. FOLFOX-4 or FOLFOX-6 combination regimen have demonstrated response rate of 38%-50% as a first-line treatment of gastric cancer.

Irinotecan (CPT-11,7-ethyl-10-[4-(1-piperidino)-1-piperidino] is a semi-synthetic plant alkaloid obtained from Camptotheca acuminate of the Nyssaceae family. After conversion to its active metabolite, SN-38, irinotecan acts by inhibiting the eukaryotic enzyme, DNA-topoisomerase I. Single-agent irinotecan has evidenced response rates of 13-23% in cases of advanced gastric cancer. 5-Fluorouracil (5-FU) and Topoisomerase I inhibitor-based regimens have demonstrated a response rate of 20-29%, and have been suggested as a first-line treatment for advanced gastric cancer.

FOLFOX followed by FOLFIRI or reverse sequence treatment regimen have been used as a standard treatment modality in metastatic colorectal cancer.

The study was designed to evaluate the safety and efficacy of FOLFOX followed by FOLFIRI or reverse sequence treatment regimen as a first-line and second line therapy for patients with relapsed or metastatic gastric cancer similar with colorectal cancer.

• Study Type: Interventional
• Enrollment (Actual): 80
• Phase: Phase 2

Contacts and Locations

Study Locations

• Korea, Republic of
  • Busan, Korea, Republic of, 602-715
    • Sung Yong Oh

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Histologically confirmed gastric cancer
• No prior chemotherapy for palliative setting
• ECOG PS <3
• Measurable lesion on CT
• adequate kidney function (CCr ≥ 40 ml/min)
• adequate liver function (Transaminase < 3 X upper normal value, Bilirubin < 2 mg%)
• adequate BM function (ANC > 1500/ul, platelet > 75000/ul)
• informed consent

Exclusion Criteria:

• other cancer history
• pregnant or breast feeding
• inadequate general condition for chemotherapy
• allergy to oxaliplatin or irinotecan

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: IROX arm: FOLFIRI -> FOLFOX; IROX arm: FOLFIRI -> FOLFOX FOLFOX REGIMEN D1 Oxaliplatin 85mg/m2 + 5DW 500ml MIV over 120min D1,D2 Leucovorin 50mg IV Push D1,D2 5-Fluorouracil 400mg/m2 IV Push D1,D2 5-Fluorouracil 600mg/m2 + 5DW 1000ml MIV over 22hr Every 2 weeks FOLFILI REGIMEN D1 Irinotecan 150mg/m2 + 5DW 500ml MIV over 120min D1,D2 Leucovorin 50mg IV Push D1,D2 5-Fluorouracil 400mg/m2 IV Push D1,D2 5-Fluorouracil 600mg/m2 + 5DW 1000ml MIV over 22hr	Drug: irinotecan, oxaliplatin; OXIR: FOLFOX -> FOLFIRI IROX: FOLFIRI -> FOLFOX FOLFOX REGIMEN D1 Oxaliplatin 85mg/m2 + 5DW 500ml MIV over 120min D1,D2 Leucovorin 50mg IV Push D1,D2 5-Fluorouracil 400mg/m2 IV Push D1,D2 5-Fluorouracil 600mg/m2 + 5DW 1000ml MIV over 22hr Every 2 weeks FOLFILI REGIMEN D1 Irinotecan 150mg/m2 + 5DW 500ml MIV over 120min D1,D2 Leucovorin 50mg IV Push D1,D2 5-Fluorouracil 400mg/m2 IV Push D1,D2 5-Fluorouracil 600mg/m2 + 5DW 1000ml MIV over 22hr Every 2 weeks
Active Comparator: OXIR arm: FOLFIRI -> FOLFOX; OXIR arm: FOLFIRI -> FOLFOX FOLFOX REGIMEN D1 Oxaliplatin 85mg/m2 + 5DW 500ml MIV over 120min D1,D2 Leucovorin 50mg IV Push D1,D2 5-Fluorouracil 400mg/m2 IV Push D1,D2 5-Fluorouracil 600mg/m2 + 5DW 1000ml MIV over 22hr Every 2 weeks FOLFILI REGIMEN D1 Irinotecan 150mg/m2 + 5DW 500ml MIV over 120min D1,D2 Leucovorin 50mg IV Push D1,D2 5-Fluorouracil 400mg/m2 IV Push D1,D2 5-Fluorouracil 600mg/m2 + 5DW 1000ml MIV over 22hr	Drug: oxaliplatin, irinotecan; FOLFOX REGIMEN D1 Oxaliplatin 85mg/m2 + 5DW 500ml MIV over 120min D1,D2 Leucovorin 50mg IV Push D1,D2 5-Fluorouracil 400mg/m2 IV Push D1,D2 5-Fluorouracil 600mg/m2 + 5DW 1000ml MIV over 22hr Every 2 weeks FOLFILI REGIMEN D1 Irinotecan 150mg/m2 + 5DW 500ml MIV over 120min D1,D2 Leucovorin 50mg IV Push D1,D2 5-Fluorouracil 400mg/m2 IV Push D1,D2 5-Fluorouracil 600mg/m2 + 5DW 1000ml MIV over 22hr Every 2 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Response rate by RECIST	6 month after treatment

Secondary Outcome Measures

Outcome Measure	Time Frame
progression free survival	1 year after start
overall survival	2 years after start

Collaborators and Investigators

• Sponsor: Dong-A University Hospital
• Collaborators: Pusan National University Yangsan Hospital
• Investigators: Principal Investigator: HYUK-CHAN KWON, M.D.,Ph.D, Dong-A University

Study record dates

Study Major Dates

• Study Start: September 1, 2009
• Primary Completion (Actual): September 1, 2013
• Study Completion (Actual): September 1, 2013

Study Registration Dates

• First Submitted: June 4, 2010
• First Submitted That Met QC Criteria: June 7, 2010
• First Posted (Estimate): June 8, 2010

Study Record Updates

• Last Update Posted (Estimate): November 4, 2014
• Last Update Submitted That Met QC Criteria: November 2, 2014
• Last Verified: November 1, 2014

More Information

Terms related to this study

• Keywords: oxaliplatin; gastric cancer; irinotecan; sequential treatment
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Stomach Diseases; Stomach Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Topoisomerase Inhibitors; Topoisomerase I Inhibitors; Oxaliplatin; Irinotecan
• Other Study ID Numbers: DAUH-AGC-10-1