Irinotecan Plus Raltitrexed as Second-line Treatment in Advanced Colorectal Cancer Patients

Irinotecan Plus Raltitrexed as Second-line Treatment in Advanced Colorectal Cancer Patients: An Open-label, Single-arm, Multicenter Phase II Study

Irinotecan and raltitrexed are active against advanced colorectal cancer (ACC), act through different mechanisms, and have only partially overlapping toxicity profiles. The purpose of this study is to evaluate efficacy and safety of irinotecan plus raltitrexed as second-line treatment in advanced colorectal cancer patients.

Study Overview

• Status: Unknown
• Conditions: ColoRectal Cancer
• Intervention / Treatment: Drug: Irinotecan; Drug: Raltitrexed

Detailed Description

The standard initial treatment for patients with advanced colorectal cancer (ACC) not amenable for surgical resection is palliative 5-fluorouracil (5-FU)-based chemotherapy. However, response rates are low and prognosis remains poor, with median survival times about one year. Until recently, second-line therapy options were limited.

Irinotecan is a semisynthetic camptothecin derivate that acts as a DNA-topoisomerase-1 inhibitor,its most frequent toxic effects are diarrhea, neutropenia and cholinergic syndrome. Raltitrexed is a quinazoline folate-based specific thymidylate synthase inhibitor, its clinical activity in this setting is similar to that of modulated 5-FU regimens but with a better toxicity profile (mainly asthenia and increased serum transaminase levels). There seems to be no cross-resistance between 5-FU and raltitrexed. Irinotecan and raltitrexed have different toxicity profiles and modes of action. Both drugs are active as single agents and may be given as a short 3-weekly infusion, thus obviating complex schedules or the need for implantable venous access devices. Preclinical studies have demonstrated a pronounced sequence-dependent synergy between SN-38 (the active metabolite of irinotecan) and raltitrexed. It seems then interesting to explore the feasibility and therapeutic potential of this association.

With this background, the investigators have performed this study to evaluate efficacy and safety of irinotecan plus raltitrexed as second-line treatment in advanced colorectal cancer patients.

• Study Type: Interventional
• Enrollment (Anticipated): 100
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Zan Teng, PhD; Phone Number: 86-024-83282542; Email: tengzan@163.com

Study Locations

• China
  • Liaoning
    • Shenyang, Liaoning, China, 110001
      • Recruiting
      • The First Hospital of China Medical University
      • Contact: Yunpeng Liu, MD., PhD; Phone Number: 86-24-83282312; Email: cmuliuyunpeng@hotmail.com
      • Principal Investigator: Yunpeng Liu, MD., PhD.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• life expectancy of at least 3 months;
• histological and/or cytological confirmation of ACC;
• disease progression while on first-line palliative oxaliplatin & fluoropyrimidine chemotherapy or relapse within 6 months after adjuvant oxaliplatin & fluoropyrimidine chemotherapy;
• wash-out time of 4 weeks after the last chemotherapy infusion or radiotherapy，and observed lesions not in the radiotherapy target；
• at least one measurable objective tumor lesion by spiral CT examination, the maximum diameter ≥ 1cm（according to RECIST 1.1）；
• ECOG performance status 0-1；
• satisfactory main organ function，laboratory test must meet the following criteria: hemoglobin (HGB) ≥90g/L, neutrophil count（ANC） ≥1.5×109/L, platelet count（PLT） ≥90×109/L, Serum creatinine（CR）≤1.5 upper normal limitation (UNL)，creatinine clearance rate (CCr) ≥60ml/min, total bilirubin (TBil) ≤1.5 upper normal limitation (UNL), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 UNL (For patients with liver metastasis, the AST/ALT must be ≤5.0 UNL);
• For women with child bearing potential, a negative serum or urine pregnancy test result should be obtained before enrollment
• written informed consent.

Exclusion Criteria:

• prior exposure to irinotecan or raltitrexed;
• chronic enteropathy on unresolved bowel obstruction;
• Pregnant or lactated women;
• previous malignant disease other than carcinoma in situ of the cervix or basal cell carcinoma of the skin;
• Concurrent administration of any other investigational drug, or have been enrolled in other clinical trial with investigational drug treatment within the 30 days of start of study treatment；
• cerebral metastases or leptomeningeal carcinomatosis;
• severe or uncompensated concomitant medical conditions.
• Unsuitable for the study or other chemotherapy determined by investigator.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Irinotecan & Raltitrexed; advanced colorectal cancer patients treated with irinotecan plus raltitrexed as second-line treatment. Irinotecan:180mg/㎡+NS250ml, ivgtt, 90min, d1 Raltitrexed: 3mg/㎡+NS100ml，ivgtt，15min, d1 Every 3 weeks	Drug: Irinotecan; Irinotecan: 180mg/㎡+NS250ml, ivgtt, 90min, d1 Every 3 weeks; Other Names: Campto; Drug: Raltitrexed; Raltitrexed: 3mg/㎡+NS100ml，ivgtt，15min, d1 Every 3 weeks; Other Names: Sai wei jian

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Progression Free Survival [PFS]	5-6 months

Secondary Outcome Measures

Outcome Measure	Time Frame
Overall Survival [OS]	12-15 months
Objective Response Rate [ORR]	12-15 months
Disease Control Rate [DCR]	12-15 months

Other Outcome Measures

Outcome Measure	Time Frame
Incidence and Degree of Treatment-Emergent Adverse Events [Safety and Tolerability]	12-15 months
Performance Status [WHO-ECOG]	12-15 months
Quality of Life [WHO-QOL]	12-15 months

Collaborators and Investigators

• Sponsor: China Medical University, China
• Collaborators: General Hospital of Shenyang Military Region; Shengjing Hospital; Liaoning Tumor Hospital & Institute; The First Affiliated Hospital of Dalian Medical University; The Second Affiliated Hospital of Dalian Medical University

Publications and helpful links

General Publications

• Chiara S, Nobile MT, Tomasello L, Acquati M, Taveggia P, Murolo C, Percivale P, Rosso R. Phase II trial of irinotecan and raltitrexed in chemotherapy-naive advanced colorectal cancer. Anticancer Res. 2005 Mar-Apr;25(2B):1391-6.
• Feliu J, Salud A, Escudero P, Lopez-Gomez L, Pericay C, Castanon C, de Tejada MR, Rodriguez-Garcia JM, Martinez MP, Martin MS, Sanchez JJ, Baron MG; Oncopaz Cooperative Group and Associated Hospitals. Irinotecan plus raltitrexed as first-line treatment in advanced colorectal cancer: a phase II study. Br J Cancer. 2004 Apr 19;90(8):1502-7. doi: 10.1038/sj.bjc.6601713.
• Aparicio J, de las Penas R, Vicent JM, Garcera S, Llorca C, Maestu I, Yuste AL, Farres J. Multicenter phase I study of irinotecan plus raltitrexed in patients with 5-fluorouracil-refractory advanced colorectal cancer. Oncology. 2002;63(1):42-7. doi: 10.1159/000065719.
• Carnaghi C, Rimassa L, Garassino I, Zucali PA, Masci G, Fallini M, Morenghi E, Santoro A. Irinotecan and raltitrexed: an active combination in advanced colorectal cancer. Ann Oncol. 2002 Sep;13(9):1424-9. doi: 10.1093/annonc/mdf229.

Study record dates

Study Major Dates

• Study Start: December 1, 2016
• Primary Completion (Anticipated): December 1, 2019
• Study Completion (Anticipated): December 1, 2020

Study Registration Dates

• First Submitted: January 23, 2017
• First Submitted That Met QC Criteria: February 13, 2017
• First Posted (Actual): February 14, 2017

Study Record Updates

• Last Update Posted (Actual): February 14, 2017
• Last Update Submitted That Met QC Criteria: February 13, 2017
• Last Verified: February 1, 2017

More Information

Terms related to this study

• Keywords: Irinotecan; Second-line Treatment; Raltitrexed; Advanced Colorectal Cancer(ACC)
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Topoisomerase Inhibitors; Topoisomerase I Inhibitors; Folic Acid Antagonists; Irinotecan; Raltitrexed
• Other Study ID Numbers: CLOG1602