A Phase III Study of 2nd-line XELIRI ± Bevacizumab vs. FOLFIRI ± Bevacizumab in mCRC

Phase 3

Completed

• Conditions: Colorectal Neoplasms; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasm Metastasis
• Interventions: Biological: bevacizumab; Drug: CPT-11 (Irinotecan); Drug: 5-FU Bolus; Drug: Capecitabine; Drug: 5-FU Infusion; Drug: l-LV (dl-LV)

• Registration Number: NCT01996306
• Lead Sponsor: Epidemiological and Clinical Research Information Network

Brief Summary

The primary purpose of this study is to determine the non-inferiority of overall survival XELIRI with or without Bevacizumab compared with FOLFIRI with or without Bevacizumab as Second-line therapy in Patient with Metastatic Colorectal Cancer.

Detailed Description

Primary endpoint: Overall survival (OS), Secondary endpoints: Progression-free survival (PFS), Time to treatment failure (TTF), Overall response rate (ORR),Disease Control Rate (DCR), Relative dose intensity, Safety, and Correlation between UGT1A1 genotype and Safety.

Study Timeline

• Study First Submitted: 2013-11-22
• Study First Submitted QC: 2013-11-22
• Study First Posted: 2013-11-27
• Study Start: 2013-12-02
• Primary Completion: 2017-11-20
• Study Completion: 2018-06-30
• Status Verified: 2019-01
• Last Update Submitted: 2019-01-06
• Last Update Posted: 2019-01-08

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 650

Inclusion Criteria

1. Histologically-confirmed inoperable colorectal adenocarcinoma excluding vermiform appendix cancer and anal canal cancer.
2. Age ≥20 years at the time of informed consent
3. ECOG performance status (PS) of 0-2
4. Written informed consent prior to study-specific screening procedures
5. Life expectancy of at least 90 days
6. Withdrawal from first-line chemotherapy (regardless of containing molecular-targeted drugs) for metastatic colorectal cancer due to intolerable toxicity or progressive disease, or relapse within 180 days after the last dose of adjuvant chemotherapy.
7. Adequate organ function according to following laboratory values obtained within 14 days before enrolment (excluding patients who received blood transfusions or hematopoietic growth factors within 14 days before the laboratory test) Neutrophil count: ≥1500/mm3 Platelet count: ≥10.0 x 104/mm3 Hemoglobin: ≥9.0 g/dL Total bilirubin: ≤1.5 mg/dL AST, ALT: ≤100 IU/L (≤200 IU/I if liver metastases present) Serum creatinine: ≤1.5 mg/dL

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Exclusion Criteria

1. History of other malignancy with a disease-free interval <5 years (other than curatively treated cutaneous basal cell carcinoma, curatively treated carcinoma in situ of the cervix, and gastroenterological cancer confirmed to be cured by endoscopic mucosal resection)

2. With massive pleural effusion or ascites requiring intervention

3. Radiological evidence of brain tumor or brain metastases

4. Active infection including hepatitis

5. Any of the following complication:

   i) Gastrointestinal bleeding or gastrointestinal obstruction (including paralytic ileus) ii) Symptomatic heart disease (including unstable angina, myocardial infarction, and heart failure) iii) Interstitial pneumonia or pulmonary fibrosis iv) Uncontrolled diabetes mellitus v) Uncontrolled diarrhea (that interferes with daily activities despite adequate therapy)

6. Any of the following medical history:

   Myocardial infarction: History of one episode within one year before enrollment or two or more lifetime episodes i) Serious hypersensitivity to any of the study drugs ii) History of adverse reaction to fluoropyrimidines suggesting dihydropyrimidine dehydrogenase (DPD) deficiency

7. Previous treatment with irinotecan hydrochloride

8. Current treatment with atazanavir sulfate

9. Previous treatment with tegafur, gimeracil, and oteracil potassium within seven days before enrollment

10. Pregnant or lactating females, and males and females unwilling to use contraception

11. Requires continuous treatment with systemic steroids

12. Psychiatric disability that would preclude study compliance

13. Otherwise determined by the investigator to be unsuitable for participation in the study

14. Concurrent gastrointestinal perforation or history of gastrointestinal perforation with 1 year before enrollment

15. History of pulmonary hemorrhage/hemoptysis ≥ Grade 2 (defined as bright red blood of at least 2.5mL) within 1 month prior to enrollment.

16. History of laparotomy, thoracotomy, or intestinal resection within 28 days before enrollment

17. Unhealed wound (except suture wounds from implantation of a central venous port), gastrointestinal ulcer, or traumatic fracture

18. Current or recent (within 1 year) thromboembolism or cerebrovascular disease

19. Currently receiving or requires anticoagulation therapy (> 325 mg/day of aspirin)

20. Bleeding diathesis, coagulopathy, or coagulation factor abnormality (INR ≥1.5 within 14 days before enrollment)

21. Uncontrolled hypertension

22. Urine dipstick for proteinuria >+2

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
FOLFIRI +/- Bevacizumab	5-FU Infusion	Bevacizumab 5 mg/kg IV 90-30 min Day 1 CPT-11 180 mg/m2 (150 mg/m2) IV 90 min Day 1 l-LV (dl-LV) 200 mg/m2 (400 mg/m2) IV 120 min Day 1 5-FU - bolus 400 mg/m2 IV bolus Day 1 5-FU - infusional 2400 mg/m2 IV continuous (46 hours) Day 1 - 3
FOLFIRI +/- Bevacizumab	bevacizumab	Bevacizumab 5 mg/kg IV 90-30 min Day 1 CPT-11 180 mg/m2 (150 mg/m2) IV 90 min Day 1 l-LV (dl-LV) 200 mg/m2 (400 mg/m2) IV 120 min Day 1 5-FU - bolus 400 mg/m2 IV bolus Day 1 5-FU - infusional 2400 mg/m2 IV continuous (46 hours) Day 1 - 3
FOLFIRI +/- Bevacizumab	5-FU Bolus	Bevacizumab 5 mg/kg IV 90-30 min Day 1 CPT-11 180 mg/m2 (150 mg/m2) IV 90 min Day 1 l-LV (dl-LV) 200 mg/m2 (400 mg/m2) IV 120 min Day 1 5-FU - bolus 400 mg/m2 IV bolus Day 1 5-FU - infusional 2400 mg/m2 IV continuous (46 hours) Day 1 - 3
FOLFIRI +/- Bevacizumab	l-LV (dl-LV)	Bevacizumab 5 mg/kg IV 90-30 min Day 1 CPT-11 180 mg/m2 (150 mg/m2) IV 90 min Day 1 l-LV (dl-LV) 200 mg/m2 (400 mg/m2) IV 120 min Day 1 5-FU - bolus 400 mg/m2 IV bolus Day 1 5-FU - infusional 2400 mg/m2 IV continuous (46 hours) Day 1 - 3
XELIRI +/- Bevacizumab	bevacizumab	Bevacizumab 7.5 mg/kg IV 90-30 min Day 1 CPT-11 200 mg/m2 (150 mg/m2) IV 90 min Day 1 Capecitabine 800 mg/m2 p.o. twice daily 14 Days consecutively
XELIRI +/- Bevacizumab	Capecitabine	Bevacizumab 7.5 mg/kg IV 90-30 min Day 1 CPT-11 200 mg/m2 (150 mg/m2) IV 90 min Day 1 Capecitabine 800 mg/m2 p.o. twice daily 14 Days consecutively
FOLFIRI +/- Bevacizumab	CPT-11 (Irinotecan)	Bevacizumab 5 mg/kg IV 90-30 min Day 1 CPT-11 180 mg/m2 (150 mg/m2) IV 90 min Day 1 l-LV (dl-LV) 200 mg/m2 (400 mg/m2) IV 120 min Day 1 5-FU - bolus 400 mg/m2 IV bolus Day 1 5-FU - infusional 2400 mg/m2 IV continuous (46 hours) Day 1 - 3
XELIRI +/- Bevacizumab	CPT-11 (Irinotecan)	Bevacizumab 7.5 mg/kg IV 90-30 min Day 1 CPT-11 200 mg/m2 (150 mg/m2) IV 90 min Day 1 Capecitabine 800 mg/m2 p.o. twice daily 14 Days consecutively

Primary Outcome Measures

Name	Time	Method
Overall survival	Assessed until 1.5 years after the last patient enrolment	Time from the date of enrollment to death from any cause.

Secondary Outcome Measures

Name	Time	Method
Overall Response Rate (ORR)	Assessed at 6, 12 week and thereafter every 8 weeks	Proportion of eligible patients with measurable lesions with a best overall response of CR or PR assessed by the attending physician.
Disease Control Rate (DCR)	Assessed at 6, 12 week and thereafter every 8 weeks	Proportion of best overall response of CR, PR, or SD assessed by the attending physician.
Progression-free survival (PFS)	Assessed until 1.5 years after the last patient enrolment	Time from the date of enrollment to the earlier of the date of confirmed progression or death from any cause.
Time to treatment failure (TTF)	Assessed until 1.5 years after the last patient enrolment	Time from the date of enrollment to the earlier of the date of confirmed progression, death from any cause, or discontinuation of protocol treatment.
Relative Dose Intensity	Assessed until final dosing to the last patient	will be calculated for each drug to evaluate treatment compliance in the all-treated population during the observation period.
Incidence of Adverse Events (Adverse Reactions)	Adverse events occurring within 30 days after treatment discontinuation will be followed until recovery	The incidence of worst-grade adverse events (toxicities) on study as graded by NCI-CTCAE v 4.0 will be determined by treatment arm in all treated patients for the following events.
Correlation between UGT1A1 genotype and safety	Adverse events occurring within 30 days after treatment discontinuation will be followed until recovery	The incidence of worst-grade adverse events on study as graded by NCI-CTCAE v 4.0 will be determined by treatment arm and UGT1A1 genotype in all treated patients with a known UGT1A1 genotype profile

Trial Locations

Locations (1)

NPO Epidemiological and Clinical Research Information Network (ECRIN); 🇯🇵 Kyoto, Japan