A randomized phase II Study of CAPOXIRI plus Bevacizumab versus FOLFOXIRI plus Bevacizumab for mCRC

JRCT ID: jRCTs041190072

Registered date:09/10/2019

Basic Information

• Recruitment status: Complete
• Health condition(s) or Problem(s) studied: Metastatic colorectal cancer
• Date of first enrollment: 08/11/2019
• Target sample size: 112
• Study type: Interventional

Intervention(s)

Step1: Confirmation of dosage of each drug (Oxaliplatin and Irinotecan)
i)Induction treatment
The following drugs will be administered in 3week/cycle for 6cycles (maximum 8cycle, if investigator required). With regard to determination of oxaliplatin (OX) and Irinotecan (IRI) dosage, initial 3patients (pts) will be enrolled of level0. After finishing initial enrollment, Steering committee (SC) will evaluate safety of 3pts at the time of starting of cycle2 and will decide whether the proceeding same level (add 3 pts) or other level (level+1 or level-0.5). Final decision of Recommended Dose (RD) of OX and IRI will be required 6pts of safety evaluation in same level and will be endorsed by SC and Independent Data monitoring committee (IDMC).

1) Each drug dosage of CAPOXIRI+Bevacizumab
Bevacizumab (BEV: 7.5 mg/kg, i.v., 90, 60, 30 min, Day 1)
Irinotecan (IRI: 130 mg/m2, i.v., 90 min, Day 1)
Oxaliplatin (OX: 200 mg/m2, i.v., 120 min, Day 1)
Capecitabine (CAP: 800 mg/m2 p.o., twice daily, 14 days consecutively)

2) OX and IRI dose level
Level +1: IRI: 200 mg/m2, OX:130mg/m2
Level 0: IRI: 200 mg/m2, OX:100mg/m2
Level -0.5: IRI: 180 mg/m2, OX:100mg/m2
Level -1: IRI: 150 mg/m2, OX:100mg/m2

ii)Maintenance treatment
After finishing the induction treatment, investigator will select 1) 5-FU/LV+BEV (2weeks cycle) or 2) CAP+BEV treatment (3weeks/cycle).

1)5-FU/LV+BEV treatment
The following drugs will be administered in 2week/cycle until meeting discontinuation criteria.

- Each drug dosage of 5-FU/LV+BEV -
Bevacizumab (BEV: 5.0 mg/kg, i.v., 90, 60, 30 min, Day 1)
Leucovorin (LV: 200 mg/m2, i.v., 120 min, Day 1)
5-FU (3200 mg/m2, c.i.v., 48 hours, Day 1-3)

2)CAP+BEV treatment
The following drugs will be administered in 2week/cycle until meeting discontinuation criteria.

- Each drug dosage of CAP+BEV -
Bevacizumab (BEV: 7.5 mg/kg, i.v., 90, 60, 30 min, Day 1)
Capecitabine (CAP: 800 mg/m2, p.o., twice daily 14 days consecutively)

Step2: Evaluation efficacy and safety of CAPOXIRI+BEV treatment in randomized setting.
i)Induction treatment
Patient who meet the criteria will be randomized Arm A (FOLFOXIRI+BEV treatment) or Arm B (CAPOXIRI+BEV treatment).

1)Arm A: FOLFOXIRI+BEV treatment
The following drugs will be administered in 3week/cycle for 8 cycles (maximum 12cycle, if investigator required).

- Each drug dosage of FOLFOXIRI+BEV -
Bevacizumab (BEV: 5.0 mg/kg, i.v., 90, 60, 30 min, Day 1)
Irinotecan (IRI: 165 mg/m2, i.v., 60 min, Day 1)
Oxaliplatin (OX: 85 mg/m2, i.v., 120 min, Day 1)
Leucovorin (LV: 200 mg/m2, i.v., 120 min, Day 1)
5-FU (3200 mg/m2, c.i.v., 48 hours, Day 1-3)

2)Arm B: CAPOXIRI+BEV treatment
The following drugs will be administered in 3week/cycle for 6 cycles (maximum 8cycle, if investigator required).

- Each drug dosage of CAPOXIRI+Bevacizumab -
Bevacizumab (BEV: 7.5 mg/kg, i.v., 90, 60, 30 min, Day 1)
Irinotecan (IRI: See below 2) dose level, i.v., 90 min, Day 1)
Oxaliplatin (OX: See below 2)dose level, i.v., 120 min, Day 1)
Capecitabine (CAP: 800 mg/m2 p.o., twice daily, 14 days consecutively)

ii)Maintenance treatment
After finishing the induction treatment, investigator will select 1)5-FU/LV+BEV (2weeks cycle) or 2) CAP+BEV treatment (3weeks/cycle).

1)5-FU/LV+BEV treatment
The following drugs will be administered in 2week/cycle until meeting discontinuation criteria.

- Each drug dosage of 5-FU/LV+BEV -
Bevacizumab (BEV: 5.0 mg/kg, i.v., 90, 60, 30 min, Day 1)
Leucovorin (LV: 200 mg/m2, i.v., 120 min, Day 1)
5-FU (3200 mg/m2, c.i.v., 48 hours, Day 1-3)

2)CAP+BEV treatment
The following drugs will be administered in 2week/cycle until meeting discontinuation criteria.

- Each drug dosage of CAP+BEV -
Bevacizumab (BEV: 7.5 mg/kg, i.v., 90, 60, 30 min, Day 1)
Capecitabine (CAP: 800 mg/m2, p.o., twice daily 14 days consecutively)

Outcome(s)

• Primary Outcome: Progression-free survival (PFS)

Secondary Outcome

Overall response rate (ORR)
Overall survival (OS)
Safety (Adverse event:Type, Grade)
Patient reported outcome assessment (FACT/GOG-Ntx4)

Key inclusion & exclusion criteria

• Age minimum: >= 20age old
• Age maximum: Not applicable
• Gender: Both

Include criteria

1.Obtaining informed consent prior to study-specific screening procedures
2.Histologically-confirmed colorectal adenocarcinoma excluding vermiform appendix cancer and anal canal cancer
3.Clinically-confirmed metastatic colorectal cancer
4.Age>=20 years at the time of informed consent
5.ECOG performance status (PS) of 0,1
6.Patients who has one or more lesion(s) of diameter 1 cm or larger (RECEST v1.1) be able to assess continuously on the basis of the protocol by contrast enhanced CT.
7.Untreated metastatic colorectal cancer. Patients who underwent to adjuvant chemotherapy can be enrolled after 24 weeks from last administration.
8.RAS / BRAF testing was performed and confirmed RAS / BRAF wild type or mutation type
9.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)
i. Neutrophil count: >= 1200/mm3
ii. Platelet count: >= 10.0 x 104/mm3
iii. Hemoglobin: >= 9.0 g/dL
iv. Total bilirubin: =< 1.5 x ULM
v. AST, ALT, ALP: =< 2.5 x ULM (<5 x ULM if liver metastases present)
vi. Serum creatinine: =<1.5 x ULM or Ccr >30 ml/min
vii. Protein Urea: =< 2+ (In case of >= 3+, UPC (Urine protein / creatinine ratio: < 2.0)
10.Confirmed UGT1A1 wild type or UGT1A1 single hetero type

Exclude criteria

1.Previously treated with irradiation to bone marrow constituting 20% or more of irradiation field.
2.Untreated brain metastases or spinal cord compression or primary brain tumors.
3.History of CNS disease.(except for asymptomatic lacunar stroke)
4.Requiring chronic systemic corticosteroid treatment.
5.Patients who have uncontrolled anticoagulant therapy.
6.History / Presence of thrombosis within 1 year requiring medication.
7.Previously participated in any clinical trials and treatment with any investigational drug within 28 days.
8.Patient with i) Uncontrolled hypertension, ii) Uncontrolled diabetes, iii) Uncontrolled diarrhea, iv) >grade 1 peripheral neuropathy, v) Active peptic ulcer, vi) Non-healing wound (except for central venous port), vii) Clinically significant cardiovascular disease (for example cerebrovascular accidents, myocardial infarction, unstable angina, congestive heart failure, serious cardiac arrhythmia requiring medication), viii) Uncontrolled venous thromboembolism, xi) Evidence or requiring systemic treatment for Infectious disease, x) Clinically important diseases.
9.Major surgical procedure within 28 days prior to study treatment start, open biopsy, or significant traumatic injury, or anticipation of the need for major surgical procedure. (except for central venous port)
10.Lack of physical integrity of the upper gastrointestinal tract.
11.Pregnant women, lactating woman, positive by pregnancy test, wishing to become pregnant, and Sexually active males.
12.Hepatitis B or hepatitis C or Evidence of HIV infection.
13.History / Presence of paralytic ileus, obstruction or gastrointestinal perforation.
14.Other active co-existing malignancies.
15.History / Presence of paralytic ileus, obstruction or gastrointestinal perforation.
16.With massive pleural effusion or ascites
17.History of allergy to the drug of fluorouracil, oxaliplatin, irinotecan, bevacizumab and Chinese hamster ovary cell proteins of any components of the study medications.
18.History of fluoropyrimidine severe side effects caused by DPD defect.
19.Patients who underwent colonic stent.
20.Patient who is judged by the investigator to be inappropriate for study participation for any reason.

Related Information

• Primary Sponsor: Tsuji Akihito
• Source(s) of Monetary Support: Chugai Pharmaceutical CO.,LTD.