Phase 2 trial of FOLFIRI plus ziv-aflibercept in patients with colorectal cancer previously treated with oxaliplatin, fluoropyrimidins, bevacizumab, and trifluridine/tipiracil

JRCT ID: jRCTs041190100

Registered date:19/12/2019

Basic Information

• Recruitment status: Complete
• Health condition(s) or Problem(s) studied: colorectal cancer
• Date of first enrollment: 23/01/2020
• Target sample size: 25
• Study type: Interventional

Intervention(s)

FOLFIRI plus ziv-aflibercept
(Day 1) Ziv-aflibercept, 4 mg/kg, intravenously (IV) over 60 min
(Day 1) Irinotecan, 150 mg/m2, IV over 90 min
(Day 1) Leucovorin (l-LV), 200 mg/m2, IV over 120 min
(Day 1) 5-FU, 400 mg/m2, bolus
(Day 1-3) 5-FU, 2400 mg/m2, continuous infusion over 46 h
Repeat the above every two weeks
The dose of irinotecan can be reduced to 120 mg/m2 if patients are homozygous for UGT1A1*28 or UGT1A1*6, or heterozygous for both UGT1A1*28 and UGT1A1*6.

Outcome(s)

• Primary Outcome: progression free survival
• Secondary Outcome: Overall survival, Response rate, Disease control rate,safety

Key inclusion & exclusion criteria

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

Include criteria

Consent, age
1) Patients provided written informed consent after receiving adequate explanation about study participation.
2) Age 20 or over 20 years on the consent date.
Histological classification, markers
3) Adenocarcinomas of the colon or the rectum (excluding the appendix and the proctodeum), diagnosed histologically or by using cytodiagnosis.
4) Patients with known RAS mutation status: wild-type, mutant, or indeterminate (analysis was performed, but failed to confirm mutation status in a certain exon, but confirmed no mutation in other exons).
[Stage, metastasis, and disease conditions]
5) Unresectable cancer (clinically determined).
6) Measurable lesions according to RECIST version 1.1.
7) Absence of clinical symptoms indicative of central nervous system metastasis. Absence of imaging findings indicative of central nervous system metastasis (brain, spinal cord, and meninges).
8) Absence of ascites, pleural effusion, and pericardial effusion that requires continuous drainage on the date of enrollment.
9) Absence of intestinal obstruction, gastrointestinal perforation, and placement of a colorectal stent.
Prior therapy
10) Patients with refractory disease or who are intolerant to oxaliplatin, fluoropyrimidines, bevacizumab, and trifluridine/tipiracil. See a)-c) below for definitions.

a) Patients refractory to preoperative and postoperative adjuvant chemotherapy are those who had clinical exacerbation or recurrence during therapy, or within 24 weeks after the final administration of anticancer agents. (Enrollment of those who had the final administration on the same day of the week 24 weeks earlier are eligible)
b) Patients refractory to chemotherapy except for preoperative and postoperative adjuvant chemotherapy are those who had clinical exacerbation during therapy, or within 8 weeks after the final administration of anticancer agents. (Enrollment of those who received the final administration on the same day of the week 8 weeks earlier are eligible).
c) Patients intolerant to the above agents are those who had related-safety issues such as allergic reaction, persistent neurotoxicity, and delayed recovery from toxicity, which resulted in withdrawal of treatment with no prospects for restarting therapy. Or those who have evidence of inadequacy of administration of these agents.
11) Patients who had no prior treatment with irinotecan, ramucirumab, or ziv-aflibercept.
Prior interventions
12) Patients who had received any of the following interventions at a defined time prior to enrollment. (Enrollment of those who had undergone a surgical procedure or interventions on the same day of the week as that of the enrollment date are eligible).
a) Surgery involving a wide area, except placement of a vascular access device*4 weeks prior to enrollment
b) Colostomy and gastrointestinal bypass2 weeks prior to enrollment
c) Treatment with any anticancer agent2 weeks prior to enrollment
d) Irradiation of the primary lesion2 weeks prior to enrollment
e) Blood transfusion, and administration of a hematopoietic agent2 weeks prior to enrollment
*: Administration of investigational agents on the same date as placement of a vascular access device are accepted.
Systemic condition and tests
13) ECOG PS of 0-1.
14) Organ functions are preserved.

Exclude criteria

Multiple primaries
1) Simultaneously active malignancies* (except malignancies with disease-free survival (DFS) over 3 years, or carcinomas in situ and intramucosal carcinomas appeared to be cured by adequate therapies).
* Multiple primaries include simultaneous multiple primaries, and non-simultaneous multiple primaries with DFS over 3 years, and do not include carcinoma in situ and intramucosal carcinomas appeared to be cured by local treatment. In patients who had postoperative chemotherapy, the DFS was the period from the date of the surgery.
Complications/infections
2) Active infections (fever 38 degrees or over 38 degrees Celsius caused by an infection)
3) Positive for either anti-HIV antibodies, or HBs antigens (HIV antibody testing is not mandatory).
Complications/organ disorders
4) Uncontrollable diabetes, hypertension, and diarrhea
5) Cardiac infarction, severe or unstable angina, and symptomatic congestive heart failure (New York Heart Association Class III or Class IV) that occur within 6 months prior to enrollment.
6) Severe pulmonary disease including pneumonitis, pulmonary fibrosis, and severe pulmonary emphysema.
7) Severe liver disease including Child Pugh B or C liver cirrhosis.
8) Treatment for thrombosis, embolism, and cerebrovascular disease that occurred within 6 months prior to the enrollment date.
9) Active gastrointestinal hemorrhage.
10) Mental disorder or psychiatric manifestation that hinder individuals from participating the study.
Concomitant agents
11) Continuous oral steroids.
12) Antiplatelet agents (e.g. clopidogrel, ticlopidine, dipyridamole). Low-dose aspirin (less than 325 mg/day) and nonsteroidal anti-inflammatory drugs (NSAIDs) are allowed, but proton-pump inhibitors are recommended. Anticoagulants are allowed (recommended agents: dabigatran, rivaroxaban, apixaban, and edoxaban) when coagulation is stable for 12 weeks or longer.
Others
13) Pregnancy, potential pregnancy or breastfeeding women, and men and women with no intended use of contraceptives.
14) Allergy to 5-FU and or l-LV.
15) Other reasons judged by investigators.

Related Information

• Primary Sponsor: Matsumoto Toshihiko
• Secondary Sponsor: Muro Kei,West Japan Oncology Group
• Secondary ID(s): Nil known