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Phase II study of primary treatment by FOLFOXIRI+bevacizumab in patients with RAS mutant-type metastatic colorectal cancer (JACCRO CC-11 )

JACCRO CC-11 study (JACCRO CC-11 )

64

A total of 64 patients were enrolled. The full analysis set consisted of 62 patients, and 63 patients were included in the safety population because 1 of the 64 patients did not meet the eligibility criteria but received the protocol treatment, and another patient did not receive any course of treatment. The median age at consent was 62.5 years (Range: 36-75), and gender was 34 (54.8%) for male and 28 (45.2%) for female. PS was 0 in 57 cases (91.9%), 1 in 5 cases (8.1%), primary tumor was colon for 34 cases (54.8%), the side was left in45 cases (72.6%), while right in 17 cases (27.4%). Distant metastasis was observed in 60 of 62 patients, 48 (77.4%) of liver metastases and 19 (30.6%) of lung metastases (bilateral). As for UGT1A1 genotypes, wild type (* 1 / * 1) for 27 cases (43.5%), heterozygous type (* 1 / * 6, * 1 / * 28) for 17 cases (27.4%), homozygous type for 5 cases (8.1%).

Feb, 2015: The first participant enrolled Mar, 2016: The 30th participant enrolled Aug, 2016: The last participant (64th) enrolled

Adverse events of Gr 3/4 were neutropenia (54%), leukopenia (28.6%), anemia (6.3%), hypokalemia (6.3%), hyponatremia (4.8%), proteinuria (3.2%), hypertension (31.7%), diarrhea (12.7%), anorexia (11.1%), nausea (7.9%), and febrile neutropenia (4.8%).

Objective response rate (95% CI) and Disease control rate (95% CI) were 75.8% and 96.8%, respectively. The result in terms of objective response rate met primary endpoint. Median PFS was 11.86 (95%CI 9.46-14.03) months, median OS was 30.16 (95%CI 25.79-34.69), median DpR was 49.2% (-28.7-100) , and ETS was 73.8%.

Modified FOLFOXIRI plus bevacizumab regimen consisted of reduced dose of irinotecan and 5FU compared to dose of the TRIBE study. Primary endpoint of response rate was almost same as one of the TRIBE trial. The incidence of febrile neutropenia was 4.8%. Considering this, modified-FOLFOXIRI plus bevacizumab regimen is feasible and very effective regimen for Japanese patients.

Sept. 30, 2020

Mar. 06, 2018

https://doi.org/10.18632/oncotarget.24702

No

None

https://jrct.mhlw.go.jp/latest-detail/jRCTs031180130

Sekikawa Takashi

Showa University Fujigaoka Hospital

1-30 Fujigaoka, Aoba-ku, Yokohama, Kanagawa, 227-8501, JAPAN

sekikawa@pop12.odn.ne.jp

Sekikawa Takashi

Showa University Fujigaoka Hospital

1-30 Fujigaoka, Aoba-ku, Yokohama, Kanagawa, 227-8501, JAPAN

+81-45-971-1151

sekikawa@pop12.odn.ne.jp

Complete

Oct. 01, 2014

Interventional

single arm study

open(masking not used)

uncontrolled control

single assignment

treatment purpose

(1) Histologically confirmed colorectal cancer. (2) KRAS mutant-type, or RAS mutant-type. (3) Measurable leision by RECIST(Ver.1.1) (4) No past history of chemotherapy in the case of unresectable primary lesion/distant metastasis/lymph node metastasis.In the case of recurrence, no treatment for the first recurrence leision after operation. (5) Age; more than 20 years old, under 76 years old. (6) ECOG Performance status 0-1.The case >=71 years is PS0. (7) Life expectancy of more than 3 months. (8) Patiens have enough organ function for study treatment within 14 days before enrollment; 1) WBC>=3,000/mm3, <12,000/mm3. 2) Neu>=1,500/mm3. 3) PLT>=10.0x104/mm3. 4) Hb>=9.0g/dL. 5) Total Bilirubin<=1.5xULN. 6) AST<=2.5xULN. 7) ALT<=2.5xULN. 8) Creatinine<=1.5xULN. 9) Proteinuria<=1+. 10) PT-INR<=1.5. (9) Written informed consent.

(1) Synchronous multiple malignancy or metachronous multiple malignancy within 5 years disease free interval. (2) Brain metastases. (3) Infectious disease. (4) Interstitial lung disease or pulmonary fibrosis. (5) Comorbidity or history of serious heart failure. (6) History of thromboembolic events. (7) Cerebrovascular disease. (8) History of hemoptysis/hematemesis. (9) Uncontrolled hypertension.(systolic BP>180mmHg, or diastolic BP>100mmHg) (10) Sensory alteration or paresthesia interfering with function. (11) Large quantity of pleural, abdominal or cardiac effusion. (12) Severe comorbidity (renal failure, liver failure, hypertension, etc) (13) Prior radiotherapy for primary and metastases leision. (14) Men/women who are unwilling to avoid pregnancy. Women who are pregnant or breastfeeding. Women with a positive pregnancy test. (15) History of severe allergy. (16) HBs-Ag(+), or HCV-Ab(+). (17) Administration of blood products/ G-CSF, and blood transfusion within 14 days. (18) Surgical procedure or such as skin-open biopy, trauma surgery, or other more intensive surgeries within 28 days. (19) Systemaic administration of antiplatelet drug or NSAIDs. (20) Diathesis of bleeding (history of hemoptysis, including cavitation and/or necrosis in lung metastasis confirmed by imaging), coagulopathy. (21) Active peptic ulcer. (22) History of gastrointestinal perforation within 1 year. (23) Unhealed traumatic bone fracture. (24) Uncontrolled diarrhea. (25) History of organ recipient . (26) Prior bevacizumab/Irinotecan/Oxaliplatin treatment.(Adjuvant therapy by Oxaliplatin is excluded) (27) Administration of atazanavir sulfate. (28) Jaundice. (29) Ileus or bowel obstruction. (30) Any other cases who are regarded as inadequate for study enrollment by investigators.

Both

Colorectal cancer

FOLFOXIRI+/-bevacizumab (To 12 courses), 5-FU+Levofolinate+/-bevacizumab (From 13 courses) given on day 1 every 2 weeks, until disease progression or unmanageable toxicity.
bevacizumab 5mg/kg/bi-weekly
Irinotecan 150mg/m2/bi-weekly
Oxaliplatin 85mg/m2/bi-weekly
Levofolinate 200mg/m2/bi-weekly
5-FU 2400mg/m2/bi-weekly

Colorectal cancer

Response Rate

Progression Free Survival
Overall Survival
Safety
Early Tumor Shrinkage
Deepness of Response
Correlation between biomarkers and therapeutic efects/prognosis

+81-3-3784-8129

Jan. 10, 2019

none