A Study of Bevacizumab Infusional Fluorouracil Leucovorin Oxaliplatin and Irinotecan (A-FOLFOXIRI) Compared With Bevacizumab Infusional Fluorouracil Leucovorin and Irinotecan/Oxaliplatin (A-FOLFIRI/FOLFOX) as First-line Treatment for Metastatic Right-sided Colon Cancer

  • STATUS
    Recruiting
  • End date
    Jun 25, 2024
  • participants needed
    120
  • sponsor
    Yonsei University
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Updated on 25 January 2021
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Summary

RATIONALE: Recently, the importance of prognosis according to the location of the primary tumor in colorectal cancer has been raised. In the CALGB / SWOG 80405 study published in 2016, the addition of bevacizumab or cetuximab to the first line FOLFIRI / FOLFOX in KRAS (codon 12, 13) wild type metastatic colorectal cancer (mCRC) patients did not show a significant difference between overall survival (OS) and progression free survival (PFS) in both groups. Alan P. Venook et al. published a follow-up subgroup analysis on the effect of primary tumor location at 2016 ASCO. In the treatment group with cetuximab, the difference in treatment effect was significant according to the primary tumor location. The right colon cancer showed a poor prognosis for cetuximab treatment. (PFS: 7.8 vs 12.4 months, HR 1.56, p <0.0001 / OS: 16.7 vs 36.0months, HR 1.87, P <0.0001).

Therefore, the investigators propose a phase II trial for the efficacy evaluation of bevacizumab-FOLFOXIRI and bevacizumab-FOLFIRI or FOLFOX treatment in patients with poor prognosis of unresectable right-sided colorectal cancer.

Description

OUTLINE: This is a multicenter study. Patients are stratified according to ECOG performance status (0 vs 1-2), prior adjuvant chemotherapy (yes vs no), and participating center. Patients are randomized to 1 of 2 treatment arms.

Arm I (A-FOLFOXIRI): Patients receive irinotecan hydrochloride IV over 1 hour, oxaliplatin IV over 2 hours, leucovorin calcium IV over 2 hours, and bevacizumab IV on day 1. Patients also receive fluorouracil IV continuously over 48 hours beginning on day 1.

Arm II (A-FOLFOX/FOLFIRI): Patients receive irinotecan hydrochloride IV over 1 hour (or oxaliplatin IV over 2 hours), leucovorin calcium IV over 2 hours, fluorouracil IV bolus, and bevacizumab IV on day 1. Patients also receive fluorouracil IV continuously over 48 hours beginning on day 1.

In both arms, treatment repeats every 2 weeks for up to 12 courses. After the 12 cycle treatment finished, investigator decides whether to keep the study drug. Treatment continues in the absence of disease progression, withdrawal consent, or unacceptable toxicity. If treatment with oxaliplatin or irinotecan is difficult due to side effects, treatment with bevacizumab, fluorouracil, and leucovorin calcium continues in the absence of disease progression, withdrawal consent, or unacceptable toxicity.

Patients undergo serum extraction and blood sample collection periodically for genomic, ctDNA and translational study. Patients also undergo collection of tumoral sections from paraffin embedded primary and/or metastatic lesions periodically for immunohistochemical analyses.

After completion of study treatment, patients are followed every 6 months for survival and other treatments.

Details
Condition Unresectable Metastatic Right-sided Colon Cancer Starting First-line Combination Chemotherapy, Unresectable Metastatic Right-sided Colon Cancer, Stage IV
Treatment A-FOLFOXIRI, Arm II (A-FOLFOX/A-FOLFIRI)
Clinical Study IdentifierNCT03641976
SponsorYonsei University
Last Modified on25 January 2021

Eligibility

 Yes No Not Sure

Inclusion Criteria

Is your age greater than or equal to 19 yrs?
Gender: Male or Female
Do you have any of these conditions: Unresectable Metastatic Right-sided Colon Cancer, Stage IV or Unresectable Metastatic Right-sided Colon Cancer Starting First-line Combination Chemoth...?
Histologically proven diagnosis of unresectable recurrent or advanced stage IV right-sided colon cancer (The definition of the right colon cancer is confirmed by the colonoscopy result, the surgical report, or the image reading paper including CT, MRI, and PET CT. (cecum~splenic flexure))
Not previously treated with chemotherapy for metastatic disease
At least one measurable lesion according to RECIST criteria
Age over 19 years old
ECOG 0~2
Life expectancy of at least 3 months
Adequate major organ functions
ANC 1.5 x 109/L
PLT 100 x 109/L
Hb 9.0 g/dL (can be corrected by blood transfusion)
Total bilirubin upper normal limit(UNL) 1.5
ALT , AST UNL 3 (in case of liver metastasis, ALT , AST UNL 5), alkaline phosphatase UNL 3 (in case of liver metastasis, ALP UNL 5
adequate renal function : corrected creatinine clearance by Cockcroft and Gault formula 30mL/min
Urine dipstick of proteinuria <2+. Patients discovered to have 2+ proteinuria on dipstick urinalysis at baseline, should undergo a 24-hour urine collection and must demonstrate 1 g of protein/24 hr
Written informed consent

Exclusion Criteria

Previously treated with chemotherapy for metastatic disease
Within 6 months after adjuvant chemotherapy
Major surgical procedure within 28 days prior to study treatment start, or patients who have not fully recovered from major surgery
Radiotherapy to target lesion within 4 weeks before the study (A 2-week washout is permitted for palliative radiation.)
Has known uncontrolled active CNS metastases and/or carcinomatous meningitis
Peripheral neuropathy CTCAE v4.03 grade 2
Has a known additional malignancy that is progressing or has required active treatment within the past 3 years
Note: Participants with basal cell carcinoma of skin, squamous cell carcinoma
of the skin, low grade thyroid cancer or carcinoma in situ (eg, cervical
cancer in situ) that have undergone potentially curative therapy are not
excluded
Has an active autoimmune disease that has required systemic treatment in the past 2 years. Replacement therapy, such as thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, is not considered a form of systemic systemic treatment and is allowed
Uncontrolled hypertension or clinically active cardiovascular disease: for example, cerebrovascular accident or transient ischemic attack, unstable angina, myocardial infarction within 24 weeks prior to randomization. Have symptomatic congestive heart failure (CHF; New York Heart Association II-IV) or symptomatic or poorly controlled cardiac arrhythmia
Have significant bleeding disorders, or evidence of bleeding diathesis or coagulopathy
Have had a significant bleeding episode from the gastrointestinal (GI) tract or lung
Have a history of GI perforation and/or fistula, or intra-abdominal abscess within 24 weeks prior to randomization
Have a history of HNPCC syndrome or polyposis
Have experienced any arterial thromboembolic event or ongoing treatment with anticoagulants for therapeutic purpose within 24 weeks prior to randomization
Has a known history of human immunodeficiency virus (HIV) infection
Are pregnant or breast feeding. Females of childbearing potential must have a negative serum or urine pregnancy test within 7 days prior to first dose of study treatment. For women of childbearing potential and men, agreement to remain abstinent or use contraceptive methods that result in a failure rate of <1% per year during the treatment period and for at least 30 days after the last dose of study drugs. Postmenopausal women is defined that : 1) must have been amenorrheic for at least 12 months, > 50 years old or 2) Age 50 years old and amenorrheic for 12 or more months in the absence of chemotherapy, tamoxifen, toremifene, or ovarian suppression and follicle-stimulating hormone (FSH) and estradiol in the postmenopausal range (>40 mIU/mL), 3) prior bilateral oophorectomy
Patients who are hypersensitive reaction to experimental drugs
Patients who are hypersensitive to CHO cell products or other recombinant or humanized antibodies
In case of contraindication of experimental drugs
Have any condition (eg, psychological, geographical, or medical) that does not permit compliance with the study and follow-up procedures or suggest that the patient is, in the investigator's opinion, not an appropriate candidate for the study
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