A Randomized, Open-label, Multicenter Phase II 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
Overview
- Phase
- Phase 2
- Intervention
- A-FOLFOXIRI
- Conditions
- Unresectable Metastatic Right-sided Colon Cancer Starting First-line Combination Chemotherapy
- Sponsor
- Yonsei University
- Enrollment
- 120
- Locations
- 1
- Primary Endpoint
- 6-month PFS rate (%)
- Last Updated
- 5 years ago
Overview
Brief 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.
Detailed 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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •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)
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.
Arms & Interventions
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.
Intervention: A-FOLFOXIRI
Arm II (A-FOLFOX/A-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.
Intervention: Arm II (A-FOLFOX/A-FOLFIRI)
Outcomes
Primary Outcomes
6-month PFS rate (%)
Time Frame: 6 months
To compare the 6-month progression free survival (PFS) rate (%) of bevacizumab in combination with oxaliplatin, irinotecan and infusional 5FU/LV (A-FOLFOXIRI regimen) to bevacizumab in combination with oxaliplatin or irinotecan and infusional 5FU/LV (A-FOLFOX/A-FOLFIRI regimen) in not previously treated, unresectable stage IV right-sided colon cancer
Secondary Outcomes
- progression free survival(PFS)(4 years)
- overall survival(OS)(4 years)
- adverse events(4 years)
- surrogate markers predictive of survival: ctDNA(4 years)