Modified FOLFOXIRI Plus Target Therapy as a First Line Treatment for Advanced Colorectal Cancer a Prospective Phase Two Study
NCT ID: NCT06575127
Last Updated: 2024-08-28
Study Results
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Basic Information
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RECRUITING
PHASE2
60 participants
INTERVENTIONAL
2024-08-17
2026-09-01
Brief Summary
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The primary endpoint is to assess the impact on the objective response rate and evaluate both acute and delayed toxicity. The secondary endpoints include studying the treatment's effectiveness as conversion therapy, along with disease-free survival (DFS) and overall survival (OS). The tertiary endpoint focuses on evaluating predictive and prognostic factors of significance.
This study seeks to balance the efficacy of FOLFOXIRI with a modified dose to minimize toxicity while maintaining therapeutic benefits, providing a potentially safer and effective option for patients with MCRC.
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Detailed Description
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Intervention:
Modified FOLFOXIRI Regimen:
Oxaliplatin: 85 mg/m² IV over 2 hours (Day 1) Irinotecan: 150 mg/m² IV over 90 minutes (Day 1) 5-FU: 2400 mg/m² IV over 48 hours infusion (Day 1)
Targeted Therapy:
KRAS/NRAS/BRAF Wild-Type (Left-Sided Tumor): Anti-EGFR treatment with either Panitumumab (6 mg/kg IV over 60 minutes, Day 1) or Cetuximab (500 mg/m² IV, Day 1).
KRAS/NRAS Mutant or Right-Sided Tumor: Bevacizumab (5 mg/kg IV over 30-90 minutes, Day 1).
Treatment Schedule: Administered biweekly for a maximum of 12 cycles (6 months).
G-CSF Prophylaxis: Administered as primary prophylaxis for patients older than 55 and as secondary prophylaxis for those who develop grade ≥3 neutropenia.
Dose Modifications and Treatment-Related Toxicity:
Toxicity will be evaluated after each cycle using the Common Toxicity Criteria for Adverse Events (CTCAE) version 5.0 (National Cancer Institute, 2017).
Dose Reduction Guidelines: A 25% dose reduction will be implemented for specific grade III/IV acute toxicities including neutropenia, febrile neutropenia, thrombocytopenia, diarrhea, mucositis/stomatitis, hand-foot syndrome, peripheral neuropathy, elevated liver enzymes, severe fatigue, hypertension, proteinuria, and dermatologic toxicity.
Treatment Discontinuation: Patients who experience further grade III/IV acute toxicity after dose reduction will be excluded from the study.
Treatment Duration:
Eligible for Surgery: Patients with a favorable response will receive a maximum of 8 cycles before surgical evaluation.
Ineligible for Surgery: Treatment will continue until the completion of 12 cycles, intolerable toxicity, or a maximum duration of 6 months.
Assessments:
Disease Assessment: Performed every 4 cycles (8 weeks) during the induction phase, followed by every 3 months. Quality of life will be evaluated using the EORTC QLQ C30 and CR 29 questionnaires.
Response Assessment: Based on RECIST v1.1 criteria, categorized as Complete Response (CR), Partial Response (PR), Stable Disease (SD), or Progressive Disease (PD).
Statistical Analysis:
Survival Analysis: Kaplan-Meier estimates with one-sided log-rank tests will be used to analyze progression-free survival (PFS). Overall survival (OS) will be calculated from the date of histological diagnosis to the date of last follow-up or death.
Data Analysis: Data will be analyzed using IBM SPSS version 26. Quantitative data will be presented as means, standard deviations, and ranges, or as medians with interquartile ranges, depending on distribution. Qualitative data will be presented as frequencies and percentages. Chi-square tests will compare groups with qualitative data. The confidence interval is set at 95%, with a significance threshold of p \< 0.05.
Conditions
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Study Design
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NA
SINGLE_GROUP
TREATMENT
NONE
Study Groups
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modified FOLFOXIRI plus target therapy
* Pre-Treatment Medications:
1. Atropine SC: Administered before irinotecan infusion to prevent side effects.
2. High-Risk Anti-Emetics Regimen: Used to prevent acute and delayed vomiting.
* Chemotherapy Regimen: All eligible patients will receive the modified FOLFOXIRI regimen as follows:
* Oxaliplatin: 85 mg/m² IV over 2 hours (Day 1)
* Irinotecan: 150 mg/m² IV over 90 minutes (Day 1)
* 5-FU: 2400 mg/m² IV over 48 hours infusion (Days 1)
* Targeted Therapy: Administered according to NRAS/KRAS status and the location of the primary tumor:
* KRAS/NRAS/BRAF Wild-Type (Left-Sided Tumor): Anti-EGFR treatment with either Panitumumab (6 mg/kg over 60 minutes, Day 1) or Cetuximab (500 mg/m², Day 1).
* KRAS/NRAS Mutant or Right-Sided Tumor: Bevacizumab at a dose of 5 mg/kg IV over 30 to 90 minutes (Day 1).
* Treatment Schedule: The treatment will be administered biweekly for a maximum of 12 cycles (6 months).
FOLFOXIRI Protocol
as mentioned in Arm description
Interventions
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FOLFOXIRI Protocol
as mentioned in Arm description
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* Patients were required to have measurable disease according to RECIST v1.1 (Response Evaluation Criteria in Solid Tumors) (Eisenhauer EA,2009)
* ECOG PS 0-1 better to exclude PS II as this protocol is known to be toxic
* Adequate baseline hematology and clinical chemistry labs
* Adequate cardiac function
Exclusion Criteria
* DPYD mutant patients
* Peripheral neuropathy grade 3 or higher patient due to other comorbidities
* Inflammatory bowel syndrome or any other chronic GIT disease
* Prior exposure to chemotherapy treatment for colorectal cancer in the metastatic setting
* Patients who have contraindications for one or more of the study protocol drugs
18 Years
65 Years
ALL
No
Sponsors
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Al-Azhar University
OTHER
Responsible Party
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Mohamed Ahmed Abdelaziz
Specialist of Oncology
Locations
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Al Hussien University Hospital
Cairo, Cairo Governorate, Egypt
Countries
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Facility Contacts
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References
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Kalyan A, Kircher S, Shah H, Mulcahy M, Benson A. Updates on immunotherapy for colorectal cancer. J Gastrointest Oncol. 2018 Feb;9(1):160-169. doi: 10.21037/jgo.2018.01.17.
Amado RG, Wolf M, Peeters M, Van Cutsem E, Siena S, Freeman DJ, Juan T, Sikorski R, Suggs S, Radinsky R, Patterson SD, Chang DD. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol. 2008 Apr 1;26(10):1626-34. doi: 10.1200/JCO.2007.14.7116. Epub 2008 Mar 3.
Arnold M, Sierra MS, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global patterns and trends in colorectal cancer incidence and mortality. Gut. 2017 Apr;66(4):683-691. doi: 10.1136/gutjnl-2015-310912. Epub 2016 Jan 27.
Douillard JY, Cunningham D, Roth AD, Navarro M, James RD, Karasek P, Jandik P, Iveson T, Carmichael J, Alakl M, Gruia G, Awad L, Rougier P. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet. 2000 Mar 25;355(9209):1041-7. doi: 10.1016/s0140-6736(00)02034-1.
Eaden JA, Abrams KR, Mayberry JF. The risk of colorectal cancer in ulcerative colitis: a meta-analysis. Gut. 2001 Apr;48(4):526-35. doi: 10.1136/gut.48.4.526.
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47. doi: 10.1016/j.ejca.2008.10.026.
Falcone A, Ricci S, Brunetti I, Pfanner E, Allegrini G, Barbara C, Crino L, Benedetti G, Evangelista W, Fanchini L, Cortesi E, Picone V, Vitello S, Chiara S, Granetto C, Porcile G, Fioretto L, Orlandini C, Andreuccetti M, Masi G; Gruppo Oncologico Nord Ovest. Phase III trial of infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) compared with infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) as first-line treatment for metastatic colorectal cancer: the Gruppo Oncologico Nord Ovest. J Clin Oncol. 2007 May 1;25(13):1670-6. doi: 10.1200/JCO.2006.09.0928.
Fearon ER. Molecular genetics of colorectal cancer. Annu Rev Pathol. 2011;6:479-507. doi: 10.1146/annurev-pathol-011110-130235.
Folprecht G, Grothey A, Alberts S, Raab HR, Kohne CH. Neoadjuvant treatment of unresectable colorectal liver metastases: correlation between tumour response and resection rates. Ann Oncol. 2005 Aug;16(8):1311-9. doi: 10.1093/annonc/mdi246. Epub 2005 May 3.
Goldberg RM, Tabah-Fisch I, Bleiberg H, de Gramont A, Tournigand C, Andre T, Rothenberg ML, Green E, Sargent DJ. Pooled analysis of safety and efficacy of oxaliplatin plus fluorouracil/leucovorin administered bimonthly in elderly patients with colorectal cancer. J Clin Oncol. 2006 Sep 1;24(25):4085-91. doi: 10.1200/JCO.2006.06.9039.
Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, Berlin J, Baron A, Griffing S, Holmgren E, Ferrara N, Fyfe G, Rogers B, Ross R, Kabbinavar F. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004 Jun 3;350(23):2335-42. doi: 10.1056/NEJMoa032691.
Loupakis F, Cremolini C, Salvatore L, Masi G, Sensi E, Schirripa M, Michelucci A, Pfanner E, Brunetti I, Lupi C, Antoniotti C, Bergamo F, Lonardi S, Zagonel V, Simi P, Fontanini G, Falcone A. FOLFOXIRI plus bevacizumab as first-line treatment in BRAF mutant metastatic colorectal cancer. Eur J Cancer. 2014 Jan;50(1):57-63. doi: 10.1016/j.ejca.2013.08.024. Epub 2013 Oct 15.
Engstrom PF, Arnoletti JP, Benson AB 3rd, Chen YJ, Choti MA, Cooper HS, Covey A, Dilawari RA, Early DS, Enzinger PC, Fakih MG, Fleshman J Jr, Fuchs C, Grem JL, Kiel K, Knol JA, Leong LA, Lin E, Mulcahy MF, Rao S, Ryan DP, Saltz L, Shibata D, Skibber JM, Sofocleous C, Thomas J, Venook AP, Willett C; National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: colon cancer. J Natl Compr Canc Netw. 2009 Sep;7(8):778-831. doi: 10.6004/jnccn.2009.0056. No abstract available.
Van Cutsem E, Kohne CH, Hitre E, Zaluski J, Chang Chien CR, Makhson A, D'Haens G, Pinter T, Lim R, Bodoky G, Roh JK, Folprecht G, Ruff P, Stroh C, Tejpar S, Schlichting M, Nippgen J, Rougier P. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 2009 Apr 2;360(14):1408-17. doi: 10.1056/NEJMoa0805019.
Study Documents
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Document Type: Informed Consent Form
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Other Identifiers
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FOXIRI
Identifier Type: -
Identifier Source: org_study_id
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