Clinical trial NCT06575127: Modified FOLFOXIRI Plus Target Therapy as a First Line Treatment for Advanced Colorectal Cancer a Prospective Phase Two Study
Official title: Modified FOLFOXIRI Plus Target Therapy as a First Line Treatment for Advanced Colorectal Cancer a Prospective Phase Two Study
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Neoplasm Malignant
Colon Cancer Stage 4
Keywords: Colon Cancer
MCRC
FOLFOXIRI
Lead sponsor: Al-Azhar University
Sponsor class: OTHER
First posted: 2024-08-28
Enrollment: 60
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Phase II single arm study
Primary purpose: TREATMENT

Brief summary: This prospective Phase II study aims to evaluate the efficacy and safety of a modified FOLFOXIRI regimen in the treatment of metastatic colorectal cancer (MCRC). FOLFOXIRI, though effective, is known for its high toxicity, necessitating close monitoring and dose adjustments. .

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.

Detailed description: This prospective Phase II clinical trial aims to assess the efficacy and safety of a modified dose regimen of FOLFOXIRI in the treatment of metastatic colorectal cancer (MCRC). FOLFOXIRI is a chemotherapy regimen known for its high toxicity, necessitating close monitoring, dose reductions, and supportive treatments. While previous studies have demonstrated the clinical efficacy of FOLFOXIRI compared to FOLIRI or FOLFOX, the regimen's toxicity remains a significant concern.

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.

Eligibility criteria: Inclusion Criteria:

Histologically confirmed unrespectable or metastatic colorectal cancer with or without primary tumor in situ.

* 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:

* Double Malignancy
* 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

Primary outcomes:
measure: Treatment-related adverse events
timeFrame: 12 months
measure: Objective Response Rate
timeFrame: 6 months
Secondary outcomes:
measure: Conversion therapy
timeFrame: 4 months
measure: Progression free survival
timeFrame: 12 months
measure: Overall survival
timeFrame: 24 months
Other outcomes:
measure: Prognostic and predictive values
timeFrame: 24 month
Locations:
city: Cairo
country: Egypt
facility: Al Hussien University Hospital
state: Cairo Governorate
Study officials:
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: Fearon ER. Molecular genetics of colorectal cancer. Annu Rev Pathol. 2011;6:479-507. doi: 10.1146/annurev-pathol-011110-130235.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.