Neoadjuvant mFOLFOXIRI Plus Bevacizumab With Selective Radiotherapy in Patients With High-Risk Locally Advanced Rectal Cancer (FOBEAR)
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|ClinicalTrials.gov Identifier: NCT04215731|
Recruitment Status : Not yet recruiting
First Posted : January 2, 2020
Last Update Posted : January 6, 2020
Multimodality treatment that comprises preoperative fluoropyrimidine with concurrent radiotherapy followed by total mesorectal excision (TME) surgery and adjuvant fluoropyrimidine-based chemotherapy is recommended as a standard treatment of patients with stage II/III rectal cancer. However, the main target of radiotherapy is local control but no improvement in disease-free survival (DFS) or overall survival (OS) has been shown with this treatment strategy, which leaves approximately 30% of patients in whom distant metastases will develop. Moreover, the short- and long-term adverse effects of radiotherapy such as chronic pain, faecal incontinence and urogenital/anal dysfunction are associated with poor quality of life.
Neadajuvant chemotherpay (NACT) alone has been proposed instead of preoperative chemoradiotherapy (CRT) with the aim of elimination of potential micrometastasis as early as possible while avoiding the adverse effects of radiotherapy, without jeopardizing local control.
Evidence from the UK CR07 trial suggests that, without RT, a local recurrence rate of 5% (27/543) can be achieved if a complete mesorectal excision is carried out with a negative CRM. A small single-center phase II pilot trial treated patients with stage II or III rectal cancer with induction FOLFOX/bevacizumab chemotherapy followed by CRT only in those with stable or progressive disease and resection in all patients. All 32 of the participants had an R0 resection, and the 4-year DFS was 84%. Another phase II trial, which included 60 patients with stage II/III rectal cancer, assessed the R0 resection rate after FOLFOX plus either bevacizumab or cetuximab. An R0 resection was achieved in 98.3% of the participants, and the pathologic complete response rate was 16.7%. The phase III FOWARC trial, compared neoadjuvant therapy with and without radiation and found that perioperative mFOLFOX6 alone led to a similar downstaging rate as fluorouracil-radiotherapy, and no significant difference in outcomes was found between mFOLFOX6 without radiotherapy and 5-FU- radiotherapy.
On the basis of the results of these trials, The investigators hypothesized that radiotherapy could be selectively omitted for patients who respond to NACT alone. The results of TRIBE showed that FOLFOXIRI plus bevacizumab yield a high objective response rate (ORR) (65%), early tumor shrinkage (ETS) (62.7%) and depth of response (DoR) (43.4%) in patients with metastatic colorectal cancer.
The investigators were motivated to investigate this triplet-drugs chemotherpay plus bevacizumab both by the possibility of avoiding the toxicities of radiation without compromising local control, and the possibility that earlier introduction of intensive systemic therapy might achieve rapid tumor shrinkage, and improve distant control.
The investigators conducted this phase III trial to compare neoadjuvant mFOLFOXIRI plus bevacizumab with selective radiotherapy with induction FOLFOX followed by concomitant chemoradiotherapy in patients with high-risk locally advanced rectal cancer.
|Condition or disease||Intervention/treatment||Phase|
|Rectal Cancer||Drug: Neoadjuvant chemotherapy with mFOLFOXIRI plus bevacizumab Procedure: Restaging Radiation: Concomitant Chemoradiotherapy Procedure: Surgery Radiation: Selective chemoradiotherapy Drug: Induction chemotherpay with FOLFOX||Phase 3|
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||500 participants|
|Intervention Model:||Parallel Assignment|
|Masking:||None (Open Label)|
|Official Title:||Neoadjuvant mFOLFOXIRI Plus Bevacizumab With Selective Radiotherapy Versus Induction FOLFOX Followed by Concomitant Chemoradiotherapy in Patients With High-Risk Locally Advanced Rectal Cancer: Multicenter Randomized Phase III Trial|
|Estimated Study Start Date :||February 1, 2020|
|Estimated Primary Completion Date :||February 1, 2025|
|Estimated Study Completion Date :||February 1, 2025|
Experimental: mFOLFOXIRI Plus Bevacizumab With Selective Chemoradiotherapy
Patients will receive neoadjuvant mFOLFOXIRI plus bevacizumab once every two weeks for 4 cycles and the same mFOLFOXIRI for 2 cycles. After completing all 6 cycles chemotherapy, the patient will have an MRI scan to examine the tumor. If MRI restaging is ycT4a/b, or MRF involved, the patient will receive concomitant chemoradiotherapy (preoperative radiotherapy consisted of 50 Gy in 25 fractions, and concurrent with capecitabine at a fixed dose of 825 mg/m2 twice daily on days 1 to 5 for 5 weeks). If MRI restaging is ycT0-3 and MRF negative, then the patient will proceed directly to surgery.
Drug: Neoadjuvant chemotherapy with mFOLFOXIRI plus bevacizumab
Bevacizumab (5 mg/kg on day 1) plus mFOLFOXIRI (oxaliplatin 85 mg/m2, irinotecan 150 mg/m2, and folinic acid 400 mg/m2 followed by 5-fluorouracil 2400mg/m2 as a 46-hour continuous infusion on day 1) for 4 cycles and mFOLFOXIRI (oxaliplatin 85 mg/m2, irinotecan 150 mg/m2, and folinic acid 400 mg/m2 followed by 5-fluorouracil 2400mg/m2 as a 46-hour continuous infusion on day 1) for 2 cycles
Restaging by pelvic magnetic resonance imaging (MRI)
Radical surgery (TME or more extended surgery)
Radiation: Selective chemoradiotherapy
Selective chemoradiotherapy (preoperative radiotherapy consisted of 50 Gy in 25 fractions, and concurrent with capecitabine at a fixed dose of 825 mg/m2 twice daily on days 1 to 5 for 5 weeks)
Active Comparator: Induction FOLFOX Followed by Concomitant Chemoradiotherapy
Patients will receive induction FOLFOX chemotherapy for 4 cycles and followed by concomitant chemoradiotherapy (preoperative radiotherapy consisted of 50 Gy in 25 fractions, and concurrent with capecitabine at a fixed dose of 825 mg/m2 twice daily on days 1 to 5 for 5 weeks), then the patient will proceed to surgery.
Radiation: Concomitant Chemoradiotherapy
Concomitant chemoradiotherapy (preoperative radiotherapy consisted of 50 Gy in 25 fractions, and concurrent with capecitabine at a fixed dose of 825 mg/m2 twice daily on days 1 to 5 for 5 weeks)
Radical surgery (TME or more extended surgery)
Drug: Induction chemotherpay with FOLFOX
mFOLFOX6 (oxaliplatin 85 mg/m2, and folinic acid 400 mg/m2 followed by bolus 5-fluorouracil 400 mg/m2 and 5-fluorouracil 2400mg/m2 as a 46-hour continuous infusion on day 1) for 4 cycles
- Disease-free survival [ Time Frame: up to 3 years ]Defined as the time from randomization to relapse or death, whichever occurred first.
- R0 resection rate [ Time Frame: up to 3 years ]R0 resection defined as complete tumor resection with all margins being negative.
- Pathologic complete response [ Time Frame: up to 3 years ]
- Overall survival (OS) [ Time Frame: up to 5 years ]Defined as the time from randomization to death from any cause.
- Toxicity assessed using the NCI common toxicity criteria, version 4.0. [ Time Frame: up to 5 years ]The grade of toxicity will be assessed using the NCI common toxicity criteria, version 5.0.
- Postoperative morbidity [ Time Frame: up to 5 years ]
- local recurrence rate [ Time Frame: up to 3 years ]
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04215731
|Contact: Xiaojian Wu, MDfirstname.lastname@example.org|
|The Sixth Affiliated Hospital of Sun Yat-sen University|
|Guangzhou, Guangdong, China, 510655|
|Contact: Yanhong Deng, MD 008613925106525 email@example.com|