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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
Sponsor:
Information provided by (Responsible Party):
Yanhong Deng, Sun Yat-sen University

Brief Summary:

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

Detailed Description:
This trial is a two-arm, multicenter, open labelled, prospective, randomized phase III studies. Eligible patients with high-risk locally advanced rectal cancer patients (cT3 with any MRF involved, any cT4a/b or lateral node positive) will be randomly assigned, in a 1:1 ratio, to receive either neoadjuvant mFOLFOXIRI plus bevacizumab with selective radiotherapy or induction FOLFOX followed by concomitant chemoradiotherapy.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 500 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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

Resource links provided by the National Library of Medicine

Drug Information available for: Bevacizumab

Arm Intervention/treatment
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
Other Names:
  • Oxaliplatin
  • Irinotecan
  • 5-Fluorouracil
  • Leucovorin
  • Bevacizumab

Procedure: Restaging
Restaging by pelvic magnetic resonance imaging (MRI)

Procedure: Surgery
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)

Procedure: Surgery
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
Other Names:
  • Oxaliplatin
  • 5-Fluorouracil
  • Leucovorin




Primary Outcome Measures :
  1. Disease-free survival [ Time Frame: up to 3 years ]
    Defined as the time from randomization to relapse or death, whichever occurred first.


Secondary Outcome Measures :
  1. R0 resection rate [ Time Frame: up to 3 years ]
    R0 resection defined as complete tumor resection with all margins being negative.

  2. Pathologic complete response [ Time Frame: up to 3 years ]
  3. Overall survival (OS) [ Time Frame: up to 5 years ]
    Defined as the time from randomization to death from any cause.

  4. 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.

  5. Postoperative morbidity [ Time Frame: up to 5 years ]
  6. local recurrence rate [ Time Frame: up to 3 years ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Willing and able to provide written informed consent.
  2. Histological or cytological documentation of adenocarcinoma of the rectal (<12 cm from the anal verge).
  3. Determined preoperatively by pelvic MRI: high risk locally advanced (cT3 with any MRF involved, any cT4a/b, or lateral node positive).
  4. Male or female subjects > 18 years < 70 of age.
  5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
  6. CT or MRI scans (done within 30 days of registration) of the chest, abdomen and pelvis all without clear evidence of distant metastatic (M1) disease.
  7. Non complicated primary tumor (complete obstruction, perforation, bleeding).
  8. No previous any systemic anticancer therapy for colon cancer disease.
  9. Adequate bone marrow, hepatic and renal function as assessed by the following laboratory requirements conducted within 7 days of starting study treatment:

Exclusion Criteria:

  1. Previous or concurrent cancer that is distinct in primary site or histology from colon cancer within 5 years prior to randomization.
  2. Significant cardiovascular disease including unstable angina or myocardial infarction within 6 months before initiating study treatment.
  3. Heart failure grade III/IV (NYHA-classification).
  4. Unresolved toxicity higher than CTCAE v.4.0 Grade 1 attributed to any prior therapy/procedure.
  5. Subjects with known allergy to the study drugs or to any of its excipients.
  6. Current or recent (within 4 weeks prior to starting study treatment) treatment of another investigational drug or participation in another investigational study.
  7. Breast- feeding or pregnant women
  8. Lack of effective contraception.

Information from the National Library of Medicine

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


Contacts
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Contact: Xiaojian Wu, MD 02038389762 wuxjian@mail.sysu.edu.cn

Locations
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China, Guangdong
The Sixth Affiliated Hospital of Sun Yat-sen University
Guangzhou, Guangdong, China, 510655
Contact: Yanhong Deng, MD    008613925106525    13925106525@163.com   
Sponsors and Collaborators
Yanhong Deng

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Responsible Party: Yanhong Deng, Professor, Sun Yat-sen University
ClinicalTrials.gov Identifier: NCT04215731    
Other Study ID Numbers: GIHSYSU-17
First Posted: January 2, 2020    Key Record Dates
Last Update Posted: January 6, 2020
Last Verified: January 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Rectal Neoplasms
Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Intestinal Diseases
Rectal Diseases
Bevacizumab
Capecitabine
Oxaliplatin
Irinotecan
Fluorouracil
Antineoplastic Agents, Immunological
Antineoplastic Agents
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Growth Inhibitors
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Topoisomerase I Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Immunosuppressive Agents