Induction Chemotherapy for Locally Advanced Rectal Cancer

NCT04838496 | Not Yet Recruiting Phase 2 DMC

• 1 other identifier: NL74465.100.20
• Study Type: interventional
• Target: 128
• Locations: 1 country
• Sites: 7

Brief Summary

Despite developments in the multidisciplinary treatment of patients with locally advanced rectal cancer (LARC), such as the introduction of total mesorectal excision (TME) by Heald et al. and the shift from adjuvant to neoadjuvant (chemo)radiotherapy ((C)RT), local and distant recurrence rates remain between 5-10% and 25-40% respectively. Several studies established tumour characteristics with particularly bad prognosis; it was demonstrated that the occurrence of mesorectal fascia involvement (MRF+), grade 4 extramural venous invasion (EMVI), tumour deposits (TD) and enlarged lateral lymph nodes (LLN) lead to high local and distant recurrence rates and decreased survival when compared with LARC without these particularly negative prognostic factors. This type of LARC is described as high risk LARC (hr-LARC). Achieving a resection with clear resection margins (R0) is an important prognostic factor for local (LR) and distant recurrence (DM) as well as survival. With the aim to further reduce the risk of recurrent rectal cancer, to diminish distant metastasis and to improve overall survival for patients with LARC, induction chemotherapy (ICT) became a growing area of research. The addition of ICT has the ability to induce more local tumour downstaging, possibly leading to resectability of previously unresectable tumours, more R0 resections and less extensive surgery. In the case of a complete clinical response, surgery may even be omitted. ICT may also have the potential to eradicate micrometastases. Hence, increased local downstaging and reducing distant metastatic spread may reduce LR and DM rates and improve survival and quality of life. In recent years, the use of ICT was investigated and showed promising results, but little is known about the addition of ICT in patients with high risk LARC. Since these patients have a particularly bad prognosis, both with regard to locoregional and distant failure, a more intensified neoadjuvant treatment with FOLFOXIRI is anticipated to improve short- and long term results.

Conditions

Rectal Cancer

Keywords

Locally advanced rectal cancer; Induction chemotherapy; Neoadjuvant chemotherapy; Chemoradiotherapy

Outcome Measures

Primary Outcomes (1)

• The main study parameter is the proportion of patients with a pathological complete response (pCR) and those patients who started a wait and see strategy and have sustained clinical complete response (cCR) at 1 year.

  The pCR is evaluated by an experienced pathologist. A pCR is defined as the absence of residual tumour cells in the complete resected specimen including all resected regional lymph nodes (ypT0N0). A cCR is defined as the absence of viable tumour tissue based on MRI, evaluated by an experienced radiologist. There is a cCR in case of a sustained clinical response at 1 year after chemoradiotherapy.

  pCR is determined after surgery directly. There is a cCR in case of a sustained clinical response until at least one year after chemoradiotherapy

Secondary Outcomes (19)

• 3-year and 5-year local recurrence free survival.

  3 and 5 year

• 3-year and 5-year distant metastasis free survival.

  3 and 5 year

• 3-year and 5-year progression free survival.

  3 and 5 year

• 3-year and 5-year disease free survival.

  3 and 5 year

• 3-year and 5-year overall survival.

  3 and 5 year

Study Arms (1)

Single-arm study

EXPERIMENTAL

All patients will receive induction chemotherapy consisting of 4-6 cycles of FOLFOXIRI. Restaging will be performed after 4 cycles with a pelvic MRI and a thoraco-abdominal CT-scan. In case of stable or responsive disease, the remaining 2 cycles of FOLFOXIRI will be provided. In case of progressive, but still resectable disease, chemoradiation will be provided immediately, without the remaining 2 cycles of FOLFOXIRI. Restaging will be performed after chemoradiation. In case of resectable disease, surgery is performed.

Drug: FOLFOXIRI Protocol

Interventions

FOLFOXIRI Protocol DRUG

FOLFOXIRI consists of oxaliplatin, irinotecan, leucovorin and 5-fluorouracil and is administered every 2 weeks: Dosing: * Day 1: irinotecan 165 mg/m2 body-surface area (BSA) intravenously (IV), followed by oxaliplatin 85mg/m2 BSA IV in combination with leucovorin 400mg/m2 BSA, followed by: * Day 1-2: 3200 mg/m2 BSA of continuous 5-fluorouracil IV * Day 3-14: rest days. Both regimen are initially administered for four cycles. In case of responsive or stable disease, a 5th and 6th cycle of FOLFOXIRI will be administered. In case of unacceptable toxicity, the aforementioned dosages can be reduced or one or more chemotherapeutical agents can be omitted at discretion of the medical oncologist and will be noted in the patient's medical file. At discretion of the medical oncologist, a start dosage of 75% of the advised dosage could be considered in patients above 70 years of age.

Single-arm study

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• years or older
• WHO performance score 0-1.
• Histopathologically confirmed rectal cancer.
• Lower border of the tumour located below the sigmoidal take-off as established on MRI of the pelvis.
• Confirmed high-risk locally advanced rectal cancer, meeting one of the following imaging based criteria:
• Tumour invasion of mesorectal fascia (MRF+)
• The presence of grade 4 extramural venous invasion (mrEMVI)
• The presence of tumour deposits (TD)
• The presence of Extramesorectal lymph nodes with a short-axis size \> 7mm (LNN)
• Resectable disease as determined on magnetic resonance imaging (MRI) or deemed resectable disease after neoadjuvant treatment.
• Expected gross incomplete resection with overt tumour remaining in the patient after resection, tumour invasion in the neuroforamina, encasement of the ischiadic nerve and invasion of the cortex from S3 and upwards are considered not resectable • Written informed consent.

You may not qualify if:

• Homozygous DPD (Dihydropyrimidine dehydrogenase) deficiency.
• Any chemotherapy within the past 6 months.
• o Any contraindication for the planned systemic therapy (e.g. severe allergy, pregnancy, kidney dysfunction and thrombocytopenia), as determined by the medical oncologist.
• Radiotherapy in the pelvic area within the past 6 months.
• Any contraindication for the planned chemoradiotherapy (e.g. severe allergy to the chemotherapy agent or no possibility to receive radiotherapy), as determined by the medical oncologist and/or radiation oncologist.
• Any contraindication to undergo surgery, as determined by the surgeon and/or anaesthesiologist.
• Concurrent malignancies that interfere with the planned study treatment or the prognosis of the resected tumour.

Sponsors & Collaborators

• Catharina Ziekenhuis Eindhoven: lead

Study Sites (7)

Catharina Hospital Eindhoven

Eindhoven, North Brabant, Netherlands

Location

Netherlands Cancer Institute

Amsterdam, North Holland, Netherlands

Location

Maastricht University Medical Centre

Maastricht, Netherlands

Location

Radboud University Medical Centre

Nijmegen, Netherlands

Location

Erasmus MC Cancer institute

Rotterdam, Netherlands

Location

University Medical Centre

Utrecht, Netherlands

Location

Isala hospital

Zwolle, Netherlands

Location

Related Publications (1)

• van den Berg K, Schaap DP, Voogt ELK, Buffart TE, Verheul HMW, de Groot JWB, Verhoef C, Melenhorst J, Roodhart JML, de Wilt JHW, van Westreenen HL, Aalbers AGJ, van 't Veer M, Marijnen CAM, Vincent J, Simkens LHJ, Peters NAJB, Berbee M, Werter IM, Snaebjornsson P, Peulen HMU, van Lijnschoten IG, Roef MJ, Nieuwenhuijzen GAP, Bloemen JG, Willems JMWE, Creemers GJM, Nederend J, Rutten HJT, Burger JWA. Neoadjuvant FOLFOXIRI prior to chemoradiotherapy for high-risk ("ugly") locally advanced rectal cancer: study protocol of a single-arm, multicentre, open-label, phase II trial (MEND-IT). BMC Cancer. 2022 Sep 6;22(1):957. doi: 10.1186/s12885-022-09947-w.

  PMID: 36068495 DERIVED

MeSH Terms

Conditions

Rectal Neoplasms

Interventions

FOLFOXIRI protocol

Condition Hierarchy (Ancestors)

Colorectal Neoplasms; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Diseases; Rectal Diseases

Study Officials

• Pim J.W.A. Burger, MD. PhD.

  Catharina Ziekenhuis Eindhoven

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Kim van den Berg, MD

CONTACT

040-2396641; kim.vd.berg@catharinaziekenhuis.nl

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal investigator

Model Details: This is a multicentre, single-arm, prospective phase 2 study.

Study Record Dates

• First Submitted: April 2, 2021
• First Posted: April 9, 2021
• Study Start: June 1, 2021
• Primary Completion: June 1, 2025
• Study Completion (Estimated): June 1, 2026
• Last Updated: April 9, 2021

Record last verified: 2021-04

Locations

NL (7)