Induction Chemotherapy for Locally Recurrent Rectal Cancer (PelvEx II)

Multicentre, Open-label, Randomised, Controlled, Parallel Arms Clinical Trial of Induction Chemotherapy Followed by Chemoradiotherapy Versus Chemoradiotherapy Alone as Neoadjuvant Treatment for Locally Recurrent Rectal Cancer - PelvEx II

This is a multicentre, open-label, parallel arms, phase IIII study that randomises patients with locally recurrent rectal cancer in a 1:1 ratio to receive either induction chemotherapy followed by neoadjuvant chemoradiotherapy and surgery (experimental arm) or neoadjuvant chemoradiotherapy and surgery alone (control arm)

Study Overview

• Status: Recruiting
• Conditions: Recurrent Rectal Cancer
• Intervention / Treatment: Drug: Combination drug; Radiation: Chemoradiotherapy; Procedure: Surgery locally recurrent rectal cancer

• Study Type: Interventional
• Enrollment (Anticipated): 364
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Stefi Nordkamp, MD; Phone Number: 0031 40 2398858; Email: stefi.nordkamp@catharinaziekenhuis.nl
• Study Contact Backup: Name: Floor Piqeur, MD; Phone Number: 0031 40 2397152; Email: floor.piqeur@catharinaziekenhuis.nl

Study Locations

• Belgium
  • Gent, Belgium
    • Not yet recruiting
    • UZ Gent
    • Contact: Gabrielle van Ramshorst, MD, PhD
• Netherlands
  • Amsterdam, Netherlands
    • Recruiting
    • Amsterdam UMC
    • Contact: Miranda Kusters, MD, PhD
  • Amsterdam, Netherlands
    • Recruiting
    • Antoni van Leeuwenhoek
    • Contact: Arend Aalbers, MD, PhD
  • Eindhoven, Netherlands, 5623EJ
    • Recruiting
    • Catharina hospital
    • Contact: Stefi Nordkamp, MD; Phone Number: 0031 40 2398858; Email: pelvex2@catharinaziekenhuis.nl
    • Contact: Pim Burger, MD, PhD; Email: pim.burger@catharinaziekenhuis.nl
  • Groningen, Netherlands
    • Recruiting
    • University Medical Centre Groningen
    • Contact: Klaas Havenga, MD, PhD
  • Leiden, Netherlands
    • Recruiting
    • Leids University Medical Centre
    • Contact: Fabian Holman, Md, PhD
  • Leidschendam, Netherlands
    • Recruiting
    • Haaglanden Medical Centre
    • Contact: Andreas Marinelli, MD, PhD
  • Maastricht, Netherlands
    • Recruiting
    • Maastricht University Medical Centre
    • Contact: Jarno Melenhorst, MD, PhD
  • Rotterdam, Netherlands
    • Recruiting
    • Erasmus Medical Centre
    • Contact: Cornelis Verhoef, MD, PhD
• Norway
  • Oslo, Norway
    • Not yet recruiting
    • Oslo Universitetssykehus
    • Contact: Marianne Guren, MD, PhD
• Portugal
  • Lisbon, Portugal
    • Not yet recruiting
    • Instituto Português de Oncologia de Lisboa Francisco Gentil, E.P.E.
    • Contact: João Maciel, MD, PhD
• Sweden
  • Göteborg, Sweden
    • Not yet recruiting
    • Sahlgrenska Universitetssjukhuset
    • Contact: Eva Angenete, MD, PhD
    • Contact: Sofia Heyman, MD, PhD
  • Malmö, Sweden
    • Not yet recruiting
    • Skåne Universitetssjukhuset
    • Contact: Pamela Buchwald, MD, PhD
  • Stockholm, Sweden
    • Not yet recruiting
    • Karolinska Universitetssjukhuset
    • Contact: Henrik Iversen, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• 18 years or older
• Confirmed locally recurrent rectal cancer after total or partial mesorectal resection for rectal or distal sigmoidal cancer either by histopathology ór clinically proven (evidence on imaging in combination with clinical findings, with consensus in MDT)
• Resectable disease determined by magnetic resonance imaging (MRI) or deemed resectable after neoadjuvant treatment with chemoradiotherapy.
• WHO performance score 0-1
• Written informed consent

Exclusion Criteria:

• Radiological evidence of metastatic disease (e.g. liver, lung) at time of randomisation or in the six months prior to randomisation.
• Known homozygous DPD deficiency
• Any chemotherapy in the past 6 months.
• Any contraindication for the planned chemotherapy, as determined by the medical oncologist.
• Radiotherapy in the past 6 months for primary rectal cancer.
• Any contraindication for the planned chemoradiotherapy, as determined by the medical oncologist and/or radiation oncologist.
• Any contraindication for surgery, as determined by the surgeon and/or anaesthesiologist.
• Concurrent malignancies that interfere with the planned study treatment or the prognosis of resected LRRC.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Induction chemotherapy + chemoradiotherapy + surgery; Induction chemotherapy followed by neoadjuvant chemoradiotherapy and surgery	Drug: Combination drug; Induction chemotherapy consists of either three three-weekly cycles of CAPOX (oxaliplatin 130 mg/m2 BSA IV + capecitabine 1000 mg/m2 BSA, orally, twice daily) or four two-weekly cycles of FOLFOX (85 mg/m2 BSA of oxaliplatin IV + 400 mg/m2 BSA of leucovorin IV + 400 mg/m2 BSA of bolus 5-fluorouracil IV followed by 2400 mg/m2 BSA of continuous 5-fluorouracil IV). It is left to the discretion of the treating medical oncologist which of the two will be administered. In case of (previous) unacceptable toxicity (physician's discretion) to oxaliplatin, FOLFIRI may be prescribed. FOLFIRI (180 mg/m2 BSA of irinotecan IV + 400 mg/m2 BSA of leucovorin IV + 400 mg/m2 BSA of bolus 5-fluorouracil IV followed by 2400 mg/m2 BSA of continuous 5-fluorouracil IV) consists of four two-weekly cycles. If a patient has stable or responsive disease, induction chemotherapy will be continued with either one three-weekly cycle of CAPOX or two two-weekly cycles of FOLFOX/FOLFIRI.; Other Names: FOLFIRI; CAPOX; FOLFOX; Radiation: Chemoradiotherapy; Concomitant chemotherapy agent: capecitabine Radiotherapy dose: full course radiotherapy consists of 25x2.0 or 28x1.8 Gy. In case of previous radiotherapy, the radiotherapy dose will consist of 15x2.0 Gy.; Procedure: Surgery locally recurrent rectal cancer; Type of surgery depends on the location of the recurrence and involvement of adjacent structures and is left to the discretion of the operating surgeon. Intraoperative radiotherapy is optional.
ACTIVE_COMPARATOR: Neoadjuvant chemotherapy + surgery; Neoadjuvant chemoradiotherapy followed by surgery	Radiation: Chemoradiotherapy; Concomitant chemotherapy agent: capecitabine Radiotherapy dose: full course radiotherapy consists of 25x2.0 or 28x1.8 Gy. In case of previous radiotherapy, the radiotherapy dose will consist of 15x2.0 Gy.; Procedure: Surgery locally recurrent rectal cancer; Type of surgery depends on the location of the recurrence and involvement of adjacent structures and is left to the discretion of the operating surgeon. Intraoperative radiotherapy is optional.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of patients with a clear resection margin	A resection margin is considered clear (R0), if there are no tumour cells in any of the resection surfaces as determined by microscopy (resection margin > 0mm)	Scored within 1 one month of surgery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival		Assessed up to 5 years
Local recurrence free survival		Assessed up to 5 years
Progression free survival		Assessed up to 5 years
Metastasis free survival		Assessed up to 5 years
Disease free survival		Assessed up to 5 years
Pathologic response	Scored according to Mandard	Scored within 1 month of surgery
Toxicity induction chemotherapy	Adverse events grade 3 or higher according to the NCI-CTCAE v5.0	Scored until one month after the last administration of the chemotherapy
Compliance induction chemotherapy		Scored within 1 month after start chemoradiotherapy
Toxicity chemoradiotherapy	Adverse events grade 3 or higher according to the NCI-CTCAE v5.0	Scored until 3 months after the last administration of the radiotherapy
Compliance chemoradiotherapy		Evaluation at time of surgery
Number of patients undergoing surgery		Surgery is scheduled 10-14 weeks after finishing chemoradiotherapy
Surgical characteristics	including data on intra-operative radiotherapy	Evaluation directly postoperative
Major surgical morbidity	Clavien-Dindo grade 3 or higher	30 and 90-days postoperative
Radiological response	mrTRG	Restaging is performed after 3 cycles of CAPOX (1 cycle is 3 weeks) or 4 cycles of CAPOX/FOLFOX (1 cycle is 2 weeks). Second restaging is performed 4-6 weeks after finishing chemoradiotherapy
Cancer specific quality of life	QLQ-C30	at baseline, 3 months and 12 months postoperative
Cost-effectiveness	EQ-5D-5L	at baseline, 3 months and 12 months postoperative
Colorectal cancer specific quality of life	QLQ-CR29	at baseline, 3 months and 12 months postoperative

Collaborators and Investigators

• Sponsor: Catharina Ziekenhuis Eindhoven
• Investigators: Principal Investigator: Pim Burger, MD, Catharina Ziekenhuis Eindhoven

Study record dates

Study Major Dates

• Study Start (ACTUAL): November 13, 2020
• Primary Completion (ANTICIPATED): March 1, 2024
• Study Completion (ANTICIPATED): March 1, 2030

Study Registration Dates

• First Submitted: May 7, 2020
• First Submitted That Met QC Criteria: May 11, 2020
• First Posted (ACTUAL): May 15, 2020

Study Record Updates

• Last Update Posted (ACTUAL): September 6, 2022
• Last Update Submitted That Met QC Criteria: September 1, 2022
• Last Verified: September 1, 2022

More Information

Terms related to this study

• Keywords: Neoadjuvant therapy; Locally recurrent rectal cancer; Induction chemotherapy; Resection margin
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Neoplasms; Neoplasms by Site; Disease Attributes; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Recurrence; Rectal Neoplasms
• Other Study ID Numbers: NL73593

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Participant-level datasets and statistical codes will become available upon reasonable request after the results of the study have been published.
• IPD Sharing Time Frame: The full protocol and Dutch informed consent forms are publicly accessible after approval of the medical ethics committee.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No