Multicentric Randomised Trial for Resectable Gastric Cancer (CRITICS-II)

A Multicentre Randomised Phase II Trial of Neo-adjuvant Chemotherapy Followed by Surgery vs. Neo-adjuvant Chemotherapy and Subsequent Chemoradiotherapy Followed by Surgery vs. Neo-adjuvant Chemoradiotherapy Followed by Surgery in Resectable Gastric Cancer

The CRITICS-II trial aims to identify the optimal preoperative regimen in resectable gastric cancer by comparing three investigational treatment arms: chemotherapy vs. chemotherapy and subsequent chemoradiotherapy vs. chemoradiotherapy. The rationale behind this trial design is based on the following concepts:

• Preoperative treatment is associated with better patient compliance than postoperative regimens
• Preoperative treatment increases the likelihood of disease downsizing/downstaging and radical R0 resections
• Preoperative paclitaxel/carboplatin-based concurrent chemoradiotherapy and DOC chemotherapy are effective, feasible and safe regimens

Study Overview

• Status: Recruiting
• Conditions: Gastric Cancer
• Intervention / Treatment: Drug: Docetaxel; Drug: Oxaliplatin; Drug: Capecitabine; Procedure: gastrectomy; Radiation: radiotherapy of gastric cancer; Drug: Paclitaxel; Drug: Carboplatin

• Study Type: Interventional
• Enrollment (Anticipated): 207
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Marcel Verheij, MD, PhD; Phone Number: +31 20 512 9111; Email: m.verheij@nki.nl
• Study Contact Backup: Name: Romy van Amelsfoort, MD; Phone Number: +31 20 512 9111; Email: epm.jansen@nki.nl

Study Locations

• Netherlands
  • 's-Hertogenbosch, Netherlands, 5223 GZ
    • Not yet recruiting
    • Jeroen Bosch Ziekenhuis
    • Contact: Jolien Tol, MD, PhD; Phone Number: +21 73 553 2000; Email: j.tol@jbz.nl
  • Amsterdam, Netherlands, 1066CX
    • Recruiting
    • Netherlands Cancer Instituut
    • Contact: Marcel Verheij, MD, PhD; Phone Number: +31 243614023; Email: marcel.verheij@radboudumc.nl
    • Contact: Romy van Amelsfoort, MD; Phone Number: +31 20 512 9111; Email: criticstrials@nki.nl
  • Amsterdam, Netherlands, 1105AZ
    • Recruiting
    • Academisch Medisch Centrum
    • Contact: Hanneke van Laarhoven, MD, PhD; Phone Number: +31 20 566 5955; Email: h.vanlaarhoven@amsterdamumc.nl
    • Contact: Maarten C Hulshof, MD, PhD; Phone Number: +31 20 566 5955; Email: m.c.hulshof@amsterdamumc.nl
  • Arnhem, Netherlands, 6815AD
    • Recruiting
    • Rijnstate
    • Contact: Theo v Voorthuizen, MD,PhD; Phone Number: +31 26 3786735; Email: tvanvoorthuizen@rijnstate.nl
  • Den Haag, Netherlands, 2545AA
    • Not yet recruiting
    • Haga ziekenhuis
    • Contact: Patricia Quarles van Ufford-Mannesse, MD; Phone Number: +31 70 210 0000
  • Ede, Netherlands, 6716RP
    • Not yet recruiting
    • Ziekenhuis Gelderse Vallei
    • Contact: Maartje Verstappen, MD, PhD; Phone Number: +31 318 434608; Email: verstappenm@zgv.nl
  • Groningen, Netherlands, 9713 GZ
    • Not yet recruiting
    • Universitair Medisch Centrum Groningen
    • Contact: Boudewijn van Etten, MD, PhD; Phone Number: +31 50 361 2317; Email: b.van.etten@umcg.nl
  • Nieuwegein, Netherlands, 3435CM
    • Recruiting
    • Ziekenhuis St Antonius
    • Contact: Maartje Los, MD, PhD; Phone Number: +31 88 320 3000; Email: m.los@antoniusziekenhuis.nl
  • Tilburg, Netherlands, 5022GC
    • Recruiting
    • Elisabeth TweeSteden Ziekenhuis
    • Contact: Laurens Beerepoot, MD, PhD; Phone Number: +31 13 221 00 00; Email: l.beerepoot@elisabeth.nl
  • Utrecht, Netherlands, 3508 GA
    • Recruiting
    • Universitair Medisch Centrum Utrecht
    • Contact: Richard van Hillergersberg, MD, PhD; Phone Number: +31 88 75 580 74; Email: r.vanhillergersberg@umcutrecht.nl
  • Friesland
    • Leeuwarden, Friesland, Netherlands, 8901BR
      • Recruiting
      • Medisch Centrum Leeuwarden
      • Contact: Marco B Polee, MD,PhD; Phone Number: +31 58 286 6963
    • Leeuwarden, Friesland, Netherlands, 8934AD
      • Not yet recruiting
      • Radiotherapeutisch Instituut Friesland
      • Contact: Vera Oppedijk, MD; Email: v.oppedijk@skf-rif.nl
  • Gelderland
    • Apeldoorn, Gelderland, Netherlands, 7334DZ
      • Withdrawn
      • Gelre Ziekenhuizen
    • Zutphen, Gelderland, Netherlands, 7207AE
      • Withdrawn
      • Gelre Ziekenhuizen
  • Limburg
    • Sittard-Geleen, Limburg, Netherlands, 6162 BG
      • Recruiting
      • Zuyderland Medisch Centrum
      • Contact: Frank PJ Peters, MD; Phone Number: +31 88 459 7777; Email: f.peters@zuyderland.nl
    • Venlo, Limburg, Netherlands, 5912 BL
      • Recruiting
      • VieCuri Medisch Centrum
      • Contact: Yes J van de Wouw, MD, PhD; Phone Number: +31 077 320 5555; Email: yvdwouw@viecuri.nl
  • Noord Brabant
    • Deurne, Noord Brabant, Netherlands, 5751 CB
      • Not yet recruiting
      • Elkerliek
      • Contact: Jeroen Vincent, MD; Phone Number: +31 493 32 88 88; Email: j.vincent@elkerliek.nl
    • Eindhoven, Noord Brabant, Netherlands, 5602 ZA
      • Recruiting
      • Catharina Ziekenhuis
      • Contact: Grard AP Nieuwenhuijzen, MD, PhD; Phone Number: +31 40 239 66 00; Email: grard.nieuwenhuijzen@catharinaziekenhuis.nl
    • Eindhoven, Noord Brabant, Netherlands, 5631 BM
      • Not yet recruiting
      • Maxima Medisch Centrum
      • Contact: Lieke HJ Simkens, MD, PhD; Phone Number: +31 40 8885320; Email: l.simkens@mmc.nl
    • Geldrop, Noord Brabant, Netherlands, 5664 EH
      • Not yet recruiting
      • St. Anna Zorggroep
      • Contact: Arno EM Smals, MD, PhD; Phone Number: +31 40 286 4040; Email: a.smals@st-anna.nl
    • Helmond, Noord Brabant, Netherlands, 5707 HA
      • Not yet recruiting
      • Elkerliek
      • Contact: Jeroen Vincent, MD; Phone Number: +31 492 59 55 55; Email: j.vincent@elkerliek.nl
    • Tilburg, Noord Brabant, Netherlands, 5022 GC
      • Not yet recruiting
      • Instituut Verbeeten
      • Contact: Tom Rozema, MD; Phone Number: +31 13 594 77 77; Email: rozema.t@bvi.nl
    • Uden, Noord Brabant, Netherlands, 5406 PT
      • Not yet recruiting
      • Bernhoven
      • Contact: Allert H Vos, MD; Phone Number: +31 413 - 40 19 41; Email: a.vos@bernhoven.nl
    • Veldhoven, Noord Brabant, Netherlands, 5504 DB
      • Not yet recruiting
      • Maxima Medisch Centrum
      • Contact: Lieke HJ Simkens, MD, PhD; Phone Number: +31 40 8885320; Email: l.simkens@mmc.nl
  • Noord-Holland
    • Hoofddorp, Noord-Holland, Netherlands, 2000 AK
      • Not yet recruiting
      • Spaarne Gasthuis
      • Contact: Aart Beeker, MD; Phone Number: +31 023 224 5805; Email: abeeker@spaarnegasthuis.nl
  • Overijssel
    • Almelo, Overijssel, Netherlands, 7609 PP
      • Recruiting
      • Ziekenhuisgroep Twente
      • Contact: Ronald Hoekstra, MD, PhD; Phone Number: +31 88 708 4087; Email: r.hoekstra@zgt.nl
    • Deventer, Overijssel, Netherlands, 7416 SE
      • Recruiting
      • Deventer Ziekenhuis
      • Contact: Lonneke L.W. Kessels, MD; Phone Number: +31 57 053 6437; Email: researchoncologie@dz.nl
    • Enschede, Overijssel, Netherlands, 7512 KZ
      • Recruiting
      • Medisch Spectrum Twente
      • Contact: Leonie J.M Mekenkamp, MD, PhD; Phone Number: +31 53 487 2000; Email: l.mekenkamp@mst.nl
  • Zuid Holland
    • Leiden, Zuid Holland, Netherlands, 2333 ZA
      • Recruiting
      • Leids Universitair Medisch Centrum
      • Contact: Henk H Hartgrink, MD, PhD; Phone Number: +31 71 526 4005; Email: h.h.hartgrink@lumc.nl
  • Zuid-Holland
    • Delft, Zuid-Holland, Netherlands, 2625 AD
      • Recruiting
      • Reinier de Graaf Gasthuis
      • Contact: Annelie J.E. Vulink, MD, PhD; Phone Number: +31 15 260 3107; Email: a.vulink@rdgg.nl

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• TNM 8th ed stage IB-IIIC gastric cancer (histologically proven); tumour bulk has to be in the stomach but may involve gastro-oesophageal junction
• WHO < 2
• Age ≥ 18 yrs
• Resectable adenocarcinoma of the stomach or gastro-oesophageal junction
• No prior abdominal radiotherapy
• Haematology: Hb ≥5.0 mmol/l; leukocytes≥3.0x109/l, neutrophils ≥1.5x109/l, thrombocytes ≥100x109/l
• Renal function: serum creatinine ≤1.25x ULN, creatinine clearance ≥ 50 ml/min (calculated by Cockcroft and Gault formula) Liver function: total bilirubin ≤1.5x ULN, alkaline phosphatase and ASAT/ALAT ≤ 3x ULN
• At staging laparoscopy (mandatory) obtained biopsies of suspected peritoneal lesions and/or substantial free peritoneal fluid if any should be pathologically proven tumor negative
• Written informed consent
• Expected adequacy of follow-up
• Caloric intake≥1500 kcal/day, verified by a dietician before registration.
• if caloric intake is < 1500 kcal/day or if bodyweight has decreased > 10% over the last 6 months or > 5% over the last month, dietary intervention such as oral nutritional support or enteral tube feeding is mandatory

Exclusion Criteria:

• T1N0 disease (assessed by endoscopic ultrasound)
• Distant metastases
• Inoperable patients; due to technical surgery-related factors or general condition
• Previous malignancy, except adequately treated non-melanoma skin cancer or in-situ cancer of the cervix uteri; in case of a previous other malignancy with a disease-free period≥5 years, inclusion can be accepted after consultation of the principal investigator
• Solitary functioning kidney that will be within the radiation field
• Major surgery within 4 weeks prior to study treatment start, or lack of complete recovery from the effects of major surgery
• Uncontrolled (bacterial) infections
• Significant concomitant diseases preventing the safe administration of study drugs or likely to interfere with study assessments
• Uncontrolled angina pectoris, cardiac failure or clinically significant arrhythmias
• Continuous use of immunosuppressive agents equivalent to >10 mg daily prednison
• Concurrent use of the antiviral agent sorivudine or chemically related analogues, such as brivudine
• Neurotoxicity > CTC grade 1
• Pregnancy or breast feeding
• Patients (M/F) with reproductive potential not implementing adequate contraceptive measures
• Gastric or gastro-esophageal stent within radiation field

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: neo-adjuvant chemotherapy followed by surgery; 4 courses of 3 weekly DOC followed by surgery	Drug: Docetaxel; 3 weekly course of docetaxel i.v in arm 1 and 2; Other Names: Taxotere; Drug: Oxaliplatin; 3 weekly course oxaliplatin as a 2 hr i.v. in arm 1 and 2; Other Names: Eloxatin; Drug: Capecitabine; oral capecitabine in arm 1 and 2; Other Names: Xeloda; Procedure: gastrectomy; resection of gastric cancer after pre-operative chemotherapy for all arms
Active Comparator: neo-adjuvant chemo and subsequent CRT followed by surgery; 2 courses of 3 weekly DOC and subsequent CRT followed by surgery	Drug: Docetaxel; 3 weekly course of docetaxel i.v in arm 1 and 2; Other Names: Taxotere; Drug: Oxaliplatin; 3 weekly course oxaliplatin as a 2 hr i.v. in arm 1 and 2; Other Names: Eloxatin; Drug: Capecitabine; oral capecitabine in arm 1 and 2; Other Names: Xeloda; Procedure: gastrectomy; resection of gastric cancer after pre-operative chemotherapy for all arms; Radiation: radiotherapy of gastric cancer; 5 weeks of radiation, 5 times a week with a total of 45 Gy (in arm 2 and 3); Drug: Paclitaxel; 5 weeks of paclitaxel i.v once a week (in arm 2 and 3); Drug: Carboplatin; 5 weeks of carboplatin i.v once a week (in arm 2 and 3)
Active Comparator: neo-adjuvant chemoradiotherapy followed by surgery; chemoradiotherapy followed by surgery	Procedure: gastrectomy; resection of gastric cancer after pre-operative chemotherapy for all arms; Radiation: radiotherapy of gastric cancer; 5 weeks of radiation, 5 times a week with a total of 45 Gy (in arm 2 and 3); Drug: Paclitaxel; 5 weeks of paclitaxel i.v once a week (in arm 2 and 3); Drug: Carboplatin; 5 weeks of carboplatin i.v once a week (in arm 2 and 3)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Event-Free survival	Event-free survival will be measured by clinical outcome and CT-scan	1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to Event (events: local recurrence, regional recurrence, local-regional recurrence or progression, distant recurrence, or death from any cause)	Interval between randomization and event measured by clinical outcome and CT scan	1 year
Time to recurrence (events: local recurrence, regional recurrence, local-regional recurrence or progression, distant recurrence)	Interval between randomization and recurrence determined by clinical outcome and CT scan	1 year
Toxicity	Number of patients with treatment-related adverse events as assessed by CTCAE v4.0	1 year

Collaborators and Investigators

• Sponsor: The Netherlands Cancer Institute
• Investigators: Principal Investigator: Marcel Verheij, MD, PhD, The Netherlands Cancer Institute

Publications and helpful links

General Publications

• Slagter AE, Jansen EPM, van Laarhoven HWM, van Sandick JW, van Grieken NCT, Sikorska K, Cats A, Muller-Timmermans P, Hulshof MCCM, Boot H, Los M, Beerepoot LV, Peters FPJ, Hospers GAP, van Etten B, Hartgrink HH, van Berge Henegouwen MI, Nieuwenhuijzen GAP, van Hillegersberg R, van der Peet DL, Grabsch HI, Verheij M. CRITICS-II: a multicentre randomised phase II trial of neo-adjuvant chemotherapy followed by surgery versus neo-adjuvant chemotherapy and subsequent chemoradiotherapy followed by surgery versus neo-adjuvant chemoradiotherapy followed by surgery in resectable gastric cancer. BMC Cancer. 2018 Sep 10;18(1):877. doi: 10.1186/s12885-018-4770-2.

Study record dates

Study Major Dates

• Study Start (Actual): December 21, 2017
• Primary Completion (Anticipated): July 1, 2024
• Study Completion (Anticipated): July 1, 2029

Study Registration Dates

• First Submitted: September 14, 2016
• First Submitted That Met QC Criteria: October 11, 2016
• First Posted (Estimate): October 13, 2016

Study Record Updates

• Last Update Posted (Actual): October 27, 2022
• Last Update Submitted That Met QC Criteria: October 26, 2022
• Last Verified: October 1, 2022

More Information

Terms related to this study

• Keywords: radiotherapy; gastric cancer; chemoradiotherapy
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Stomach Diseases; Stomach Neoplasms; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Docetaxel; Carboplatin; Paclitaxel; Capecitabine; Oxaliplatin
• Other Study ID Numbers: M15CRI; NL 55436.031.015 (Registry Identifier: CCMO); 2015-004627-31 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

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