MODUL—a multicenter randomized clinical trial of biomarker-driven maintenance therapy following first-line standard induction treatment of metastatic colorectal cancer: an adaptable signal-seeking approach

  • Hans-Joachim Schmoll
  • Dirk Arnold
  • Aimery de Gramont
  • Michel Ducreux
  • Axel Grothey
  • Peter J. O’Dwyer
  • Eric Van Cutsem
  • Frank Hermann
  • Ivan Bosanac
  • Belguendouz Bendahmane
  • Christoph Mancao
  • Josep Tabernero
Original Article – Clinical Oncology

Abstract

Purpose

The old approach of one therapeutic for all patients with mCRC is evolving with a need to target specific molecular aberrations or cell-signalling pathways. Molecular screening approaches and new biomarkers are required to fully characterize tumours, identify patients most likely to benefit, and predict treatment response.

Methods

MODUL is a signal-seeking trial with a design that is highly adaptable, permitting modification of different treatment cohorts and inclusion of further additional cohorts based on novel evidence on new compounds/combinations that emerge during the study.

Results

MODUL is ongoing and its adaptable nature permits timely and efficient recruitment of patients into the most appropriate cohort. Recruitment will take place over approximately 5 years in Europe, Asia, Africa, and South America. The design of MODUL with ongoing parallel/sequential treatment cohorts means that the overall size and duration of the trial can be modified/prolonged based on accumulation of new data.

Conclusions

The early success of the current trial suggests that the design may provide definitive leads in a patient-friendly and relatively economical trial structure. Along with other biomarker-driven trials that are currently underway, it is hoped that MODUL will contribute to the continuing evolution of clinical trial design and permit a more ‘tailored’ approach to the treatment of patients with mCRC.

Keywords

MODUL Biomarker Switch maintenance therapy Metastatic colorectal cancer Signal seeking FOLFOX + bevacizumab 

Notes

Acknowledgements

The MODUL trial is sponsored by F. Hoffmann-La Roche Ltd (ClinicalTrials.gov identifier: NCT02291289). The authors would like to thank Daniel Waterkamp (Genentech) and Barbara Leutgeb (Roche) for their role in facilitating and assisting with the development of the MODUL trial design. Third-party medical editing/writing assistance for this manuscript was provided by Miller Medical Communications Ltd (funded by F. Hoffmann-La Roche Ltd). Posters providing details on the MODUL trial have been presented previously at the European Society for Medical Oncology Congress, 26–30 September 2014, Madrid, Spain, and at the 17th World Congress on Gastrointestinal Cancer, 1–4 July 2015, Barcelona, Spain. Principal investigators: Argentina: Diego Lucas Kaen (Centro Oncologico Riojano Integral (CORI), La Rioja); Rubén Dario Kowalyszyn (Clínica Viedma, Viedma, Rio Negro); Soledad Iseas (Hospital de Gastroenterologia Dr Bonorino Udaondo, Buenos Aires). Belgium: Eric Van Cutsem (University Hospitals Gasthuisberg, Leuven and KULeuven, Leuven); Jochen Decaestecker (AZ Delta (Campus Wilgenstraat), Roeselare); Ghislain Houbiers (Clinique Saint-Joseph, Liège); Jean-Luc Van Laethem (Clin Univ de Bxl Hôpital Erasme, Brussels); Alain Hendlisz (Institut Jules Bordet X, Brussels). Bosnia and Herzegovina: Anes Pasic (University Clinical Center Sarajevo, Sarajevo); Sasa Jungic (University Clinical Center of the Republic of Srpska, Banja Luka). Brazil: Nicolas Lazaretti (CITO - Centro Integrado de Terapia Onco-Hematológica-Hospital da Cidade de Passo Fundo, Passo Fundo); Fernando Vieira (Clinicas Oncologicas Integradas-COI, Rio de Janeiro); Ederson Mattos (Hospital Amaral Carvalho, Jau); Rodrigo Pereira (Hospital das Clinicas-UFRGS, Porto Alegre); Gustavo Girotto (Hospital de Base de Sao Jose do Rio Preto, Sao Jose do Rio Preto); Kathia Cristina Abdalla (Hospital de Cancer de Barretos, Barretos); Carlos Gorini (Hospital Nossa Senhora da Conceicao, Porto Alegre); Luciana Viola (Hospital Sao Lucas-PUCRS, Porto Alegre); Helio Pinczowski (Instituto de Ensino e Pesquisa Sao Lucas-IEP, Sao Paulo); Rachel Riechelmann (Instituto do Cancer do Estado de Sao Paulo-ICESP, Sao Paulo). Cyprus: Demetris Papamichael (Bank of Cyprus Oncology Center, Nicosia). Denmark: Benny Vittrup Jensen (Herlev Hospital, Herlev); Fahimeh Zarifkar Anderson (Hillerød Sygehus, Hillerød); Per Pfeiffer (Odense Universitetshospital, Odense); Halla Skuladottir (Regionshospitalet Herning, Herning); Lone Nørgaard Petersen (Rigshospitalet, København); Jim Stenfatt Larsen (Sygehus Syd Roskilde, Roskilde). Egypt: Mohamed Elbassiouny (Ain Shams University Hospital, Cairo); Amr Abdel Aziz (Cancer Epidemiology Research Cluster, Alexandria); Mustafa El Serafy (National Cancer Institute, Cairo). France: Michel Ducreux (Institut Gustave Roussy, Villejuif); Meher Ben Abdelghani (Centre Paul Strauss, Strasbourg); Stefano Kim (Ch De Montbeliard, Montbeliard); Caroline Petorin (Chu Estaing, Clermont Ferrand); David Tougeron (Chu La Miletrie, Poitiers); Laurent Mineur (Clinique Sainte Catherine, Avignon); Jean-Philippe Metges (Hopital Augustin Morvan, Brest); Stephane Obled (Hopital Caremeau, Nimes); Mohamed Hebbar (Hopital Claude Huriez, Lille); Denis Smith (Hopital Haut Leveque, Pessac); Marine Jary (Hopital Jean Minjoz, Besancon); Rosine Guimbaud (Hopital Rangueil, Toulouse); Thierry Andre (Hopital Saint Antoine, Paris); Aimery De Gramont (Institut Hospitalier Franco-Britannique, Levallois-Perret). Germany: Harald Müller-Huesmann (Brüderkrankenhaus St. Josef, Paderborn); Patrick Stübs (DRK Kliniken Berlin Köpenick Darmzentrum, Berlin); Rüdiger Liersch (Gemeinschaftspraxis für Hämatologie und Onkologie, Münster); Stefan Bauer (Gemeinschaftspraxis, Onkologisches Zentrum Lebach, Caritas Krankenhaus Lebach, Lebach); Bernhard Heinrich (Hämatologisch-onkologische Praxis Dr. med. - Brudler, - Heinrich, - Bangerter, Augsburg); Dirk Strumberg (Klinik der Ruhr-Uni Bochum, Marien-Hospital Herne, Herne); Ullrich Graeven (Kliniken Maria Hilf GmbH, Mönchengladbach); Andrea Distelrath (Medizinisches Versorgungszentrum Osthessen GmbH, Fulda); Uwe Martens (SLK-Kliniken Heilbronn GmbH, Heilbronn); Stefan Kubicka (Klinikum am Steinenberg / Ermstalklinik, Reutlingen); Kersten Borchert (Klinikum Magdeburg GmbH Klinik, Magdeburg); Rolf Mahlberg (Klinikum Mutterhaus der Borromaeerinnen GmbH, Trier); Birgitta Killing (Klinikum Wetzlar-Braunfels, Wetzlar); Nicolas Moosmann (Krankenhaus Barmherziger Brüder, Regensburg); Salah-Eddin Al Batran (Krankenhaus Nordwest, Frankfurt); Arndt Vogel (Medizinische Hochschule, Hannover); Johannes Meiler (MVZ für Hämatologie, Stade); Thomas Illmer (Onkologische Gemeinschaftspraxis, Dresden); Hendrik Kröning (Onkologische Gemeinschaftspraxis, Magedburg); Ingo Schwaner (Onkologische Schwerpunktpraxis Kurfürstendamm, Berlin); Roland Schnell (PIOH, Frechen); Georg Jacobs (Praxis für Haematologie & Onkologie, Saarbruecken); Thomas Höhler (Prosper-Hospital, Recklinghausen); Meinolf Karthaus (Städt. Klinikum München GmbH Klinikum Neuperlach Klinik, München); Thomas Decker (Studienzentrum Onkologie Ravensburg, Onkologie Ravensburg, Ravensburg); Alexander Stein (Universitätsklinikum Hamburg-Eppendorf, Hamburg); Benjamin Garlipp (Universitätsklinikum Magdeburg, Magdeburg); Volker Kunzmann (Universitätsklinikum Würzburg, Würzburg). Greece: Epaminondas Samantas (Agioi Anargyroi, Athens); Ioannis Boukovinas (Bioclinic Thessaloniki, Thessaloniki); Georgios Fountzilas (Thermi Clinic, Thermi Thessalonikis); George Pentheroudakis (Univ Hospital of Ioannina, Ioannina); Haralabos Kalofonos (University Hospital of Patras, Patras); Dimitris Mavroudis (Univ General Hosp Heraklion, Heraklion). Italy: Carlo Barone (Policlinico Universitario “Agostino Gemelli”, Roma); Giordano Beretta (Humanitas Gavazzeni, Bergamo); Maria Di Bartolomeo (IRCCS Istituto Nazionale Dei Tumori (INT), Milano); Francesco Di Costanzo (Azienda Ospedaliero-Universitaria Careggi, Firenze); Giovanni Frassineti (IRST Istituto Scientifico Romagnolo Per Lo Studio E Cura Dei Tumori, Sede Meldola, Meldola); Sara Lonardi (IRCCS Istituto Oncologico Veneto (IOV), Padova); Evaristo Maiello (IRCCS Ospedale Casa Sollievo Della Sofferenza, San Giovanni Rotondo); Guglielmo Nasti (IRCCS Istituto Nazionale Tumori Fondazione Pascale, Napoli); Francesca Negri (A.O. Universitaria Di Parma, Parma); Patrizia Racca (A.O. Città della Salute e della Scienza - Presidio Molinette, Torino); Salvatore Siena (Asst Grande Ospedale Metropolitano Niguarda, Milano); Giampaolo Tortora (A.O.U.I. Verona-Ospedale Policlinico G.B. Rossi Borgo Roma, Verona); Giulia Zampino (IRCCS Istituto Europeo Di Oncologia (IEO), Milano); Massimo Zeuli (Istituto Regina Elena, Roma). Korea, Republic of: Tae Won Kim (Asan Medical Center, Seoul); Joon Oh Park (Samsung Medical Center, Seoul); Yoo Joo Lim (Seoul National University Hospital, Seoul); Joong-Bae Ahn (Severance Hospital, Yonsei University Health System, Seoul). Mexico: Adriana Dominguez (Cancerologia de Queretaro, Queretaro); Jose Luis Gonzalez Trujillo (Fundacion Rodolfo Padilla Padilla A.C., León); Maria del Consuelo Diaz Romero (Instituto Nacional de Cancerologia, Distrito Federal); Carlos Alberto Hernandez (Oaxaca Site Management Organization, Oaxaca). Netherlands: Geert Jan M. Creemers (Catharina ZKHS, Eindhoven); J.C. de Graaf (Isala Klinieken, Zwolle); Cecile (M.I) Grootscholten (Antoni van Leeuwenhoek Ziekenhuis, Amsterdam); Jarmo Hunting (St. Antonius locatie Leidsche Rijn, Utrecht); A.L.T. Imholz (Deventer Ziekenhuis, Deventer); D.F.S. Kehrer (Ijsselland Ziekenhuis, Capelle ad Yssel); C.J.A. PUNT (Academisch Medisch Centrum Universiteit Amsterdam, Amsterdam). Poland: Jacek Krynski (Centrum Onkologii - Instytut im. M. Sklodowskiej-Curie, Warszawa); Joanna Streb (Szpital Uniwersytecki w Krakowie, Krakow). Portugal: Anabela Barros (HUC, Coimbra); Antonio Quintela (Hospital de Santa Maria, Lisboa). Russian Federation: Dina Sakaeva (Bashkirian Republican Clinical Oncology Dispensary, UFA); Sergei Tjulandin (Russian Oncology Research Center n.a. N.N. Blokhin, Moscow); Vladimir Moiseenko (S-Pb Clinical Scientific Practical Center of Specialized Kinds of Medical Care, Saint-Petersburg). Serbia: Zoran Andric (Clinical Center Bezanijska Kosa, Belgrade); Davorin Radosavljevic (Institute for Oncology and Radiology of Serbia, Belgrade); Biljana Kukic (Institute for Oncology of Vojvodina, Sremska Kamenica). Slovakia: Marian Kakalejcik (POKO Poprad, Poprad); Tomas Salek (Narodny Onkologicky Ustav, Bratislava); Vanda Usakova (Onkologicky ustav sv. Alzbety, S.R.O., Bratislava). Slovenia: Janja Ocvirk (Institute of Oncology Ljubljana, Ljubljana). Spain: Josep Maria Tabernero (Val d’Hebron University Hospital, Barcelona); Ruth Afonso Gomez (Complejo Hospitalario Nuestra Señora de la Candelaria, Santa Cruz de Tenerife); Vicente Alonso Orduña (Hospital Universitario Miguel Servet, Zaragoza); Jorge Aparicio Urtasun (Hospital Universitario la Fe, Valencia); Enrique Aranda Aguilar (Hospital Universitario Reina Sofia, Cordoba); Andres Cervantes (Hospital Clinico Universitario de Valencia, Valencia); Rosario Dueñas Garcia (Complejo Hospitalario de Jaen-Hospital Universitario Medico Quirurgico, Jaen); M. Pilar Escudero Emperador (Hospital Clinico Universitario Lozano Blesa, Zaragoza); Javier Gallego Plazas (Hospital General Universitario de Elche, Elche); Pilar Garcia Alfonso (Hospital General Universitario Gregorio Marañon, Madrid); Rocio Garcia Carbonero (Hospital Universitario 12 de Octubre, Madrid); Silvia Gil Calles (Hospital Regional Universitario Carlos Haya, Malaga); Carmen Guillen Ponce (Hospital Ramon y Cajal, Madrid); Monica Guillot Morales (Hospital Universitario Son Espases, Palma de Mallorca); Adelaida Lacasta Muñoa (Hospital de Donostia, San Sebastian); Rafael Lopez Lopez (Complejo Hospitalario Universitario de Santiago (CHUS), Santiago de Compostela); Guillermo Lopez Vivanco (Hospital de Cruces, Barakaldo); Jose Luis Manzano Mozo (Hospital Universitari Germans Trias i Pujol, Barcelona); Bartomeu Massuti Sureda (Hospital General Univ. de Alicante, Alicante); Fernando Rivera Herrero (Hospital Universitario Marques de Valdecilla, Santander); Nuria Rodríguez Salas (Hospital Universitario la Paz, Madrid); Ana Ruiz Casado (Hospital Universitario Puerta de Hierro, Madrid); M. Jose Safont Aguilera (Hospital General Universitario de Valencia, Valencia); Mercedes Salgado Fernandez (Complejo Hospitalario de Orense, Orense); Antonia Salud Salvia (Hospital Universitari Arnau de Vilanova de Lleida, Lerida); Ruth Vera Garcia (Hospital de Navarra, Navarra); Jose Maria Vieitez De Prado (Hospital Univ. Central de Asturias, Oviedo). Sweden: Anders Johnsson (Skånes University Hospital, Lund); Masoud Karimi (Karolinska Hospital, Stockholm). Turkey: Huseyin Abali (Acibadem University School of Medicine, Adana Hospital, Adana); Irfan Cicin (Trakya University Medical Faculty Research and Practice Hospital, Edirne); Ruchan Uslu (EGE Uni Medical Faculty Hospital, Izmir); Sezai Vatansever (Istanbul Uni Capa Medical Faculty, Inst. Of Oncology, Istanbul); Suayib Yalcin (Hacettepe Uni Medical Faculty Hospital, Sıhhiye, Ankara); Fulden Yumuk (Marmara Uni Faculty of Medicine, Istanbul). United Kingdom: Leslie Samuel (Aberdeen Royal Infirmary, Aberdeen); Shobhit Baijal (Birmingham Heartlands Hospital, Birmingham); Gopalakrishnan Srinivasan (Broomfield Hospital, Chelsmford); Amandeep Dhadda (Castle Hill Hospital, The Queens Centre for Oncology and Haematology, Cottingham); Saifee Mullamitha (Christie Hospital NHS Trust, Manchester); Paul Ross (Guys and St Thomas NHS Foundation Trust, Guys Hospital, London); Mark Harrison (Mount Vernon Hospital, Northwood, Middlesex); Sherif Raouf (Queen’s Hospital, Romford); Ian Chau (Royal Marsden Hospital, Sutton, London); Tim Iveson (Southampton General Hospital, Southampton).

Compliance with ethical standards

Conflict of interest

Ivan Bosanac, Belguendouz Bendahmane, and Christoph Mancao are employees of the study sponsor (F. Hoffmann-La Roche). All other authors report no relevant conflict of interest.

Ethical approval

All procedures performed in MODUL were in accordance with the ICH E6 guideline for Good Clinical Practice and the principles of the Declaration of Helsinki, or the laws and regulations of the country in which the research was conducted. All patients provided written informed consent to participate in the study. The study protocol, informed consent forms, any information to be given to the patient, and relevant supporting information were all reviewed and approved by the IRB/EC before the study was initiated.

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Hans-Joachim Schmoll
    • 1
  • Dirk Arnold
    • 2
  • Aimery de Gramont
    • 3
  • Michel Ducreux
    • 4
  • Axel Grothey
    • 5
  • Peter J. O’Dwyer
    • 6
  • Eric Van Cutsem
    • 7
  • Frank Hermann
    • 8
  • Ivan Bosanac
    • 9
  • Belguendouz Bendahmane
    • 9
  • Christoph Mancao
    • 10
  • Josep Tabernero
    • 11
  1. 1.Division of Clinical Oncology ResearchUniversity Clinic Halle (Saale), Martin-Luther-University Halle-WittenbergHalleGermany
  2. 2.Instituto CUF de OncologiaLisbonPortugal
  3. 3.Hôpital Saint AntoineParisFrance
  4. 4.Gustave Roussy, Villejuif, Université Paris SaclayParisFrance
  5. 5.Mayo Clinic College of MedicineRochesterUSA
  6. 6.Abramson Cancer CenterUniversity of PennsylvaniaPhiladelphiaUSA
  7. 7.University Hospitals Gasthuisberg, Leuven and KULeuvenLeuvenBelgium
  8. 8.Molecular Partners, Zurich (previously F. Hoffmann-La Roche Ltd)BaselSwitzerland
  9. 9.F. Hoffmann-La Roche LtdBaselSwitzerland
  10. 10.Genentech Inc.BaselSwitzerland
  11. 11.Vall d’Hebron University Hospital and Institute of Oncology (VHIO)Universitat Autònoma de BarcelonaBarcelonaSpain

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