Authors:

Marinus W. Lobbezoo

Herbert M. Pinedo

Abstract

The EORTC New Drug Development Office (NDDO) was established by Professor Bob Pinedo in 1984 following a decision by the EORTC Board on a proposal by the EORTC New Drug Development Coordinating Committee. The aim of the NDDO was to accelerate the drug development process for new anticancer agents in Europe, from discovery through preclinical development to early-phase clinical studies. Preclinical drug development projects were conducted in collaboration with a range of partner organizations, including the EORTC Screening and Pharmacology Group, the EORTC Pharmacokinetics and Metabolism Group (later renamed ‘Pharmacology and Molecular Mechanisms Group’), the Pharmacy Department of the Netherlands Cancer Institute in Amsterdam and contract toxicology laboratories. Phase I and II studies were conducted in close collaboration with the EORTC Early Clinical Trials Group/Early Clinical Studies group, the EORTC Data Center, and the Data Management Group at the Netherlands Cancer Institute. NDDO represented the EORTC in various collaborations with the US National Cancer Institute and the UK Cancer Research Campaign. The Academic Hospital Vrije Universiteit (or Free University Hospital) provided important support to NDDO in the fields of funding, administration, housing and office facilities. Its Medical Oncology Department provided valuable scientific input through its medical and research laboratory staff and by participating in NDDO’s clinical studies. NDDO was the organizer of the NCI-EORTC Symposium on New Drugs in Cancer Therapy from 1986 to 2000.

Introduction

In the early 1980s key people at the European Organization for Research and Treatment of Cancer (EORTC), including dr. Loek van Putten (TNO, Rijswijk, The Netherlands) and dr. Heine Hansen (Rigshospitalet, Copenhagen, Denmark), realized that there was a need for a dedicated entity to speed up the development of new anticancer agents and make these available for clinical evaluation and ultimately regulatory approval as soon as possible. This was at a time when the pharmaceutical industry showed limited interest in oncology; only a handful of pharma companies had active research and development programs in this therapeutic area. A proposal to establish an EORTC center for anticancer drug development was made by the EORTC New Drug Development Coordinating Committee (NDDCC) and was accepted by the EORTC Board. Professor Bob Pinedo, who had been appointed Professor of Medical Oncology and Director of the Department of Medical Oncology at the Academic Hospital Vrije Universiteit (later renamed ‘VU University medical center’; VUmc), currently part of Amsterdam UMC, took on the task to establish the EORTC New Drug Development Office (further referred to as NDDO) which occurred in 1984. Bob Pinedo was the first NDDO Director; prof. Gordon McVie was the first Associate Director. Pinedo got permission from the VUmc Board to host the NDDO in his department of the clinic building. Clinical pharmacologist, Benjamin Winograd, MD, was the first NDDO employee; medicinal chemist, Marinus Lobbezoo, PhD, came on board as the second in 1985. They were supported by a parttime secretary. By 1999, NDDO had grown to an organization of a few dozen of employees.

Funding and governance

NDDO’s operations were greatly facilitated by administrative and financial support by various entities. The Board of Directors of the VUmc provided housing, office facilities and personnel management, as well as initial funding by means of loan. The EORTC NDDCC provided a starting grant while the EORTC Board provided an annual grant until 1997. In December 1985, a foundation named ‘Stichting N.D.D.O.’ was established to generate funding on an ongoing basis. The board included Bob Pinedo (chairman), Heine Hansen (secretary), mr. Guup Kraijenhoff (treasurer), and members Professor Umberto Veronesi (EORTC President at that time), Mrs. Ann Money-Coutts (secretary EORTC Foundation); mr. Ivar Samrén and Professor Frans Cleton. Stichting N.D.D.O. received annual grants from four pharmaceutical companies (Bristol-Myers Squibb, Pharmachemie, ICI and Lederle). In addition, NDDO received several earmarked grants from European cancer charities, including KWF Dutch Cancer Society for preclinical toxicology studies and the VSB Fund for a study on the predictive power of animal models for cancer therapies. For its drug development activities, NDDO reported to NDDCC, initially chaired by Heine Hansen. NDDCC members in the early years of NDDO included professors Tom Connors, Brian Fox, Ken Harrap, Bob Pinedo Paul Workman, and others. NDDO Directors were ex officio members of the EORTC Board to which they reported for organizational and financial matters. Successors to prof. Bob Pinedo as NDDO Director were prof. Gilberto Schwartsmann (1989-1992), dr. Marinus Lobbezoo (1992-1994) and dr. Coenraad van Kalken (1994-1999).

NDDO’s role in drug development

Drug development in the 1980s and 1990s was a stepwise process starting with the discovery of promising drug molecules through screening, followed by preclinical development, early-phase and late-phase clinical development. NDDO’s focus was on essential preclinical development studies, including screening and antitumor profiling of candidate drugs in tumor models, drug formulation, stability testing, animal toxicology studies and production of drug supplies for clinical studies. Clinical studies included first-in-human dose-escalation phase I studies and small phase II studies in a range of solid tumors. The main aim of NDDO’s early-phase drug development program was to identify new drugs warranting full clinical evaluation in large-scale clinical studies and the tumor types in which they were most likely to show meaningful clinical antitumor activity. Van Kalken (1998) published a brief outline of NDDO’s objectives and collaborations in new drug development.

Details of NDDO’s achievements in preclinical and clinical drug development are provided by Part 2 of the ‘History of the EORTC New Drug Development Office, 1984-1999’.

Preclinical development

NDDO’s preclinical studies, conducted by partner institutes, were managed and coordinated by Marinus Lobbezoo , Hans Hendriks and Roland Henrar. In the execution of these studies, NDDO collaborated closely with entities and organizations, both within the EORTC as well as outside, including the UK Cancer Research Campaign (CRC, currently known as CRUK), and the US National Cancer Institute (NCI) in Bethesda, MD. These organizations ran similar drug discovery and development programs as NDDO. Collaborations involving the NCI were greatly facilitated by the NCI Liaison Office in Brussels, led by dr. Omar Yoder, who was succeeded by Ms. Susanne Radtke.

Drug acquisition

To obtain compounds of interest for evaluation in its new drug development program, NDDO set up acquisition activities, primarily directed at academic institutes, such as departments of organic chemistry or medicinal chemistry at European universities. Compounds could be candidates based on their chemical structure (e.g. analogs of clinically active cytostatic or cytotoxic agents) or mechanism of action, and compounds with signs of possible antitumor activity (e.g. in tumor cell cultures). An example of the former is a series of indoloquinones originating from the Department of Organic Chemistry, University of Amsterdam. The lead compound of the series, EO9 (later renamed apaziquone) is discussed in detail in Part 2 of this paper.

A source of compounds having shown antitumor activity in tumor cell lines was the NCI. At that time (in the 1980s), the NCI ran an in vitro screening program using the murine P388 leukemia cell line as the primary screen (Boyd 1997). Professors Ken Harrap and Bob Pinedo got the opportunity to select compounds with promising antitumor activity in the NCI program for further European development within the EORTC and CRC. One of these compounds, picked by Pinedo, was 5-aza-2’-deoxycytidine (DAC, currently known as decitabine). It was taken into preclinical development by NDDO. Later, Marinus Lobbezoo spent some time at the NCI as well to select further compounds of interest for further preclinical testing and development in Europe.

Drug screening and antitumor profiling

Compounds acquired by NDDO were screened for antitumor activity and often subjected to further profiling by European cancer research laboratories. Among those were the oncology laboratories of the VUmc in Amsterdam (Professors Wim van der Vijgh, Frits Peters, Epie Boven), Institut Jules Bordet in Brussels (dr. Ghanem Atassi), the University of Freiburg (Prof. Heiner Fiebig), the University of Bradford (dr. John Double) and the Radiobiological Institute TNO, Rijswijk, The Netherlands (dr. Peter Lelieveld). The collaboration with the Fiebig laboratory in Freiburg, using human tumor xenografts in vitro and in vivo, became a structural part of the NDDO program which remained in place for many years during which dozens of compounds were evaluated. By 1992, about 200 compounds had been screened by Fiebig’s group (Hendriks et al, 1992a).

Antitumor data were also generated by (other) members of the EORTC Screening and Pharmacology Group (SPG) and the EORTC Pharmacokinetics and Metabolism Group (PAM Group), later renamed to Pharmacology and Molecular Mechanism Group (PAMM Group). An NDDO staff member usually attended the meetings of these groups. The history and achievements of PAMM and SPG have been described in detail by Peters et al (2012). A European perspective of anticancer drug screening and discovery in the 1990s has been provided by Schwartsmann and Workman (1992).

In 1991, the NDDCC established a subcommittee with members from EORTC, CRC, NCI, external experts and NDDO to oversee drug screening efforts in Europe. In 1993, the European NCI compounds program, a joint initiative of the EORTC Research Branch, CRC and NCI, was launched. The objective was to help the NCI in reducing the backlog of in vivo testing of anticancer compounds, synthesized in Europe that had emerged from the NCI in vitro 60-cell line screen. NDDO was represented in the CRC/EORTC Review Committee of this program by Hans Hendriks, who published an overview of its achievements (Hendriks et al. 2017). Prof. Jos Beijnen provided support for formulation of these compounds to be tested in vivo. Several compounds originating from the approximately 2,000 compounds reviewed in this program, ultimately proceeded to phase I clinical evaluation.

Special project on human tumor xenografts

In the 1980s, human tumor xenografts in nude mice (HTX) were emerging as promising tumor models with possibly better predictability of clinical antitumor activity than the conventional models used until that time. In a European multicenter collaboration, coordinated by NDDO, so-called preclinical phase II studies were conducted using panels of HTX of solid tumors available at the six participating laboratories. Tumor types investigated were breast, colorectal, head and neck, non-small cell lung, small cell lung and ovarian cancer, and melanoma. The aim was to better identify promising clinical candidate compounds as well as the tumor types likely to respond to investigational drugs in the clinic (Winograd et al, 1987; Boven et al, 1988; Boven et al, 1992).

Formulation development, stability testing and clinical drug supplies

Before a promising agent was offered to clinical investigators for phase I evaluation a drug formulation for the intended route of administration, usually intravenous injection or infusion, was developed. For this purpose, NDDO collaborated closely with the Pharmacy Department of Slotervaart Hospital/Netherlands Cancer Institute, Amsterdam (prof. Jos Beijnen) and Aston University, Birmingham, U.K. (dr. John Slack). The preferred formulation for intravenous use was mostly a freeze-dried product that could conveniently be reconstituted at a clinical trial site. After successful formulation development, stability of the product was tested under different conditions of temperature and lightning in order to advise shipment and storage conditions.

Formulation experience was exchanged between NDDO (represented by Roland Henrar), CRC and NCI in the CRC/EORTC/NCI Joint Formulation Working Party (JFWP). Its main goal was to speed up the pharmaceutical development of new drugs to get those ready for preclinical toxicology and subsequent phase I clinical trials. In 1988, JFWP members issued ‘EORTC/CRC/NCI guidelines for the formulation of investigational cytotoxic drugs’ (Davignon et al, 1988). Slack et al (1989) and Beijnen et al (1995) published progress reports on behalf of the JFWP showing that by 1995 around 50 compounds had been handled or were being handled by member institutes.

Clinical drug supplies, prepared by NDDO’s formulation partners or provided by study sponsors, were stored at the VUmc Pharmacy Department until dispatch to the pharmacies of clinical study sites. NDDO maintained clinical supply records and collected reconciliation statements from clinical sites after closing of a study.

Preclinical pharmacokinetics and metabolism

The EORTC PAMM Group and others encouraged the use of pharmacokinetically-guided dose escalation in EORTC’s phase I clinical trials (Anonymous 1987). Several NDDO drugs therefore underwent pharmacokinetic evaluation in animals by PAMM Group members to generate the pharmacokinetic and metabolism information needed to support subsequent or ongoing early clinical studies (Newell et al, 1999). In most cases, bioanalytical assays were developed for these studies by partner institutes. Pharmacokinetic evaluations were conducted in several phase I and II studies.

Preclinical toxicology

The main aims of preclinical toxicology studies coordinated by NDDO were to define a safe starting dose for phase I clinical studies and to identify the potential target organs of a drug’s toxicity. Studies were conducted according to the ‘General guidelines for the preclinical toxicology of new cytotoxic anticancer agents in Europe’, issued by the Joint Steering Committee of the EORTC and CRC (Anonymous 1990). Studies recommended by these guidelines were rodent-only investigations and comprise determination of the maximum tolerated dose (MTD) and the dose lethal to 10% of animals (LD10) in mice after intraperitoneal, intravenous or oral dosing, depending on de intended clinical route of administration. Hematology, histopathology and bone marrow cytology evaluations were conducted up to 28 days after a single dose close to the MTD/LD10 of the drug. The same evaluations were made after repeated dosing of mice for 4 weeks. Finally, one-tenth of the mouse LD10, calculated on the basis of body surface area, expressed in mg/m2, was evaluated in rats during and after 4 weeks of administration, again by hematology, histopathology and bone marrow cytology assessments. The rat study was performed to check the safety of the proposed phase I starting dose (one-tenth mouse LD10) in a second species. In case significant toxicity was encountered, reversibility of such toxicity was evaluated by longer follow-up and repeat assessments.

The feasibility of this rodent-only approach was based on earlier evaluations such as the one published by Grieshaber and Marsoni (1986). An extensive review of the CRC experiences using the rodent-only approach for 25 new drugs was provided by Newell et al (1999). NDDO’s experience with selected drugs was described by Schwartsmann et al (1991a), Hendriks et al (1992a) and Henrar et al (1993). Burtles et al (1995) published a revised version of the rodent-only protocols based on the extensive experience gained by CRC and NDDO. Revisions concerned among others the use of clinically relevant dosing schedules, doses and routes of administration.

One of the requirements of the joint EORTC CRC toxicology guidelines is that preclinical toxicology studies be performed according to the standards of Good Laboratory Practice (GLP). NDDO’s toxicology studies were therefore outsourced to the GLP-certified laboratories of TNO-CIVO in Zeist (The Netherlands) and NOTOX B.V. in ‘s-Hertogenbosch (The Netherlands).

Early-phase clinical studies

Over the years, NDDO managed many phase I studies and disease-oriented phase II studies of new anticancer agents. All studies were conducted in close collaboration with members of the EORTC Early Clinical Trials Group (ECTG). After a fusion with the EORTC Clinical Studies Group, the ECTG was re-named EORTC Early Clinical Studies Group or ECSG). Data management of these studies was shared between the EORTC Data Center and the NDDO Data Center at the Department of Biometrics (headed by dr. Otillia Dalesio) of the Netherlands Cancer Institute in Amsterdam. Study protocols were reviewed by the EORTC Protocol Review Committee before being activated.

The ECTG had been established in the mid 1970s when Heine Hansen, Marcel Rozenzweig Franco Cavalli, and others felt the need to introduce disease-oriented phase II trials in Europe. Until that time, most phase II trials included patients with multiple tumor types. The ECTG changed its name twice, the first time around 1993 into EORTC Early Clinical Studies Group (ECSG) after fusing with the EORTC Clinical Studies Group. Later it was renamed again, now into EORTC New Drug Development Group (NDDG).

Chairmen of the ECTG/ECSG/NDDG during the period when NDDO managed phase I and II trials were Bob Pinedo (Netherlands, from start until 1988), Franco Cavalli (Switzerland, 1988-1991), Stan Kaye (United Kingdom, 1991-1994), Jaap Verweij (Netherlands, 1994-1997), Axel Hanauske (Belgium, 1997-199), Pierre Fumoleau (France, 1999-2002) and Chris Twelves (United Kingdom, 2002-2005).

Not all drugs evaluated in phase I and/or II trials were managed by NDDO at the stages of preclinical tumor testing or preclinical development; several drugs proceeded directly to clinical testing based on (pre)clinical data generated by other entities, including pharmaceutical companies.

Phase I studies

Phase I studies conducted by NDDO-ECTG were almost exclusively first-in-man dose escalation studies of single agents aiming to determine the maximum tolerated dose (MTD), to characterize the most frequent toxic effects and to define the dose-limiting toxicities of the drug. An important outcome for the further evaluation of a drug in phase II studies was the recommended phase II dose (RP2D). Possible hints of antitumor activity were to be reported as well. EORTC Guidelines for Phase I Trials with Single Agents in Adult were published by the NDDCC in 1985 (EORTC New Drug Development Committee, 1985).

Phase I studies were usually conducted with one or two ECTG member sites per protocol and were coordinated by the NDDO. Dr. Benjamin Winograd served as the clinical monitor for the first NDDO phase I studies, but this role was soon taken over by a medical oncologist, dr. Jantien Wanders, who monitored almost all studies in the 1980s and 1990s. In 1992, NDDO participated in the formulation and publication of Minimal guidelines for the monitoring of early clinical trials (phase I-II) in Europe under CRC/EORTC/NCI joint agreement (Arrigo et al, 1992)

To determine the MTD of a drug, a careful dose escalation strategy according to a modified Fibonacci three-by-three scheme was followed. The usual starting dose was one-tenth of the mouse LD10, based on body surface area, as determined in the rodent-only toxicology evaluation. Normally, three patients were entered sequentially at each dose level until dose-limiting toxicity as defined in the study protocol was encountered in one or more patients. Toxicity was graded according to the prevailing Common Terminology Criteria for Adverse Events (CTCAE). What constituted a DLT was defined by the specific nature of the toxicity (hematologic or non-hematologic/organ-specific) and the toxicity grade.

After the DLT had been reached, the MTD for the drug under study was defined, usually as the highest dose that could safely be administered at the dose schedule and route of administration used. The RP2D was usually defined as the dose level just below the MTD. At the RP2D dose level additional patients, up to a total of at least five, were entered to ensure the safety of this dose before starting phase II studies. In practice, the number of patients entered in a phase I study varied largely, ranging from just over a dozen to several dozens, depending on how close/remote the starting dose was to the actual MTD. Nowadays, oncology phase I studies generally recruit far larger numbers of patients by the addition of expansion cohorts in the second part of the study, often at or near the MTD.

Phase II studies

After the RP2D had been defined, non-randomized disease-oriented phase II trials were initiated in which, in principle, all ECTG/ECSG members could participate. Studies of a specific agent were frequently conducted in multiple tumor types simultaneously. Tumor types were selected on the basis of pre-existing knowledge about the drug under study, such as mechanism of action, structural analogy with clinically active anticancer agents, preclinical activity in HTX models or possible hints of clinical activity in phase I.

Phase II studies were usually conducted according to the Gehan two-stage design. The aim of such studies was to ascertain whether the drug and regimen under study provided sufficient anticancer activity to justify advancing it to further evaluation in larger scale clinical trials. ECTG/ESCG studies were mostly designed such that a new drug was considered inactive if none of the first 14 patients entered showed a tumor response. If one or more patients in stage 1 of the study responded, the second stage was activated. Further patients were then entered to achieve an initial estimate of the response rate. In practice drugs were considered active in a given tumor type if the response rate was at least 20%.

In the 1970s and 1980s, international guidelines for the ethical conduct of clinical trials emerged, culminating in the adoption of the ICH Guidelines for Good Clinical Practice (ICH-GCP) in 1996. NDDO and ECTG/ECSG therefore had to implement new policies to ensure adherence to these guidelines in their phase I and II studies. So, verifying that GCP requirements were met by the participating clinical sites became a new responsibility of NDDO, in particular its clinical monitor.

Several drugs developed in NDDO’s preclinical and phase I program moved on to subsequent phase II evaluation by ECTG/ECSG. In addition, new drugs entered phase II evaluation after initial development had been conducted by external parties, mainly pharmaceutical companies, who wished to contract out (some of) their phase II studies. Examples are gemcitabine, topotecan and docetaxel, which were ultimately approved and became frequently used anticancer agents in a range of indications.

Development of RECIST Criteria

In 2000 an international group of clinical investigators published New guidelines to evaluate the response to treatment in solid tumors, including new Response Evaluation Criteria in Solid Tumors (RECIST) to replace the historically used WHO response criteria from 1979 (Therasse et al, 1998; Therasse et al, 2000). This group acted on behalf of the EORTC, the US National Cancer Institute and the National Cancer Institute of Canada. NDDO was represented by dr. Jantien Wanders who brought the NDDO experience in response evaluation in many early phase clinical studies to the table. A revised version of the guideline (version 1.1) was published by Eisenhauer et al (2008).

NCI-EORTC Symposium on New Drugs in Cancer Therapy

NDDO has been instrumental in developing the NCI-EORTC Symposium on New Drugs in Cancer Therapy into an internationally high-ranking meeting on early-phase clinical studies of new anticancer agents and translational research of new drugs and new drug targets. Joint meetings of EORTC and NCI on new drugs had been organized in Brussels by dr. Marcel Rozenzweig before the NDDO had been established. In 1985, the organization of further meetings was put in the hands of Bob Pinedo and NDDO. The fifth NCI-EORTC Symposium, held in Amsterdam in 1986, was the first meeting in this new setting. The sixth through the tenth symposia were all organized by NDDO in Amsterdam in 1989, 1992, 1994, 1996, 1998 and 2000, always using the VU University’s conference facilities as the venue. The eleventh meeting was organized in a partnership with the American Association for Cancer Research (AACR) in 2000. The number of delegates attending increased from a few hundred in 1986 to about two thousand in 2000.

All meetings in Amsterdam were chaired by Bob Pinedo who was supported by co-chairs from EORTC and NCI and an organizing committee comprising European and North American leaders in basic and clinical science. Local organizers on behalf of NDDO were Marinus Lobbezoo, Roland Henrar and Mark Krul, who worked in close collaboration with the Congress Bureau of the VU University in Amsterdam led by Nicolette van Erven.

The symposium series quickly developed great popularity among the target audience and was soon dubbed ‘The Amsterdam new drug meeting’. Here, many new drug targets and new agents were discussed extensively between basic scientists, clinical investigators and industry drug development specialists. New drugs and targets presented and discussed included new DNA interactive agents, novel antimetabolites, biologicals, taxanes, anti-angiogenic agents, tyrosine kinase inhibitors, immune checkpoint inhibitors, novel rationally designed combinations (e.g. gemcitabine-cisplatin) and much more. Dr. Greg Curt of the NCI characterized the meeting as follows: “One meeting which has remained true to its initial mission is the NCI-EORTC Symposium on New Drugs in Cancer Therapy which occurs every two years in Amsterdam. Originally organized to help coordinate phase I cancer drug development between the United States and Europe, the meeting fills an important scientific niche” (Curt 1998). The meeting was also used as an opportunity for EORTC groups to discuss ongoing drug screening and development studies (e.g. the SPG and PAMM, the European NCI compounds).

A brief history of this symposium series has been published by Krul (1998). Proceedings of the 6th symposium have been published in Investigational New Drugs (Anonymous 1989), those of the 7th - 10th symposium in Annals of Oncology (Anonymous 1992, Anonymous 1994, Anonymous 1996, Anonymous 1998b) and those of the 11th symposium in Clinical Cancer Research (Anonymous 2000).

On the occasion of the 9th NCI-EORTC Symposium in 1996, a workshop on phase I study design was held, organized by dr. Elizabeth Eisenhauer and dr. Franco Cavalli. It was focused on possibilities for more efficient phase I trials in oncology. Dr. Susan Arbuck published an extensive report of the workshop (Arbuck1996).

In 1998, the organization of future meetings in this series was assigned to EORTC and AACR because of the split between NDDO and EORTC (see below for details). Further meetings were held under the title AACR-NCI-EORTC or EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics, the first one in Washington DC in 1999. This meeting has been held annually since 2001. In November 2000, the last NCI-EORTC Symposium on New Drugs in Cancer Therapy organized by NDDO took place in Amsterdam.

NDDO Oncology

In late 1998, the relationship between EORTC and NDDO came to an end. There was increasing difference between the philosophies of both entities about the way forward in new drug development in Europe. By 1998, NDDO had developed from an academic-based entity to a full contract research organization (CRO) with a few dozen employees and collaborations with several drug companies. It appeared increasingly difficult for NDDO to meet the international regulatory and quality requirements in its clinical drug development activities within the EORTC environment. Unwinding the ties between EORTC and NDDO - and for the most part also between NDDO and VUmc - took place in the course of 1999. NDDO continued as a private company under the name NDDO Oncology with Stichting N.D.D.O (later re-named NDDO Research Foundation) as the main shareholder and dr. Coenraad van Kalken as Managing Director. The portfolio of ongoing projects was divided in good consultation between NDDO Oncology and EORTC. On the EORTC side, the New Drug Development Programme (NDDP) and New Drug Development Group (NDDG) took over the management and conduct of the trials assigned to EORTC (Lacombe et al, 2002). This program was terminated in 2005. After the split between NDDO and EORTC, individual members of the ECSG continued to serve as clinical investigators for NDDO Oncology’s trials.

In 2005, NDDO Oncology was incorporated into INC Research (later re-named Syneos Health), an American CRO. NDDO Oncology’s Amsterdam office became one of their European offices and was still operational in late 2024.

In 2002, the NDDO Research Foundation initiated a new annual symposium series entitled International Symposium on Signal Transduction Modulators in Cancer Therapy (Lobbezoo et al, 2003) which was continued as International Congress on Targeted Anticancer Therapies (TAT) as of 2005. Meetings were held in Amsterdam (2005, 2006, 2007, 2009, 2012), Bethesda, MD (2008, 2010, 2014), Paris (2011, 2013, 2015, 2017), and Washington, DC (2016) with professors Giuseppe Giaccone and Jean-Charles Soria as (co-)chairs. These meetings were organized in varying partnerships with ESMO, NCI and/or Institut Gustave Roussy. Proceedings were usually published in Annals of Oncology supplements. Since 2018, this congress series is being continued by ESMO.

Conclusions

During its 15 years of operations, the EORTC New Drug Development Office (NDDO) has made significant contributions to establishing an infrastructure for academic new drug development in oncology and to the preclinical and early clinical development of promising new anticancer agents. Hundreds of compounds were tested in the laboratory for antitumor activity, at least a dozen of which proceeded to pharmaceutical development and preclinical toxicology testing at partner research institutes. Most of these agents subsequently underwent clinical evaluation in phase I and II studies, conducted in close collaboration with the EORTC ECTG/ECSG.

Once the value of the NDDO-ECTG/ECSG mechanism had become known, new drugs coming from pharmaceutical and biotech companies were offered for early clinical evaluation.

NDDO contributed to the development of various guidelines for anticancer drug development, in international collaborations with the NCI and CRC, and to the development of the well-known RECIST criteria for tumor response evaluation.

NDDO also made important contributions to the exchange of new drug development strategies and study results by means of the NCI-EORTC Symposium on New Drug in Cancer Therapy. Seven symposia with increasing international participation and recognition were held in Amsterdam. This symposium series is being continued annually (alternating between Europe and the USA) by EORTC and AACR under the title AACR-NCI-EORTC/EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics.

Acknowledgements

The authors gratefully acknowledge information provided for the development of this manuscript by dr. Denis Lacombe, prof. Jaap Verweij, prof. Frits Peters and mrs. Nicolette van Erven.

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