Prospective assessment of a gene signature potentially predictive of clinical benefit in metastatic melanoma patients following MAGE-A3 immunotherapeutic (PREDICT).

BACKGROUND: Genomic profiling of tumor tissue may aid in identifying predictive or prognostic gene signatures (GS) in some cancers. Retrospective gene expression profiling of melanoma and non-small-cell lung cancer led to the characterization of a GS associated with clinical benefit, including improved overall survival (OS), following immunization with the MAGE-A3 immunotherapeutic. The goal of the present study was to prospectively evaluate the predictive value of the previously characterized GS. PATIENTS AND METHODS: An open-label prospective phase II trial ('PREDICT') in patients with MAGE-A3-positive unresectable stage IIIB-C/IV-M1a melanoma. RESULTS: Of 123 subjects who received the MAGE-A3 immunotherapeutic, 71 (58.7%) displayed the predictive GS (GS+). The 1-year OS rate was 83.1%/83.3% in the GS+/GS- populations. The rate of progression-free survival at 12 months was 5.8%/4.1% in GS+/GS- patients. The median time-to-treatment failure was 2.7/2.4 months (GS+/GS-). There was one complete response (GS-) and two partial responses (GS+). The MAGE-A3 immunotherapeutic was similarly immunogenic in both populations and had a clinically acceptable safety profile. CONCLUSION: Treatment of patients with MAGE-A3-positive unresectable stage IIIB-C/IV-M1a melanoma with the MAGE-A3 immunotherapeutic demonstrated an overall 1-year OS rate of 83.5%. GS- and GS+ patients had similar 1-year OS rates, indicating that in this study, GS was not predictive of outcome. Unexpectedly, the objective response rate was lower in this study than in other studies carried out in the same setting with the MAGE-A3 immunotherapeutic. Investigation of a GS to predict clinical benefit to adjuvant MAGE-A3 immunotherapeutic treatment is ongoing in another melanoma study.This study is registered at www.clinicatrials.gov NCT00942162.

Lessons learned from independent central review.

Independent central review (ICR) is advocated by regulatory authorities as a means of independent verification of clinical trial end-points dependent on medical imaging, when the data from the trials may be submitted for licensing applications [Food and Drug Administration. United States food and drug administration guidance for industry: clinical trial endpoints for the approval of cancer drugs and biologics. Rockville, MD: US Department of Health and Human Services; 2007; Committee for Medicinal Products for Human Use. European Medicines Agency Committee for Medicinal Products for Human Use (CHMP) guideline on the evaluation of anticancer medicinal products in man. London, UK: European Medicines Agency; 2006; United States Food and Drug Administration Center for Drug Evaluation and Research. Approval package for application number NDA 21-492 (oxaliplatin). Rockville, MD: US Department of Health and Human Services; 2002; United States Food and Drug Administration Center for Drug Evaluation and Research. Approval package for application number NDA 21-923 (sorafenib tosylate). Rockville, MD: US Department of Health and Human Services; 2005; United States Food and Drug Administration Center for Drug Evaluation and Research. Approval package for application number NDA 22-065 (ixabepilone). Rockville, MD: US Department of Health and Human Services; 2007; United States Food and Drug Administration Center for Drug Evaluation and Research. Approval package for application number NDA 22-059 (lapatinib ditosylate). Rockville, MD: US Department of Health and Human Services; 2007; United States Food and Drug Administration Center for Biologics Evaluation and Research. Approval package for BLA numbers 97-0260 and BLA Number 97-0244 (rituximab). Rockville, MD: US Department of Health and Human Services; 1997; United States Food and Drug Administration. FDA clinical review of BLA 98-0369 (Herceptin((R)) trastuzumab (rhuMAb HER2)). FDA Center for Biologics Evaluation and Research; 1998; United States Food and Drug Administration. FDA Briefing Document Oncology Drugs Advisory Committee meeting NDA 21801 (satraplatin). Rockville, MD: US Department of Health and Human Services; 2007; Thomas ES, Gomez HL, Li RK, et al. Ixabepilone plus capecitabine for metastatic breast cancer progressing after anthracycline and taxane treatment. JCO 2007(November):5210-7]. In addition, clinical trial sponsors have used ICR in Phase I-II studies to assist in critical pathway decisions including in-licensing of compounds [Cannistra SA, Matulonis UA, Penson RT, et al. Phase II study of bevacizumab in patients with platinum-resistant ovarian cancer or peritoneal serous cancer. JCO 2007(November):5180-6; Perez EA, Lerzo G, Pivot X, et al. Efficacy and safety of ixabepilone (BMS-247550) in a phase II study of patients with advanced breast cancer resistant to an anthracycline, a taxane, and capecitabine. JCO 2007(August):3407-14; Vermorken JB, Trigo J, Hitt R, et al. Open-label, uncontrolled, multicenter phase II study to evaluate the efficacy and toxicity of cetuximab as a single agent in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck who failed to respond to platinum-based therapy. JCO 2007(June):2171-7; Ghassan KA, Schwartz L, Ricci S, et al. Phase II study of sorafenib in patients with advanced hepatocellular carcinoma. JCO 2006(September):4293-300; Boué F, Gabarre J, GaBarre J, et al. Phase II trial of CHOP plus rituximab in patients with HIV-associated non-Hodgkin's lymphoma. JCO 2006(September):4123-8; Chen HX, Mooney M, Boron M, et al. Phase II multicenter trial of bevacizumab plus fluorouracil and leucovorin in patients with advanced refractory colorectal cancer: an NCI Treatment Referral Center Trial TRC-0301. JCO 2006(July):3354-60; Ratain MJ, Eisen T, Stadler WM, et al. Phase II placebo-controlled randomized discontinuation trial of sorafenib in patients with metastatic renal cell carcinoma. JCO 2006(June):2502-12; Jaffer AA, Lee FC, Singh DA, et al. Multicenter phase II trial of S-1 plus cisplatin in patients with untreated advanced gastric or gastroesophageal junction adenocarcinoma. JCO 2006(February):663-7; Bouché O, Raoul JL, Bonnetain F, et al. Randomized multicenter phase II trial of a biweekly regimen of fluorouracil and leucovorin (LV5FU2), LV5FU2 plus cisplatin, or LV5FU2 plus irinotecan in patients with previously untreated metastatic gastric cancer: a Fédération Francophone de Cancérologie Digestive Group Study-FFCD 9803. JCO 2004(November):4319-28]. This article will focus on the definition and purpose of ICR and the issues and lessons learned in the ICR setting primarily in Phase II and III oncology studies. This will include a discussion on discordance between local and central interpretations, consequences of ICR, reader discordance during the ICR, operational considerations and the need for specific imaging requirements as part of the study protocol.

New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1).

BACKGROUND: Assessment of the change in tumour burden is an important feature of the clinical evaluation of cancer therapeutics: both tumour shrinkage (objective response) and disease progression are useful endpoints in clinical trials. Since RECIST was published in 2000, many investigators, cooperative groups, industry and government authorities have adopted these criteria in the assessment of treatment outcomes. However, a number of questions and issues have arisen which have led to the development of a revised RECIST guideline (version 1.1). Evidence for changes, summarised in separate papers in this special issue, has come from assessment of a large data warehouse (>6500 patients), simulation studies and literature reviews. HIGHLIGHTS OF REVISED RECIST 1.1: Major changes include: Number of lesions to be assessed: based on evidence from numerous trial databases merged into a data warehouse for analysis purposes, the number of lesions required to assess tumour burden for response determination has been reduced from a maximum of 10 to a maximum of five total (and from five to two per organ, maximum). Assessment of pathological lymph nodes is now incorporated: nodes with a short axis of 15 mm are considered measurable and assessable as target lesions. The short axis measurement should be included in the sum of lesions in calculation of tumour response. Nodes that shrink to <10mm short axis are considered normal. Confirmation of response is required for trials with response primary endpoint but is no longer required in randomised studies since the control arm serves as appropriate means of interpretation of data. Disease progression is clarified in several aspects: in addition to the previous definition of progression in target disease of 20% increase in sum, a 5mm absolute increase is now required as well to guard against over calling PD when the total sum is very small. Furthermore, there is guidance offered on what constitutes 'unequivocal progression' of non-measurable/non-target disease, a source of confusion in the original RECIST guideline. Finally, a section on detection of new lesions, including the interpretation of FDG-PET scan assessment is included. Imaging guidance: the revised RECIST includes a new imaging appendix with updated recommendations on the optimal anatomical assessment of lesions. FUTURE WORK: A key question considered by the RECIST Working Group in developing RECIST 1.1 was whether it was appropriate to move from anatomic unidimensional assessment of tumour burden to either volumetric anatomical assessment or to functional assessment with PET or MRI. It was concluded that, at present, there is not sufficient standardisation or evidence to abandon anatomical assessment of tumour burden. The only exception to this is in the use of FDG-PET imaging as an adjunct to determination of progression. As is detailed in the final paper in this special issue, the use of these promising newer approaches requires appropriate clinical validation studies.

Recommendations for the assessment of progression in randomised cancer treatment trials.

Progression-free survival (PFS) is an increasingly important end-point in cancer drug development. However, several concerns exist regarding the use of PFS as a basis to compare treatments. Unlike survival, the exact time of progression is unknown, so progression times might be over-estimated (or under-estimated) and, consequently, bias may be introduced when comparing treatments. In addition, the assessment of progression is subject to measurement variability which may introduce error or bias. Ideally trials with PFS as the primary end-point should be randomised and, when feasible, double-blinded. All patients eligible for study should be evaluable for the primary end-point and thus, in general, have measurable disease at baseline. Appropriate definitions should be provided in the protocol and data collected on the case-report forms, if patients with only non-measurable disease are eligible and/or clinical, or symptomatic progression are to be considered progression events for analysis. Protocol defined assessments of disease burden should be obtained at intervals that are symmetrical between arms. Independent review of imaging may be of value in randomised phase II trials and phase III trials as an auditing tool to detect possible bias.

Evaluation of lymph nodes with RECIST 1.1.

Lymph nodes are common sites of metastatic disease in many solid tumours. Unlike most metastases, lymph nodes are normal anatomic structures and as such, normal lymph nodes will have a measurable size. Additionally, the imaging literature recommends that lymph nodes be measured in the short axis, since the short axis measurement is a more reproducible measurement and predictive of malignancy. Therefore, the RECIST committee recommends that lymph nodes be measured in their short axis and proposes measurement values and rules for categorising lymph nodes as normal or pathologic; either target or non-target lesions. Data for the RECIST warehouse are presented to demonstrate the potential change in response assessment following these rules. These standardised lymph node guidelines are designed to be easy to implement, focus target lesion measurements on lesions that are likely to be metastatic and prevent false progressions due to minimal change in size.

TuBaFrost: European virtual tumor tissue banking.

TuBaFrost is a consortium responsible for the task to create a virtual European human frozen tumor tissue bank, composed of high quality frozen tumor tissue collections with corresponding accurate diagnosis stored in European cancer centers and universities, searchable on the Internet, providing rules for access and use and a code of conduct to comply with the various legal and ethical regulations in European countries. Such infrastructure would enlarge tissue availability and accessibility in large amounts of specified or even rare tumor samples. Design of an infrastructure for European residual tissue banking with the described characteristics, clear focus points emerge that can be broken down in dedicated subjects: (1) standardization and quality assurance (QA) to avoid inter-institute quality variation; (2) law and ethics enabling exchange of tissue samples possible between institutes in the different European countries, where law and ethics are characterized by a strong variability; (3) rules for access, with sufficient incentives for collectors; (4) central database application containing innovations on search and selection procedures; (5) support when needed with histology images; and (6) Internet access to search and upload, with in addition a solid website giving proper information on the procedures, intentions and activities not only to the scientific community, but also to the general public. One consortium decision, part of the incentives for collectors, had major impact on the infrastructure; custodianship over the tissues as well as the tissues stay with the collector institute. Resulting in specimens that are not given to an organization, taking decisions on participation of requests, but instead the local collected tissues stay very easy to access by the collector and allows autonomous negotiation between collector and requestor on cooperation, coauthorship in publication or compensation in costs. Thereby, improving availability of large amounts of high quality samples of a highly specified or rare tumor types and contact opportunities for cooperation with other institutes.

Virtual microscopy in virtual tumor banking.

Many systems have already been designed and successfully used for sharing histology images over large distances, without transfer of the original glass slides. Rapid evolution was seen when digital images could be transferred over the Internet. Nowadays, sophisticated virtual microscope systems can be acquired, with the capability to quickly scan large batches of glass slides at high magnification and compress and store the large images on disc, which subsequently can be consulted through the Internet. The images are stored on an image server, which can give simple, easy to transfer pictures to the user specifying a certain magnification on any position in the scan. This offers new opportunities in histology review, overcoming the necessity of the dynamic telepathology systems to have compatible software systems and microscopes and in addition, an adequate connection of sufficient bandwidth. Consulting the images now only requires an Internet connection and a computer with a high quality monitor. A system of complete pathology review supporting biorepositories is described, based on the implementation of this technique in the European Human Frozen Tumor Tissue Bank (TuBaFrost).

TuBaFrost 3: regulatory and ethical issues on the exchange of residual tissue for research across Europe.

The regulatory regimes for research with residual tissue and accompanying data differ widely between countries in the European Union (EU): from specific consent to opt-out or even no consent at all. This could greatly hamper research where the exchange of tissue and accompanying data has become the gold standard, like in TubaFrost. Instead of adhering to international guidelines, which have a democratic deficit, or an attempt for a new set of possible harmonising rules, TubaFrost chose to create a coordinating rule: if tissue may legitimately be used for a certain kind of research in the country where it was taken and under whose jurisdiction the patient falls, it may also be used for such research in the country where it is sent to in the context of a scientific program even if in that other country other regulations would apply for research with residual tissue taken from patients under their jurisdiction. This coordinating rule has a sound basis in EU law in general and will solve the problems related to diverging national regulatory regimes in the case of cross national research with residual tissue.

TuBaFrost 5: multifunctional central database application for a European tumor bank.

Developing a tissue bank database has become more than just logically arranging data in tables combined with a search engine. Current demand for high quality samples and data, and the ever-changing legal and ethical regulations mean that the application must reflect TuBaFrost rules and protocols for the collection, exchange and use of tissue. To ensure continuation and extension of the TuBaFrost European tissue bank, the custodianship of the samples, and hence the decision over whether to issue samples to requestors, remains with the local collecting centre. The database application described in this article has been developed to facilitate this open structure virtual tissue bank model serving a large group. It encompasses many key tasks, without the requirement for personnel, hence minimising operational costs. The Internet-accessible database application enables search, selection and request submission for requestors, whereas collectors can upload and edit their collection. Communication between requestor and involved collectors is started with automatically generated e-mails.

TuBaFrost 6: virtual microscopy in virtual tumour banking.

Many systems have already been designed and successfully used for sharing histology images over large distances, without transfer of the original glass slides. Rapid evolution was seen when digital images could be transferred over the Internet. Nowadays, sophisticated Virtual Microscope systems can be acquired, with the capability to quickly scan large batches of glass slides at high magnification and compress and store the large images on disc, which subsequently can be consulted through the Internet. The images are stored on an image server, which can give simple, easy to transfer pictures to the user specifying a certain magnification on any position in the scan. This offers new opportunities in histology review, overcoming the necessity of the dynamic telepathology systems to have compatible software systems and microscopes and in addition, an adequate connection of sufficient bandwidth. Consulting the images now only requires an Internet connection and a computer with a high quality monitor. A system of complete pathology review supporting bio-repositories is described, based on the implementation of this technique in the European Human Frozen Tumor Tissue Bank (TuBaFrost).

TuBaFrost 1: Uniting local frozen tumour banks into a European network: an overview.

TuBaFrost is the consortium responsible for the creation of a virtual European human frozen tumour tissue bank: a collection of high quality frozen residual, accurately classified tumour tissue samples, which are stored in European cancer centres and universities. This virtual tissue bank, searchable on the internet, has rules for access and use, and a code of conduct to comply with the various legal and ethical regulations in European countries. The easy accessibility and the European scale of the bank will result in the availability of a large number of samples even of rarer tumour types. Standardisation of collection, storage and quality control throughout the network is achieved minimising inter-institutional variability. A website providing access to upload, search and request samples is a key tool of the tissue bank. The search engine makes use of virtual microscopy. An overview of the development of the European virtual frozen tissue bank infrastructure is described in this paper. The various key aspects are described in more detail in a series of articles to appear in this Journal.

TuBaFrost 2: Standardising tissue collection and quality control procedures for a European virtual frozen tissue bank network.

Tumour Bank Networking presents a great challenge for oncological research as in order to carry out large-scale, multi-centre studies with minimal intrinsic bias, each tumour bank in the network must have some fundamental similarities and be using the same standardised and validated procedures. The European Human Frozen Tumour Tissue Bank (TuBaFrost) has responded to this need by the promotion of an integrated platform of tumour banks in Europe. The operational framework for TuBaFrost has drawn upon the best practice of standard workflows and operating procedures employed by members of the TuBaFrost project and key initiatives worldwide.

TuBaFrost 4: access rules and incentives for a European tumour bank.

When designing infrastructure for a networked virtual tumour bank (samples remain at the collector institutes and sample data are collected in a searchable central database), it is apparent that this can only function properly after developing an adequate set of rules for use and access. These rules must include sufficient incentives for the tissue sample collectors to remain active within the network and maintain sufficient sample levels in the local bank. These requirements resulted in a key TuBaFrost rule, stating that the custodianship of the samples remains under the authority of the local collector. As a consequence, the samples and the decision to issue the samples to a requestor are not transferred to a large organisation but instead remain with the collector, thus allowing autonomous negotiation between collector and requestor, potential co-authorship in publications or compensation for collection and processing costs. Furthermore, it realises a streamlined cost effective network, ensuring tissue visibility and accessibility thereby improving the availability of large amounts of samples of highly specific or rare tumour types as well as providing contact opportunities for collaboration between scientists with cutting edge technology and tissue collectors. With this general purpose in mind, the rules and responsibilities for collectors, requestors and central office were generated.

Update in methodology and conduct of cancer clinical trials.

Many interesting changes are regularly brought into the methodology of cancer clinical trials. This position paper focuses on three topics which are felt to appear as recurrent problems which deserve more attention from the scientific community. RECIST guidelines were published five years ago and have since then been largely implemented and used in clinical trials. Although the criteria were initially designed for screening phase II trials they have been used also in most phase III studies aiming at determining the efficacy of new treatments. Problems have been identified some of which require further clarifications and others deserve further research which is being undertaken. Overall RECIST is well accepted and a revised version is being considered for 2007. Interim analysis is also an important issue revealed recently through many large adjuvant or advanced trials being prematurely discontinued at the time of an interim analysis. In most instances trials were stopped because of evidence of superiority of the investigational treatment over the standard treatment. Premature discontinuation of trial poses a number of challenges addressed in this paper. Finally, the consequences of the implementation of the EU clinical trial directive are being discussed. The conclusions are without equivoque. There is much less academic research conducted in Europe, there is a lot of discrepancy and inconsistency in the implementation of the directive across member states and there is no apparent direct benefit for the patients.

RECIST revisited: a review of validation studies on tumour assessment.

The response evaluation criteria in solid tumours (RECIST) was developed in the late 1990s to replace the WHO criteria for response evaluation. The new criteria included important changes such as unidimensional tumour measurement, selection of target lesions with a minimum size, details concerning imaging modalities and a new threshold for assignment of objective progression. RECIST was published in February 2000 and very quickly came into operation first in clinical trials performed under the auspices of EORTC, US NCI or NCI Canada Clinical Trials Group but was adopted quickly thereafter by the entire cancer clinical research community. As several key features of RECIST were based on analysis of retrospective clinical data, it was felt important to carefully monitor the implementation of the guidelines and stimulate prospective validation studies. This paper reviews the literature that has been published on RECIST from 2000 up to November 2005. In total 60 papers and ASCO, abstracts directly refer to research studies or reviews related to RECIST and its implementation. Amongst the 60 references identified for this review, 11 papers refer to validation studies (seven prospective and four retrospective), six papers refer to the comparison of unidimensional measurements versus bi or tri-dimensional measurements, 12 papers address issues raised with the implementation of RECIST in Mesothelioma and Gastro-Intestinal Stromal Tumours and four papers report on an adaptation of RECIST for specific tumour types. In general, RECIST has been well received by the scientific community and most validation studies fully support the implementation of the new criteria. As expected, however, some issues have been identified. In keeping with the mathematical differences in definition of progression, RECIST delays the identification of progression as compared to WHO criteria in some instances. RECIST criteria are not easily applicable in some types of trials such as those in paediatric tumours and in mesothelioma. Furthermore, anatomical changes in the tumour as described by RECIST may be detected later than functional changes in some circumstances, as for example in Gastro-Intestinal Stromal Tumours treated with Imatinib. However, there is no other universal method of tumour assessment as yet and functional imaging methods have not been validated and will not be widely available for some time. The findings of this review, together with experience acquired thus far and the results of some ongoing research projects, have paved the way for RECIST 2.0 to be hopefully announced later this year.

Clinical trials design and treatment tailoring: general principles applied to breast cancer research.

Nowadays tailored therapy tends to replace standard cancer treatment approaches. Tailoring treatment is possible thanks to clinical trials results that identified subgroups of patients benefiting most from some treatments. Treatment can be tailored on the basis of specific clinical characteristics of the population or on the basis of predictive or prognostic markers. Finally treatment can be tailored for specific molecular targets. This evolution in cancer treatment has triggered the development of innovative trial designs to validate these new hypotheses. The real challenge of the next coming years resides in recruiting large number of patients from specific subgroups to validate tailored therapies.

Health related quality of life outcomes in cancer clinical trials.

Over the last decade, health related quality of life (HRQOL) investigations have become an increasingly important part of many cancer clinical trial research programs. This paper presents a review of all HRQOL studies published by the European Organisation for Research and Treatment of Cancer (EORTC), one of the largest clinical trials organisations in Europe. The findings highlight 24 clinical trials that have been published to date, enrolling over 9000 patients. HRQOL is fully integrated into EORTC phase III trials. In many trials, HRQOL provides a valuable source of additional information useful to both clinician and patient when making treatment decisions. Furthermore, several trials have found that the combined use of clinical information along with HRQOL data has led to the development of new standards of care in several different cancer sites. With more than 40 ongoing HRQOL studies in the EORTC, we expect HRQOL to play an even greater role over the coming decade in helping establish the optimal treatment and care approach for cancer patients.

RECIST vs. WHO: prospective comparison of response criteria in an EORTC phase II clinical trial investigating ET-743 in advanced soft tissue sarcoma.

The present study was set up just after the publication of the response evaluation criteria in solid tumors (RECIST) as a prospective validation exercise in soft tissue sarcoma. Forty-nine patients were entered into a phase II clinical trial aiming at determining the activity and safety of ET-743 (Ecteinascidin) in second line advanced soft tissue sarcoma. Response to treatment and progression were monitored following the WHO criteria and RECIST. Discordances between WHO and RECIST criteria for the best response were reported for two cases: one no-change (WHO) reported as partial response (RECIST) and one progression (WHO) reported as no-change (RECIST). In terms of date of progression, 3 patients progressed on WHO criteria while they were still stable with RECIST. Overall the results of the study would not have changed if RECIST had been used instead of WHO criteria. In conclusion, response criteria as defined by RECIST are adequate to measure response and progression in non-GIST soft tissue sarcoma and can be used instead of the modified WHO criteria.