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412a Combined modality treatment: challenges in phase II trial design
$186 Wednesday, October 27, 2004
Y o u n g scientists p r o g r a m m e Phase II combined modality clinical trial design: realising the potential 412a Combined modality treatment: challenges in phase II trial design
R. Popescu FMH Onkologie-H~matologie, Onkologie Zentrum, Hirslanden Klinik Aarau, Switzerland Young researcher's opportunies to be actively involved in design and conduct of large scale phase III trials is mostly limited. Early clinical trials, preferably with translational research components are however essential in establishment of concepts and identification of promising avenues - at a time of competing resources and novel substances/radiation techniques, writing a good phase II clinical trial is a worthy challenge. This session aims to highlight some characteristics of good early trial design and should hopefully stimulate discussion and research. 412 The challenge of design of phase II trials of combined modality therapy
S. Errid.qe University of Edinburgh, Edinburgh Cancer Centre, Edinburgh, United Kingdom The trial design of Phase II studies of chemo-radiation presents a particular challenge. Unlike a phase II study for systemic therapy where primarily tumour response is being assessed, the question in these studies is; 'does the combination under investigation have a potential incremental benefit over existing published regimes and hence is it worthwhile taking forward to a Phase III study?' The efficacy is not only measured as improved tumour shrinkage, local control, progression free or overall survival, but also an assessment of toxicity. The trial should be of sufficient size not only to identify a potential clinically relevant improvement in outcome, but also must be large enough to ensure that this is not at the cost of unacceptable toxicity. There is an increasing trend to use randomised Phase II studies. The aim of these is to establish which of two or more combinations should be selected for comparison with the existing standard treatment in a Phase III randomised controlled trial. However, they are frequently, especially if positive, misinterpreted and change management; in order to ensure lack of bias only studies which are randomised against existing standards of care, should used to influence treatment choice. Whatever trial design is used, it is important that if the combination under investigation is to be applicable to the wider population, the scheduling, mode of delivery, monitoring and toxicity are acceptable to the patient, health-care providers and the health-care delivery service. 413 Predictive markers
E. Deutsch Institut Gustave Roussy, Laboratoire radiosensibilit6 radiocarcinog6n#se, Villejuif, France The therapeutic ratio of radiation therapy (RTE) is relying on differences between tumor control and normal tissue
complication probabilities at a given dose. Despite extensive studies there are no clear candidates to predict tumor response to RTE, clinical and conventional histological parameters fail to predict radiation sensitivity. There is also lack of clear evidence of a predictive factor for normal tissue tolerance to RTE. Several markers of tumor response have been studied, among them tumor hypoxia, cell kinetics and intrinsic radio-sensitivity have been proposed as predictive assays. The recent increase in the knowledge about molecular mechanisms of cancerrelated pathways has prompted studies that attempt to identify molecular markers. These markers of interest include those associated with "intrinsic" tumor radiosensitivity: apoptosis (p53, Bcl-2, Bax), cell cycle arrest (p21, p16, cyclin D1), signal transduction (EGFR, Her-2neu) and cyclo oxygenase-2. Recently markers associated with "extrinsic" tumor radiosensitivity have also been studied: angiogenesis (vascular endothelial growth factor) and invasiveness (Metalo proteinases). The individual normal tissue cellular radiosensitivity appears to be the dose limiting factor in clinical radiotherapy because it determines the tolerance of surrounding normal tissues. Identification of individual cellular radiosensitivity would allow individualisation of prescribed doses in order to optimise the therapeutic ratio. Morbidity could be n:educed in radiosensitive patients by decreasing the RT dose, and dose escalation could be performed in radio resistant patients in radioresistant patients which could lead to an increase in tumor control rates. Pre clinical results strongly suggest that new biological parameters identified recently could be targeted for therapy and used to improve the response to ionising radiation. Regarding the amount of recent promising in vivo results, the need for information about these mechanisms from clinical studies is becoming more pressing with the recent ongoing development of drugs that targets some of these markers and pathways with could be used in order to modify tumor response to RTE. Despite extensive study and a vast array of tumor biomarkers established so far in some specific tumor types, none of them has been shown to have general predictive value across all tumor subtypes. Although there are some candidate markers that predict tumor or individuals radiation sensitivity, there are equivocal data for a limited number of set of tumor types. Testing some of these markers in larges Clinical studies would therefore be required before definitively integrating these parameters into routine clinical practice. 414 Towards valid markers of response: the case of PET
O.S. Hoekstra Vrije Universiteit Amsterdam, Amsterdam, The Netherlands PET is the most selective and sensitive (picomolar range) tomographic method for measuring molecular pathways and interactions in vivo. It offers pharmacodynamic and -kinetic data which can help to understand the mechanism of action of therapy, to improve the efficacy of early clinical trials and to improve patient management. Expertise in sophisticated pharmacokinetic PET is restricted to a few centres, and most PET literature concerns the use of 18FDG. Conceptually, this is not the ideal tumour tracer, but it effectively capitalizes that cancer has higher glucose metabolism than most tissues. Obviously, when evaluating the validity of a new test as biomarker of response, changes of tracer signal over time should be associated with relevant clinical outcome measures. There is ample 'proof of principle' that FDG PET performs better than volumetric (CT) measurements: change of FDG uptake indeed reflects responsiveness to therapy, and
Y o u n g scientists p r o g r a m m e Phase II combined modality clinical trial design: realising the potential 412a Combined modality treatment: challenges in phase II trial design
R. Popescu FMH Onkologie-H~matologie, Onkologie Zentrum, Hirslanden Klinik Aarau, Switzerland Young researcher's opportunies to be actively involved in design and conduct of large scale phase III trials is mostly limited. Early clinical trials, preferably with translational research components are however essential in establishment of concepts and identification of promising avenues - at a time of competing resources and novel substances/radiation techniques, writing a good phase II clinical trial is a worthy challenge. This session aims to highlight some characteristics of good early trial design and should hopefully stimulate discussion and research. 412 The challenge of design of phase II trials of combined modality therapy
S. Errid.qe University of Edinburgh, Edinburgh Cancer Centre, Edinburgh, United Kingdom The trial design of Phase II studies of chemo-radiation presents a particular challenge. Unlike a phase II study for systemic therapy where primarily tumour response is being assessed, the question in these studies is; 'does the combination under investigation have a potential incremental benefit over existing published regimes and hence is it worthwhile taking forward to a Phase III study?' The efficacy is not only measured as improved tumour shrinkage, local control, progression free or overall survival, but also an assessment of toxicity. The trial should be of sufficient size not only to identify a potential clinically relevant improvement in outcome, but also must be large enough to ensure that this is not at the cost of unacceptable toxicity. There is an increasing trend to use randomised Phase II studies. The aim of these is to establish which of two or more combinations should be selected for comparison with the existing standard treatment in a Phase III randomised controlled trial. However, they are frequently, especially if positive, misinterpreted and change management; in order to ensure lack of bias only studies which are randomised against existing standards of care, should used to influence treatment choice. Whatever trial design is used, it is important that if the combination under investigation is to be applicable to the wider population, the scheduling, mode of delivery, monitoring and toxicity are acceptable to the patient, health-care providers and the health-care delivery service. 413 Predictive markers
E. Deutsch Institut Gustave Roussy, Laboratoire radiosensibilit6 radiocarcinog6n#se, Villejuif, France The therapeutic ratio of radiation therapy (RTE) is relying on differences between tumor control and normal tissue
complication probabilities at a given dose. Despite extensive studies there are no clear candidates to predict tumor response to RTE, clinical and conventional histological parameters fail to predict radiation sensitivity. There is also lack of clear evidence of a predictive factor for normal tissue tolerance to RTE. Several markers of tumor response have been studied, among them tumor hypoxia, cell kinetics and intrinsic radio-sensitivity have been proposed as predictive assays. The recent increase in the knowledge about molecular mechanisms of cancerrelated pathways has prompted studies that attempt to identify molecular markers. These markers of interest include those associated with "intrinsic" tumor radiosensitivity: apoptosis (p53, Bcl-2, Bax), cell cycle arrest (p21, p16, cyclin D1), signal transduction (EGFR, Her-2neu) and cyclo oxygenase-2. Recently markers associated with "extrinsic" tumor radiosensitivity have also been studied: angiogenesis (vascular endothelial growth factor) and invasiveness (Metalo proteinases). The individual normal tissue cellular radiosensitivity appears to be the dose limiting factor in clinical radiotherapy because it determines the tolerance of surrounding normal tissues. Identification of individual cellular radiosensitivity would allow individualisation of prescribed doses in order to optimise the therapeutic ratio. Morbidity could be n:educed in radiosensitive patients by decreasing the RT dose, and dose escalation could be performed in radio resistant patients in radioresistant patients which could lead to an increase in tumor control rates. Pre clinical results strongly suggest that new biological parameters identified recently could be targeted for therapy and used to improve the response to ionising radiation. Regarding the amount of recent promising in vivo results, the need for information about these mechanisms from clinical studies is becoming more pressing with the recent ongoing development of drugs that targets some of these markers and pathways with could be used in order to modify tumor response to RTE. Despite extensive study and a vast array of tumor biomarkers established so far in some specific tumor types, none of them has been shown to have general predictive value across all tumor subtypes. Although there are some candidate markers that predict tumor or individuals radiation sensitivity, there are equivocal data for a limited number of set of tumor types. Testing some of these markers in larges Clinical studies would therefore be required before definitively integrating these parameters into routine clinical practice. 414 Towards valid markers of response: the case of PET
O.S. Hoekstra Vrije Universiteit Amsterdam, Amsterdam, The Netherlands PET is the most selective and sensitive (picomolar range) tomographic method for measuring molecular pathways and interactions in vivo. It offers pharmacodynamic and -kinetic data which can help to understand the mechanism of action of therapy, to improve the efficacy of early clinical trials and to improve patient management. Expertise in sophisticated pharmacokinetic PET is restricted to a few centres, and most PET literature concerns the use of 18FDG. Conceptually, this is not the ideal tumour tracer, but it effectively capitalizes that cancer has higher glucose metabolism than most tissues. Obviously, when evaluating the validity of a new test as biomarker of response, changes of tracer signal over time should be associated with relevant clinical outcome measures. There is ample 'proof of principle' that FDG PET performs better than volumetric (CT) measurements: change of FDG uptake indeed reflects responsiveness to therapy, and