Phase I trials as valid therapeutic options for patients with cancer

Adashek, Jacob J.; LoRusso, Patricia; Hong, David S.; Kurzrock, Razelle

doi:10.1038/s41571-019-0262-9

Cited by 89 publications

(74 citation statements)

References 69 publications

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“…The primary aims of ECMTs are to identify treatment-related toxicities and determine the recommended drug dose [ 47 ]. These trials are increasingly complex [ 48 ], intensive, with risks of toxicity for patients, but there is a growing recognition that they are a valid therapeutic option [ 49 ].…”

Section: The Importance Of Supportive Care In Experimental Cancer Medmentioning

confidence: 99%

Supportive Care: An Indispensable Component of Modern Oncology

et al. 2020

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The advent of new cancer therapies, alongside expected growth and ageing of the population, better survival rates and associated costs of care, is uncovering a need to more clearly define and integrate supportive care services across the whole spectrum of the disease. The current focus of cancer care is on initial diagnosis and treatment, and end of life care. The Multinational Association of Supportive Care in Cancer defines supportive care as ‘the prevention and management of the adverse effects of cancer and its treatment’. This encompasses the entire cancer journey, and necessitates involvement and integration of most clinical specialties. Optimal supportive care can assist in accurate diagnosis and management, and ultimately improve outcomes. A national strategy to implement supportive care is needed to acknowledge evolving oncology practice, changing disease patterns and the changing patient demographic.

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Section: The Importance Of Supportive Care In Experimental Cancer Medmentioning

confidence: 99%

Supportive Care: An Indispensable Component of Modern Oncology

et al. 2020

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“…Phase I clinical trials allow to translate findings from preclinical research into clinical practice [1]. Although they have been historically considered as “toxicity trials” with no therapeutic intent, the deeper understanding of the molecular and immune bases of cancer and the increasing availability of molecular targeted and immunotherapy agents allow us to refine patient selection and to unveil rapidly the potential efficacy of the drugs [2]. This is also demonstrated by the increased number of phase I trials that incorporate phase II extension cohorts to investigate efficacy [3].…”

Section: Introductionmentioning

confidence: 99%

Pretreatment Blood Parameters Predict Efficacy from Immunotherapy Agents in Early Phase Clinical Trials

et al. 2020

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Background Peripheral blood parameters are correlated to immune‐checkpoint inhibitor efficacy in solid tumors, such as melanoma and non‐small cell lung cancer. Few data are currently available on the prognostic role of these immune‐inflammatory biomarkers for other solid tumors and immunotherapy combinations. Material and Methods From August 2014 to May 2019, 153 patients with metastatic solid tumors were enrolled in phase I clinical trials testing immunotherapy both as single agents and as combinations. Primary endpoint was to evaluate the impact of baseline blood parameters on progression‐free survival (PFS) and overall survival (OS). Results The most common tumor types were gastrointestinal, breast, and gynecological cancers (22.9%, 22.2%, and 15.0%, respectively). Higher lactate dehydrogenase (LDH) and derived neutrophil‐to‐lymphocyte ratio (dNLR) were independently associated with reduced PFS (hazard ratio [HR], 1.97; 95% confidence interval [CI], 1.30–2.99; p = .001, and HR, 2.29; 95% CI, 1.39–3.77; p = .001, respectively) and reduced OS (HR, 2.04; 95% CI, 1.26–3.28; p = .004, and HR, 2.06; 95% CI, 1.12–3.79; p = .02, respectively). In the subgroup analysis, (single agent vs. combination), patients at “good” (dNLR <3 and LDH < upper limit of normal [ULN]) and “intermediate and poor” (dNLR >3 and/or LDH > ULN) risk had higher and lower PFS, respectively (p for interaction = .002). Conversely, patients receiving monotherapy presented statistically significant difference in OS according to the risk group, whereas this effect was not observed for those treated with combinations (p for interaction = .004). Conclusion Elevated LDH and dNLR are associated with poorer survival outcomes in patients treated with immunotherapy in phase I clinical trials, regardless of tumor type. These parameters represent an easy tool that might be considered as stratification factors in immunotherapy‐based clinical trials. Implications for Practice In this retrospective cohort study of 153 patients with metastatic solid tumors treated with immunotherapy in the context of phase I clinical trials, elevated baseline lactate dehydrogenase and derived neutrophil‐to‐lymphocyte ratio were associated with reduced survival regardless of tumor subtype. If prospectively validated, these parameters might represent low‐cost and easy biomarkers that could help patient selection for early phase immunotherapy trials and be applied as a stratification factor in randomized studies testing immunotherapy agents.

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“…As a result, most antivenom dosing is based on animal models that are known to extrapolate poorly to humans [30]. As for the development of many novel oncology therapies, due to the high risk of adverse reactions related to antivenom and lack of alternative therapeutic options, conventional phase 1 clinical trials in healthy volunteers to establish safety are considered unethical [34]. The unknown rate of toxicity and possibly narrow therapeutic window further underlines the need for well designed dose-finding trials with well defined efficacy and toxicity endpoints.…”

Section: Discussionmentioning

confidence: 99%

A Bayesian phase 2 model based adaptive design to optimise antivenom dosing: application to a dose-finding trial for a novel Russell’s viper antivenom in Myanmar

Watson

Lamb

Holmes

et al. 2020

Preprint

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For most antivenoms there is little information from clinical studies to infer the relationship between dose and efficacy or dose and toxicity. Antivenom dose-finding studies usually recruit too few patients (e.g. less than 20) relative to clinically significant event rates (e.g. 5%). Model based adaptive dose-finding studies make efficient use of accrued patient data by using information across dosing levels, and converge rapidly to the contextually defined 'optimal dose'. Adequate sample sizes for adaptive dose-finding trials can be determined by simulation studies.We propose a model based, Bayesian phase 2 type, adaptive clinical trial design for the characterisation of optimal initial antivenom doses in contexts where both efficacy and toxicity are measured as binary endpoints. This design is illustrated in the context of dose-finding for Daboia siamensis (Eastern Russell's viper) envenoming in Myanmar. The design formalises the optimal initial dose of antivenom as the dose closest to that giving a pre-specified desired efficacy, but resulting in less than a pre-specified maximum toxicity. For Russell's viper efficacy is defined as the restoration of blood coagulability within six hours, and toxicity is defined as anaphylaxis. Comprehensive simulation studies compared the expected behaviour of the model based design to a simpler rule based design (a modified '3+3' design). The model based design can identify the optimal dose after fewer patients than the rule based design. Open source code for the simulations can be used to calculate sample sizes under a priori beliefs of efficacy and toxicity.Antivenom dose-finding trials would benefit from using standard model based adaptive designs. Dose-finding trials where rare events (e.g. 5% occurrence) are of clinical importance necessitate larger sample sizes than current practice. We will apply the model based design to determine a safe and efficacious dose for a novel lyophilised antivenom to treat Daboia siamensis envenoming in Myanmar.February 1, 2020 1/21Snakebite envenoming is one of the most neglected tropical diseases relative to its mortality and morbidity. Antivenoms are the only known effective treatment for snake-bite envenoming but are frequently responsible for high rates of adverse reactions. Clinical development of antivenoms rarely follows the iterative phases of clinical development applied to other drugs. Dosing is typically based on pre-clinical testing.Here we propose a Bayesian model based adaptive design for clinical trials aiming to determine the optimal dose of antivenom needed. Optimality is defined using safety and efficacy thresholds contextual to the study. This design can be applied to all antivenoms which have binary efficacy and toxicity endpoints. Our design formally specifies a desired efficacy and a maximum tolerated toxicity. We use simulation studies to characterise the sample size necessary to determine the optimal dose in different scenarios. The simulation studies highlight the advantages of a model based design over simpler ru...

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Phase I trials as valid therapeutic options for patients with cancer

Cited by 89 publications

References 69 publications

Supportive Care: An Indispensable Component of Modern Oncology

Supportive Care: An Indispensable Component of Modern Oncology

Pretreatment Blood Parameters Predict Efficacy from Immunotherapy Agents in Early Phase Clinical Trials

A Bayesian phase 2 model based adaptive design to optimise antivenom dosing: application to a dose-finding trial for a novel Russell’s viper antivenom in Myanmar

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