CWL: A conditional weighted likelihood method to account for the delayed joint toxicity–efficacy outcomes for phase I/II clinical trials

2020 ◽  
pp. 096228022097932
Author(s):  
Yifei Zhang ◽  
Yong Zang
Keyword(s):  
Clinical Trials ◽  
Phase I ◽  
Joint Probability ◽  
Dose Finding ◽  
Likelihood Method ◽  
Joint Toxicity ◽  
Weighted Likelihood ◽  
Operating Characteristics ◽  
Model Assumption

The delayed outcome issue is common in early phase dose-finding clinical trials. This problem becomes more intractable in phase I/II clinical trials because both toxicity and efficacy responses are subject to the delayed outcome issue. The existing methods applying for the phase I trials cannot be used directly for the phase I/II trial due to a lack of capability to model the joint toxicity–efficacy distribution. In this paper, we propose a conditional weighted likelihood (CWL) method to circumvent this issue. The key idea of the CWL method is to decompose the joint probability into the product of marginal and conditional probabilities and then weight each probability based on each patient’s actual follow-up time. The CWL method makes no parametric model assumption on either the dose–response curve or the toxicity–efficacy correlation and therefore can be applied to any existing phase I/II trial design. Numerical trial applications show that the proposed CWL method yields desirable operating characteristics.

Probability-of-decision interval 3+3 (POD-i3+3) design for phase I dose finding trials with late-onset toxicity

2021 ◽  
pp. 096228022110527
Author(s):  
Zichun Xu ◽  
Xiaolei Lin
Keyword(s):  
Phase I ◽  
Late Onset ◽  
Dose Finding ◽  
Operating Characteristics ◽  
Trial Duration ◽  
Probability Interval ◽  
Optimal Interval ◽  
Patient Resources ◽  
Safety And Reliability

Late-onset toxicities often occur in phase I trials investigating novel immunotherapy and molecular targeted therapies. For trials with cohort based designs (such as modified toxicity probability interval, Bayesian optimal interval, and i3+3), patients are often turned away since the current cohort are still being followed without definite dose-limiting toxicities, which results in prolonged trial duration and waste of patient resources. In this paper, we incorporate a probability-of-decision framework into the i3+3 design and allow real-time dosing inference when the next patient becomes available. Both follow-up time for the pending patients and time to dose-limiting toxicities for the observed patients are used in calculating the posterior probability of each possible dosing decision. An intensive simulation study is conducted to evaluate the operating characteristics of the newly proposed probability-of-decision-i3+3 design under various dosing scenarios and patient accrual settings. Results show that the probability-of-decision-i3+3 design achieves comparable safety and reliability performances but much shorter trial duration compared to the complete designs.

scholarly journals Phase I/II dose-finding design for molecularly targeted agent: Plateau determination using adaptive randomization

2016 ◽  
Vol 27 (2) ◽  
pp. 466-479 ◽  
Author(s):  
Marie-Karelle Riviere ◽  
Ying Yuan ◽  
Jacques-Henri Jourdan ◽  
Frédéric Dubois ◽  
Sarah Zohar
Keyword(s):  
Phase I ◽  
Late Onset ◽  
Optimal Dose ◽  
Maximum Tolerated Dose ◽  
Dose Finding ◽  
Targeted Agents ◽  
Weighted Likelihood ◽  
Operating Characteristics ◽  
Phase I Clinical Trials ◽  
Molecularly Targeted Agents

Conventionally, phase I dose-finding trials aim to determine the maximum tolerated dose of a new drug under the assumption that both toxicity and efficacy monotonically increase with the dose. This paradigm, however, is not suitable for some molecularly targeted agents, such as monoclonal antibodies, for which efficacy often increases initially with the dose and then plateaus. For molecularly targeted agents, the goal is to find the optimal dose, defined as the lowest safe dose that achieves the highest efficacy. We develop a Bayesian phase I/II dose-finding design to find the optimal dose. We employ a logistic model with a plateau parameter to capture the increasing-then-plateau feature of the dose–efficacy relationship. We take the weighted likelihood approach to accommodate for the case where efficacy is possibly late-onset. Based on observed data, we continuously update the posterior estimates of toxicity and efficacy probabilities and adaptively assign patients to the optimal dose. The simulation studies show that the proposed design has good operating characteristics. This method is going to be applied in more than two phase I clinical trials as no other method is available for this specific setting. We also provide an R package dfmta that can be downloaded from CRAN website.

scholarly journals Unconventional Anticancer Agents: A Systematic Review of Clinical Trials

2006 ◽  
Vol 24 (1) ◽  
pp. 136-140 ◽  
Author(s):  
Andrew J. Vickers ◽  
Joyce Kuo ◽  
Barrie R. Cassileth
Keyword(s):  
Clinical Trials ◽  
Phase I ◽  
Cancer Patients ◽  
Phase Ii ◽  
Dose Finding ◽  
Phase Iii ◽  
High Dose ◽  
Free Text ◽  
Phase Ii Trials ◽  
Off Label

Purpose A substantial number of cancer patients turn to treatments other than those recommended by mainstream oncologists in an effort to sustain tumor remission or halt the spread of cancer. These unconventional approaches include botanicals, high-dose nutritional supplementation, off-label pharmaceuticals, and animal products. The objective of this study was to review systematically the methodologies applied in clinical trials of unconventional treatments specifically for cancer. Methods MEDLINE 1966 to 2005 was searched using approximately 200 different medical subject heading terms (eg, alternative medicine) and free text words (eg, laetrile). We sought prospective clinical trials of unconventional treatments in cancer patients, excluding studies with only symptom control or nonclinical (eg, immune) end points. Trial data were extracted by two reviewers using a standardized protocol. Results We identified 14,735 articles, of which 214, describing 198 different clinical trials, were included. Twenty trials were phase I, three were phase I and II, 70 were phase II, and 105 were phase III. Approximately half of the trials investigated fungal products, 20% investigated other botanicals, 10% investigated vitamins and supplements, and 10% investigated off-label pharmaceuticals. Only eight of the phase I trials were dose-finding trials, and a mere 20% of phase II trials reported a statistical design. Of the 27 different agents tested in phase III, only one agent had a prior dose-finding trial, and only for three agents was the definitive study initiated after the publication of phase II data. Conclusion Unconventional cancer treatments have not been subject to appropriate early-phase trial development. Future research on unconventional therapies should involve dose-finding and phase II studies to determine the suitability of definitive trials.

Sequential or combined designs for Phase I/II clinical trials? A simulation study

2019 ◽  
Vol 16 (6) ◽  
pp. 635-644 ◽  
Author(s):  
Caroline Rossoni ◽  
Aurélie Bardet ◽  
Birgit Geoerger ◽  
Xavier Paoletti
Keyword(s):  
Clinical Trials ◽  
Phase I ◽  
Phase Ii ◽  
Dose Escalation ◽  
Therapeutic Index ◽  
Maximum Tolerated Dose ◽  
Correct Decision ◽  
Operating Characteristics ◽  
In Series ◽  
Expansion Cohort

Background: Phase I and Phase II clinical trials aim at identifying a dose that is safe and active. Both phases are increasingly combined. For Phase I/II trials, two main types of designs are debated: a dose-escalation stage to select the maximum tolerated dose, followed by an expansion cohort to investigate its activity (dose-escalation followed by an expansion cohort), or a joint modelling to identify the best trade-off between toxicity and activity (efficacy–toxicity). We explore this question in the context of a paediatric Phase I/II platform trial. Methods: In series of simulations, we assessed the operating characteristics of dose-escalation followed by an expansion cohort (DE-EC) designs without and with reassessment of the maximum tolerated dose during the expansion cohort (DE-ECext) and of the efficacy–toxicity (EffTox) design. We investigated the probability to identify an active and tolerable agent, that is, the percentage of correct decision, for various dose-toxicity activity scenarios. Results: For a large therapeutic index, the percentage of correct decision reached 96.0% for efficacy–toxicity versus 76.1% for dose-escalation followed by an expansion cohort versus 79.6% for DE-ECext. Conversely, when all doses were deemed not active, the percentage of correct decision was 47% versus 55.9% versus 69.2%, respectively, for efficacy–toxicity, dose-escalation followed by an expansion cohort and DE-ECext. Finally, in the case of a narrow therapeutic index, the percentage of correct decision was 48.0% versus 64.3% versus 67.2%, respectively, efficacy–toxicity, dose-escalation followed by an expansion cohort and DE-ECext. Conclusion: As narrow indexes are common in oncology, according to the present results, the sequential dose-escalation followed by an expansion cohort is recommended. The importance to re-estimate the maximum tolerated dose during the expansion cohort is confirmed. However, despite their theoretical advantages, Phase I/II designs are challenged by the variations in populations between the Phase I and the Phase II parts and by the lagtime in the evaluation of toxicity and activity.

Informed consent in phase I clinical trials: Implications for trends in design.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e14077-e14077
Author(s):  
Paul Henry Frankel ◽  
Susan G. Groshen
Keyword(s):  
Clinical Trials ◽  
Informed Consent ◽  
Phase I ◽  
Dose Finding ◽  
Institutional Review Boards ◽  
Severe Toxicity ◽  
Phase I Clinical Trials ◽  
Traditional Use ◽  
Phase I Studies ◽  
Definition Of

e14077 Background: Informed Consent (IC) is a critical aspect of human subjects protection. Institutional Review Boards are tasked with insuring proper IC as one aspect of protecting participants in clinical trials. Phase I trials in oncology present special issues with IC, as often neither the risks nor the benefits are well-known. This has resulted in carefully worded IC templates for Phase I studies based on the traditional use of dose-finding designs that are geared towards finding the “Maximum Tolerated Dose (MTD)”. As the definition of this term varies by study, the implication for patient risk and informed consent are rarely discussed. Methods: We reviewed Phase I designs to present options for improving the informed consent process for Phase I oncology trials. Results: Phase I studies have seen an increase in designs based on work from the early 1990s seeking a dose that results in a targeted percent of patients experiencing a “Dose Limiting Toxicity (DLT)” to define the MTD. The most common definition of a DLT is a treatment-related toxicity that results in a particularly concerning severe toxicity (grade 3 or higher) in the first cycle of therapy and the most common rate targeted (in designs that define toxicity as a goal) is 25%. In that setting, while lower doses may have a lower likelihood of DLT, higher doses or the expansion cohort are likely to have a 25% chance of DLT if the target is pursued. This information is rarely quantitatively communicated in the informed consent. Conclusions: IRBs and investigators should consider communicating through informed consent the quantitative summary of goals of the study and related risk. For example, transparency suggests conveying when the goal (target) of the study is to find the dose where there is a one in four chance of experiencing a severe adverse event in the first cycle.

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