TRAFIC: Statistical Plan for a Pragmatic Early Phase 1/2 Bayesian Adaptive Dose Escalation Trial in Rheumatoid Arthritis

Abstract Background: Adaptive model-based dose-finding designs have demonstrated advantages over traditional rule-based designs but have increased statistical complexity resulting in slow uptake especially outside of cancer trials. TRAFIC is a multi-centre, early phase trial in Rheumatoid Arthritis incorporating a model-based design.Methods: A Bayesian adaptive dose-finding phase I trial rolling into a single arm, single stage phase II trial. Model parameters for phase I were chosen via Monte Carlo simulation evaluating objective performance measures under clinically relevant scenarios and incorporated stopping rules for early termination. Potential designs were further calibrated utilising dose transition pathways.Discussion: TRAFIC is an MRC funded trial of a re-purposed treatment demonstrating that it is possible to design, fund and implement a model-based phase I trial in a non-cancer population within conventional research funding tracks and regulatory constraints. The phase I design allows borrowing of information from previous trials; all accumulated data to be utilised in decision-making; verification of operating characteristics through simulation; improved understanding for management and oversight teams through dose transition pathways. The rolling phase II design brings efficiencies in trial conduct including site and monitoring activities, and cost.TRAFIC is the first funded model-based dose-finding trial in inflammatory disease demonstrating that small phase I/II trials can have an underlying statistical basis for decision-making and interpretation.Trial Registration: ISRCTN 36667085

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TRAFIC: statistical design and analysis plan for a pragmatic early phase 1/2 Bayesian adaptive dose escalation trial in rheumatoid arthritis

Trials ◽

10.1186/s13063-021-05384-5 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

M. Cole ◽

C. Yap ◽

C. Buckley ◽

W. F. Ng ◽

I. McInnes ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Decision Making ◽

Phase I ◽

Phase Ii ◽

Early Phase ◽

Phase I Trial ◽

Dose Finding ◽

Model Parameters ◽

Model Based ◽

Transition Pathways

Abstract Background Adaptive model-based dose-finding designs have demonstrated advantages over traditional rule-based designs but have increased statistical complexity but uptake has been slow especially outside of cancer trials. TRAFIC is a multi-centre, early phase trial in rheumatoid arthritis incorporating a model-based design. Methods A Bayesian adaptive dose-finding phase I trial rolling into a single-arm, single-stage phase II trial. Model parameters for phase I were chosen via Monte Carlo simulation evaluating objective performance measures under clinically relevant scenarios and incorporated stopping rules for early termination. Potential designs were further calibrated utilising dose transition pathways. Discussion TRAFIC is an MRC-funded trial of a re-purposed treatment demonstrating that it is possible to design, fund and implement a model-based phase I trial in a non-cancer population within conventional research funding tracks and regulatory constraints. The phase I design allows borrowing of information from previous trials, all accumulated data to be utilised in decision-making, verification of operating characteristics through simulation, improved understanding for management and oversight teams through dose transition pathways. The rolling phase II design brings efficiencies in trial conduct including site and monitoring activities and cost. TRAFIC is the first funded model-based dose-finding trial in inflammatory disease demonstrating that small phase I/II trials can have an underlying statistical basis for decision-making and interpretation. Trial registration Trials Registration: ISRCTN, ISRCTN36667085. Registered on September 26, 2014.

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A Bayesian dose-finding design for outcomes evaluated with uncertainty

Clinical Trials ◽

10.1177/17407745211001521 ◽

2021 ◽

pp. 174077452110015

Author(s):

Matthew J Schipper ◽

Ying Yuan ◽

Jeremy MG Taylor ◽

Randall K Ten Haken ◽

Christina Tsien ◽

...

Keyword(s):

Phase I ◽

Phase I Trial ◽

Data Augmentation ◽

Maximum Tolerated Dose ◽

Dose Finding ◽

Continual Reassessment Method ◽

Number Of Patients ◽

Continual Reassessment ◽

Partially Observed ◽

Dose Limiting Toxicity

Introduction: In some phase I trial settings, there is uncertainty in assessing whether a given patient meets the criteria for dose-limiting toxicity. Methods: We present a design which accommodates dose-limiting toxicity outcomes that are assessed with uncertainty for some patients. Our approach could be utilized in many available phase I trial designs, but we focus on the continual reassessment method due to its popularity. We assume that for some patients, instead of the usual binary dose-limiting toxicity outcome, we observe a physician-assessed probability of dose-limiting toxicity specific to a given patient. Data augmentation is used to estimate the posterior probabilities of dose-limiting toxicity at each dose level based on both the fully observed and partially observed patient outcomes. A simulation study is used to assess the performance of the design relative to using the continual reassessment method on the true dose-limiting toxicity outcomes (available in simulation setting only) and relative to simple thresholding approaches. Results: Among the designs utilizing the partially observed outcomes, our proposed design has the best overall performance in terms of probability of selecting correct maximum tolerated dose and number of patients treated at the maximum tolerated dose. Conclusion: Incorporating uncertainty in dose-limiting toxicity assessment can improve the performance of the continual reassessment method design.

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Multidimensional Phase I Dose Ranging Trials for Stroke Recovery Interventions: Key Challenges and How to Address Them

Neurorehabilitation and Neural Repair ◽

10.1177/15459683211019362 ◽

2021 ◽

pp. 154596832110193

Author(s):

Emily J. Dalton ◽

Leonid Churilov ◽

Natasha A. Lannin ◽

Dale Corbett ◽

Bruce C. V. Campbell ◽

...

Keyword(s):

Decision Support ◽

Phase I ◽

Early Phase ◽

Phase I Trial ◽

Systematic Approach ◽

Decision Support Tool ◽

Maximum Tolerated Dose ◽

Stroke Recovery ◽

Support Tool ◽

Dose Ranging

Despite an increase in the amount of published stroke recovery research, interventions have failed to markedly affect the trajectory of recovery poststroke. We argue that early-phase research to systematically investigate dose is an important contributor to advance the science underpinning stroke recovery. In this article, we aim to ( a) define the problem of insufficient use of a systematic approach to early-phase, multidimensional dose articulation research and ( b) propose a solution that applies this approach to design a multidimensional phase I trial to identify the maximum tolerated dose (MTD). We put forward a design template as a decision support tool to increase knowledge of how to develop a phase I dose-ranging trial for nonpharmaceutical stroke recovery interventions. This solution has the potential to advance the development of efficacious stroke recovery interventions, which include activity-based rehabilitation interventions.

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AB0332 IMMUNOSUPPRESSIVE AND IMMONOMODULATING AGENTS IN RHEUMATOID ARTHRITIS: A SYSTEMATIC REVIEW OF CLINICAL TRIALS AND THEIR CURRENT DEVELOPMENT STAGE

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.1124 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 1464.1-1465

Author(s):

J. Blaess ◽

J. Walther ◽

J. E. Gottenberg ◽

J. Sibilia ◽

L. Arnaud ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Systematic Review ◽

B Cells ◽

Phase I ◽

Phase Ii ◽

Clinical Development ◽

Phase Iii ◽

Jak Inhibitors ◽

Exclusion Criteria ◽

Immunomodulating Drugs

Background:Rheumatoid arthritis (RA) is the most frequent chronic inflammatory diseases with an incidence of 0.5% to 1%. Therapeutic arsenal of RA has continuously expanded in recent years with the recent therapeutic progress with the arrival of conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs), biological (bDMARDs) and targeted synthetic (tsDMARDs), JAK inhibitors. However, there are still some unmet needs for patients who do not achieve remission and who continue to worsen despite treatments. Of note, only approximately 40% of patients are ACR70 responders, in most randomized controlled trials. For these patients, finding new therapeutic avenues is challenging.Objectives:The objective of our study was to analyze the whole pipeline of immunosuppressive and immunomodulating drugs evaluated in RA and describe their mechanisms of action and stage of clinical development.Methods:We conducted a systematic review of all drug therapies in clinical development in RA in 17 databases of international clinical trials. Inclusion criterion: study from one of the databases using the keywords “Rheumatoid arthritis” (search date: June 1, 2019). Exclusion criteria: non-drug trials, trials not related to RA or duplicates. We also excluded dietary regimen or supplementations, cellular therapies, NSAIDs, glucorticoids or their derivatives and non-immunosuppressive or non-immunomodulating drugs. For each csDMARD, bDMARD and tsDMARD, we considered the study at the most advanced stage. For bDMARDs, we did not take into account biosimilars.Results:The research identified 4652 trials, of which 242 for 243 molecules met the inclusion and exclusion criteria. The developed molecules belong to csDMARDs (n=21), bDMARDs (n=117), tsDMARDs (n=105).Among the 21 csDMARDs molecules: 8 (38%) has been withdrawn, 4 (19%) are already labelled in RA (hydroxychloroquine, leflunomide, methotrexate and sulfasalazine) and 9 (43%) are in development: 1 (11%) is in phase I/II, 5 (56%) in phase II, 3 (33%) in phase IV.Among the 117 bDMARDs molecules: 69 (59%) has been withdrawn, 9 (8%) are labeled in RA (abatacept, adalimumab, anakinra, certolizumab, etanercept, golimumab, infliximab, rituximab, sarilumab, tocilizumab) and 39 (33%) are in development: 9 (23%) in phase I, 3 (8%) in phase I/II, 21 (54%) in phase II, 5 (12%) are in phase III, 1 (3%) in phase IV. bDMARDs currently under development target B cells (n=4), T cells (n=2), T/B cells costimulation (n=2),TNF alpha (n=2), Interleukine 1 or his receptor (n=3), Interleukine 6 or his receptor (n=7), Interleukine 17 (n=4), Interleukine 23 (n=1), GM-CSF (n=1), other cytokines or chemokines (n=5), integrins or adhesion proteins (n=3), interferon receptor (n=1) and various other targets (n=4).Among the 105 tsDMARDs molecules: 64 (61%) has been withdrawn, 6 (6%) JAK inhibitors, have just been or will probably soon be labelled (baricitinib, filgotinib, peficitinib, tofacitinib and upadacitinib), 35 (33%) are in development: 8 (24%) in phase I, 26 (74%) in phase II, 1 (3%) in phase III and. tsDMARDs currently under development target tyrosine kinase (n=12), janus kinase (JAK) (n=3), sphingosine phostate (n=3), PI3K pathway (n=1), phosphodiesterase-4 (n=3) B cells signaling pathways (n=3) and various other targets (n=10).Conclusion:A total of 242 therapeutic trials involving 243 molecules have been or are being evaluated in RA. This development does not always lead to new treatments since 141 (58%) have already been withdrawn. Hopefully, some of the currently evaluated drugs will contribute to improve the therapeutic management of RA patients, requiring a greater personalization of therapeutic strategies, both in the choice of molecules and their place in therapeutic sequences.Disclosure of Interests:Julien Blaess: None declared, Julia Walther: None declared, Jacques-Eric Gottenberg Grant/research support from: BMS, Pfizer, Consultant of: BMS, Sanofi-Genzyme, UCB, Speakers bureau: Abbvie, Eli Lilly and Co., Roche, Sanofi-Genzyme, UCB, Jean Sibilia: None declared, Laurent Arnaud: None declared, Renaud FELTEN: None declared

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Intrathecal Mafosfamide: A Preclinical Pharmacology and Phase I Trial

Journal of Clinical Oncology ◽

10.1200/jco.2005.06.053 ◽

2005 ◽

Vol 23 (7) ◽

pp. 1555-1563 ◽

Cited By ~ 47

Author(s):

Susan M. Blaney ◽

Frank M. Balis ◽

Stacey Berg ◽

Carola A.S. Arndt ◽

Richard Heideman ◽

...

Keyword(s):

Phase I ◽

Phase Ii ◽

Phase I Trial ◽

Neoplastic Meningitis ◽

In Vitro Cytotoxicity ◽

Pharmacokinetic Studies ◽

Preclinical Studies ◽

Phase Ii Trials ◽

Cytotoxicity Studies

Purpose Preclinical studies of mafosfamide, a preactivated cyclophosphamide analog, were performed to define a tolerable and potentially active target concentration for intrathecal (IT) administration. A phase I and pharmacokinetic study of IT mafosfamide was performed to determine a dose for subsequent phase II trials. Patients and Methods In vitro cytotoxicity studies were performed in MCF-7, Molt-4, and rhabdomyosarcoma cell lines. Feasibility and pharmacokinetic studies were performed in nonhuman primates. These preclinical studies were followed by a phase I trial in patients with neoplastic meningitis. There were five dose levels ranging from 1 mg to 6.5 mg. Serial CSF samples were obtained for pharmacokinetic studies in a subset of patients with Ommaya reservoirs. Results The cytotoxic target exposure for mafosfamide was 10 μmol/L. Preclinical studies demonstrated that this concentration could be easily achieved in ventricular CSF after intraventricular dosing. In the phase I clinical trial, headache was the dose-limiting toxicity. Headache was ameliorated at 5 mg by prolonging the infusion rate to 20 minutes, but dose-limiting headache occurred at 6.5 mg dose with prolonged infusion. Ventricular CSF mafosfamide concentrations at 5 mg exceeded target cytotoxic concentrations after an intraventricular dose, but lumbar CSF concentrations 2 hours after the dose were less than 10 μmol/L. Therefore, a strategy to alternate dosing between the intralumbar and intraventricular routes was tested. Seven of 30 registrants who were assessable for response had a partial response, and six had stable disease. Conclusion The recommended phase II dose for IT mafosfamide, administered without concomitant analgesia, is 5 mg over 20 minutes.

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Unconventional Anticancer Agents: A Systematic Review of Clinical Trials

Journal of Clinical Oncology ◽

10.1200/jco.2005.03.8406 ◽

2006 ◽

Vol 24 (1) ◽

pp. 136-140 ◽

Cited By ~ 20

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.

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Using an Interaction Parameter in Model-Based Phase I Trials for Combination Treatments? A Simulation Study

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph18010345 ◽

2021 ◽

Vol 18 (1) ◽

pp. 345

Author(s):

Pavel Mozgunov ◽

Rochelle Knight ◽

Helen Barnett ◽

Thomas Jaki

Keyword(s):

Phase I ◽

Interaction Parameter ◽

Simulation Study ◽

Small Sample Size ◽

Small Sample ◽

Dose Finding ◽

Phase I Trials ◽

Model Based ◽

Combination Toxicity ◽

Toxicity Relationship

There is growing interest in Phase I dose-finding studies studying several doses of more than one agent simultaneously. A number of combination dose-finding designs were recently proposed to guide escalation/de-escalation decisions during the trials. The majority of these proposals are model-based: a parametric combination-toxicity relationship is fitted as data accumulates. Various parameter shapes were considered but the unifying theme for many of these is that typically between 4 and 6 parameters are to be estimated. While more parameters allow for more flexible modelling of the combination-toxicity relationship, this is a challenging estimation problem given the typically small sample size in Phase I trials of between 20 and 60 patients. These concerns gave raise to an ongoing debate whether including more parameters into combination-toxicity model leads to more accurate combination selection. In this work, we extensively study two variants of a 4-parameter logistic model with reduced number of parameters to investigate the effect of modelling assumptions. A framework to calibrate the prior distributions for a given parametric model is proposed to allow for fair comparisons. Via a comprehensive simulation study, we have found that the inclusion of the interaction parameter between two compounds does not provide any benefit in terms of the accuracy of selection, on average, but is found to result in fewer patients allocated to the target combination during the trial.

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Phase I Trial of Escalating-Dose Irinotecan Given Weekly With Cisplatin and Concurrent Radiotherapy in Locally Advanced Esophageal Cancer

Journal of Clinical Oncology ◽

10.1200/jco.2003.02.147 ◽

2003 ◽

Vol 21 (15) ◽

pp. 2926-2932 ◽

Cited By ~ 77

Author(s):

David H. Ilson ◽

Manjit Bains ◽

David P. Kelsen ◽

Eileen O’Reilly ◽

Martin Karpeh ◽

...

Keyword(s):

Esophageal Cancer ◽

Phase I ◽

Induction Chemotherapy ◽

Phase Ii ◽

Phase I Trial ◽

Locally Advanced ◽

Phase Iii ◽

Concurrent Radiotherapy ◽

Minimal Toxicity ◽

Grade 3

Purpose: To identify the maximum-tolerated dose and dose-limiting toxicity (DLT) of weekly irinotecan combined with cisplatin and radiation in esophageal cancer. Patients and Methods: Nineteen patients with clinical stage II to III esophageal squamous cell or adenocarcinoma were treated on this phase I trial. Induction chemotherapy with weekly cisplatin 30 mg/m2 and irinotecan 65 mg/m2 was administered for four treatments during weeks 1 to 5. Radiotherapy was delivered weeks 8 to 13 in 1.8-Gy daily fractions to a dose of 50.4 Gy. Cisplatin 30 mg/m2 and escalating-dose irinotecan (40, 50, 65, and 80 mg/m2) were administered on days 1, 8, 22, and 29 of radiotherapy. DLT was defined as a 2-week delay in radiotherapy for grade 3 to 4 toxicity. Results: Minimal toxicity was observed during chemoradiotherapy, with no grade 3 or 4 esophagitis, diarrhea, or stomatitis. DLT caused by myelosuppression was seen in two of six patients treated at the 80-mg/m2 dose level, thus irinotecan 65 mg/m2 was defined as the recommended phase II dose. Dysphagia improved or resolved after induction chemotherapy in 13 (81%) of 16 patients who reported dysphagia before therapy. Only one patient (5%) required a feeding tube. Six complete responses (32%) were observed, including four pathologic complete responses in 15 patients selected to undergo surgery (27%). Conclusion: Cisplatin, irinotecan, and concurrent radiotherapy can be administered on a convenient schedule with relatively minimal toxicity and an acceptable rate of complete response in esophageal cancer. Further phase II evaluation of this regimen is ongoing. A phase III comparison to fluorouracil or taxane-containing chemoradiotherapy should be considered.

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Provider Recommendations for Phase I Clinical Trials Within a Shared Decision-Making Model in Phase I Cancer Clinical Trial Discussions

JCO Oncology Practice ◽

10.1200/jop.19.00772 ◽

2020 ◽

Vol 16 (9) ◽

pp. e859-e867

Author(s):

Rachel S. Hianik ◽

Gavin P. Campbell ◽

Eli Abernethy ◽

Colleen Lewis ◽

Christina S. Wu ◽

...

Keyword(s):

Clinical Trial ◽

Decision Making ◽

Clinical Trials ◽

Phase I ◽

Shared Decision Making ◽

Phase I Trial ◽

Performance Status ◽

Shared Decision ◽

Phase I Clinical Trials ◽

Decision Making Model

PURPOSE: Debate continues over whether explicit recommendations for a clinical trial should be included as an element of shared decision making within oncology. We aimed to determine if and how providers make explicit recommendations in the setting of phase I cancer clinical trials. METHODS: Twenty-three patient/provider conversations about phase I trials were analyzed to determine how recommendations are made and how the conversations align with a shared decision-making framework. In addition, 19 providers (9 of whose patient encounters were observed) were interviewed about the factors they consider when deciding whether to recommend a phase I trial. RESULTS: We found that providers are comprehensive in the factors they consider when recommending clinical trials. The two most frequently stated factors were performance status (89%) and patient preferences (84%). Providers made explicit recommendations in 19 conversations (83%), with 12 of those being for a phase I trial (12 [63%] of 19). They made these recommendations in a manner consistent with a shared decision-making model; 18 (95%) of the 19 conversations during which a recommendation was made included all steps, or all but 1 step, of shared decision making, as did 11 of the 12 conversations during which a phase I trial was recommended. In 7 (58%) of these later conversations, providers also emphasized the importance of the patient’s opinion. CONCLUSION: We suggest that providers not hesitate to make explicit recommendations for phase I clinical trials, because they are able to do so in a manner consistent with shared decision making. With further research, these results can be applied to other clinical trial settings.

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