Dose-finding Clinical Trial Research Articles

First-in-Human Phase I Trial to Assess the Safety and Immunogenicity of an Orf Virus-Based COVID-19 Vaccine Booster

The emergence of SARS-CoV-2 has necessitated the development of versatile vaccines capable of addressing evolving variants. Prime-2-CoV_Beta, a novel Orf virus-based COVID-19 vaccine, was developed to express the SARS-CoV-2 spike and nucleocapsid antigens. This first-in-human, phase I, dose-finding clinical trial was conducted to assess the safety, reactogenicity, and immunogenicity of Prime-2-CoV_Beta as a booster in healthy adults. From June 2022 to June 2023, 60 participants in Germany received varying doses of Prime-2-CoV_Beta. The study demonstrated a favorable safety profile, with no serious adverse events (AEs) reported. All AEs were mild (107) or moderate (10), with the most common symptoms being pain at the injection site, fatigue, and headache. Immunogenicity assessments revealed robust vaccine-induced antigen-specific immune responses. High doses notably elicited significant increases in antibodies against the spike and nucleocapsid proteins as well as neutralizing antibodies against SARS-CoV-2 and its variants. Additionally, the vaccine did not induce ORFV-neutralizing antibodies, indicating the potential for repeated administration. In conclusion, Prime-2-CoV_Beta was safe, well tolerated, and immunogenic, demonstrating potential as a broadly protective vaccine against SARS-CoV-2 and its variants. These promising results support further evaluation of higher doses and additional studies to confirm efficacy and long-term protection. This trial was registered at ClinicalTrials, NCT05389319.

Statistical operating characteristics of current early phase dose finding designs with toxicity and efficacy in oncology.

Traditional phase I dose finding cancer clinical trial designs aim to determine the maximum tolerated dose (MTD) of the investigational cytotoxic agent based on a single toxicity outcome, assuming a monotone dose-response relationship. However, this assumption might not always hold for newly emerging therapies such as immuno-oncology therapies and molecularly targeted therapies, making conventional dose finding trial designs based on toxicity no longer appropriate. To tackle this issue, numerous early-phase dose finding clinical trial designs have been developed to identify the optimal biological dose (OBD), which takes both toxicity and efficacy outcomes into account. In this article, we review the current model-assisted dose finding designs, BOIN-ET, BOIN12, UBI, TEPI-2, PRINTE, STEIN, and uTPI to identify the OBD and compare their operating characteristics. Extensive simulation studies and a case study using a CAR T-cell therapy phase I trial have been conducted to compare the performance of the aforementioned designs under different possible dose-response relationship scenarios. The simulation results demonstrate that the performance of different designs varies depending on the particular dose-response relationship and the specific metric considered. Based on our simulation results and practical considerations, STEIN, PRINTE, and BOIN12 outperform the other designs from different perspectives.

Orismilast for the treatment of mild to severe hidradenitis suppurativa: Week 16 data from OSIRIS, a Phase 2a, open-label, single-centre, single-arm, dose-finding clinical trial.

Hidradenitis suppurativa (HS) is a disease with an unmet need for treatment. To examine tolerability, safety and efficacy of oral phosphodiesterase-4 (PDE4) inhibitior orismilast 10-40 mg twice daily (BID) in HS. A Phase 2a, single-arm, single-centre, open-label, 16-week trial in HS patients. Adjustments in maximal dose and titration were allowed, to improve tolerability, dividing the study population in two groups who completed and discontinued 16 weeks of treatment. Descriptive statistics were applied to efficacy data from patients who completed treatment and patients who discontinued treatment prematurely. A last-observation-carried-forward (LOCF) approach was used for patients who discontinued treatment. The primary endpoint was percent change in the total number of abscesses and nodules (AN-count) at Week 16, with the HS Clinical Response with a 50% reduction in the AN-count (HiSCR50) as key secondary endpoint. Of the 20 patients included, 9 completed 16 weeks of treatment and 11 discontinued treatment prematurely. The mean AN-count was reduced with 33.1% in patients who completed treatment and with 12.0% in patients who discontinued. HiSCR50 was achieved by 67.0% and 27.0% of patients who completed and discontinued treatment, respectively. Most adverse events were mild to moderate. Oral orismilast demonstrated a dose-dependent tolerability, with mild to moderate adverse effects. Further, the results of this exploratory trial indicate that orismilast may lead to clinical improvements in HS. However, larger trials with tolerable dose ranges are warranted. The Trial is registered at Clinicaltrials.gov (UNI50007201) and EudraCT.ema.europa.eu (2021-000049-42).

Reporting quality of CONSORT flow diagrams in published early phase dose-finding clinical trial reports: Improvement is needed

BackgroundThis project aims to: (1) assess the completeness of information in flow diagrams of published early phase dose-finding (EPDF) trials based on CONSORT recommendations, and if additional features on dose (de-)escalation were presented; (2) propose new flow diagrams presenting how doses were (de-)escalated throughout the trial. MethodsFlow diagrams were extracted from a random sample of 259 EPDF trials, published from 2011 to 2020 indexed in PubMed. Diagrams were scored out of 15 following CONSORT recommendations with an additional score for presence of (de-)escalation. New templates were proposed for features that were deficient and presented to 39 methodologists and 11 clinical trialists in October and December 2022. Results98 (38%) papers included a flow diagram. Flow diagrams were most deficient in the reporting of reasons for lost to follow up (2%) and reasons for not receiving allocated intervention (14%). Few (39%) presented sequential dose-decision stages.Of voting methodologists, 33/38 (87%) agreed or strongly agreed that for participants recruited in cohorts, presenting the (de-)escalation steps in the flow diagram is a useful feature, also expressed by the trial investigators. Most workshop attendees (35/39, 90%) preferred a larger dose to be displayed higher up within the flow diagram than a smaller dose. ConclusionMost published trials do not provide a flow diagram, and for those that do, essential information is often omitted. EPDF flow diagrams capturing information on participant flow in the trial's journey, encapsulated within one figure, are highly recommended to promote transparency and interpretability of trial results.

Data-dependent contrast test for dose-finding clinical trials

We propose a simple and powerful data-dependent contrast test with ordinal-constraint contrast coefficients of the dose response determined from observed responses. The contrast coefficients are easily calculated using a pool-adjacent-violators algorithm and making assumptions for the contrast coefficients. Once the dose response is determined for p < 0.05 in the data-dependent contrast test, the best dose-response model is selected from multiple dose-response models. Using the best model, a recommended dose is identified. We demonstrate the data-dependent contrast test for sample data. In addition, we calculate the ordinal-constraint contrast coefficients and test statistic for an actual study, and we obtain a recommended dose. Finally, we perform a simulation study with 11 scenarios to evaluate the performance of the data-dependent contrast test by comparing multiple comparison procedures with modeling techniques.We confirm the dose response for both the sample data and the actual study. In the simulation study, the data-dependent contrast test is more powerful than the conventional method on the simulation datasets generated using non-dose-response models. In addition, the type-1 error rate of the data-dependent contrast test remains at a significant level when there is no difference between the treatment groups. We conclude that the data-dependent contrast test can be applied unproblematically in a dose-finding clinical trial.

Omega-3 Fatty Acids for Major Depressive Disorder With High Inflammation: A Randomized Dose-Finding Clinical Trial.

Objective: This study compared the impact of 3 eicosapentaenoic acid (EPA) doses versus placebo on inflammatory biomarkers and depressive symptoms.Methods: Sixty-one unmedicated adults (75% female; 45.5 ± 13.8 years) with DSM-5 major depressive disorder (MDD), body mass index > 25 kg/m2, and plasma high-sensitivity C-reactive protein (hs-CRP) ≥ 3.0 mg/L were randomly assigned to receive EPA 1 g/d, 2 g/d, or 4 g/d or placebo for 12 weeks. Prespecified endpoints were a ≥ 0.40 effect size decrease in plasma interleukin (IL)-6, peripheral blood mononuclear cell (PBMC) cytokines, and lipopolysaccharide-stimulated tumor necrosis factor (TNF) production. Response was defined as a ≥ 50% decrease of Inventory of Depressive Symptomatology, Clinician-Rated version (IDS-C30) scores. We compared outcomes for the 3 EPA doses versus placebo.Results: In 45 completers, only median PBMC TNF decreased at 2 g/d EPA. No EPA dose produced a ≥ 0.35 effect size reduction in plasma IL-6 or mitogen-stimulated TNF. Response rates for EPA 4 g/d were 64%, versus 40% for placebo (odds ratio [OR] = 2.63; Cohen d = 0.53), 38% for EPA 1 g/d, and 36% for EPA 2 g/d (all P > .05). EPA 4 g/d showed a significant correlation between percent decrease in plasma hs-CRP and IDS-C30 symptom reduction at 12 weeks (Spearman ρ = 0.691, P = .019).Conclusions: EPA 4 g/d demonstrated a medium effect size for response rates versus placebo. This dose may alleviate MDD in overweight individuals with elevated inflammatory markers, and change in hs-CRP may be correlated with clinical response.Trial Registration: ClinicalTrials.gov identifier: NCT02553915.

DIPG-38. Significant tumor regression of H3K27M-mutated diffuse midline glioma of the brainstem with panobinostat: a case report.

INTRODUCTION: Diffuse midline glioma is a fatal CNS tumor that chiefly occurs in children. To date, standard of care has been limited to local field radiation. A histone mutation in H3K27M is seen in 80% of diffuse midline gliomas of the brainstem, also called diffuse intrinsic pontine glioma (DIPG). Panobinostat, a potent inhibitor of histone deacetylases, has shown moderate efficacy in DIPG/DMGs in preclinical models, and a dose-finding clinical trial (PBTC-047) is ongoing. We report on a case of a child with biopsy-proven H3K27M-mutated DMG of the brainstem treated off-trial with panobinostat monotherapy after radiation. METHODS: This is a case report of a 12-year-old female with H3K27M-mutated DMG of the medulla and cerebellum that exhibited gadolinium-enhancement on MRI. The patient was treated with 54 Gy focal photon radiation to the tumor field over six weeks after biopsy demonstrating the H3.3K27M mutation (H3F3A), as well as mutations in TP53, PIK3R1 and AXSL1 genes. She was not eligible for PBTC-047 due to uncontrolled hypertension. She received panobinostat as per the ongoing PBTC protocol at a dose of 28 mg/m2 given on Monday, Wednesday, and Friday on alternating weeks. She received three 28-day cycles over three months. RESULTS: The patient tolerated the therapy well, with minimal adverse reactions of low-grade abdominal pain and constipation. MRI imaging after three cycles revealed an 80% reduction in tumor volume. Together with this radiographic response, she exhibited improvement in left-sided motor strength and improved left facial sensation. Due to an unrelated need for oral surgery, panobinostat was held. MRI imaging six weeks after cessation of panobinostat revealed extensive relapse with supratentorial and spinal disease. CONCLUSION: Systemic panobinostat may demonstrate anti-tumor efficacy in some cases of H3K27M-mutated DMG. Future work is required to determine factors predictive of favorable response.

86 Intra-nasal ketamine for laceration repair in the Emergency Department: The DosINK studies

Abstract Introduction/Background Lacerations are common in children presenting to the emergency department (ED). Children can be uncooperative and in pain when repair with sutures is performed and may require procedural sedation. There is a growing interest in the intranasal (IN) route of administration for procedural sedation and pain control. In contrast to intravenous (IV) line placement, IN administration is relatively painless for the patient, is simple and rapid to administer by the healthcare provider and requires minimal training. Few studies have evaluated intranasal (IN) ketamine for procedural sedation in children, mostly for brief dental procedures, with doses between 3 to 9 mg/kg. Objectives We sought to determine the optimal IN ketamine dose for effective and safe procedural sedation for laceration repair with sutures in children aged 1 to 12 years presenting to the ED using a two-step (dosINK- 1 trial and dosINK-2 trial) dose-finding clinical trial design. Design/Methods We enrolled otherwise healthy children 1 to 12 years requiring PS for their laceration repair by sutures in the ED. DosINK-1 consisted in a single center 3 + 3 dose escalation trial design with an initial dose of 3 up to 9 mg/kg of IN ketamine. For each dose, 3 patients were enrolled. Escalation to the next dose was performed if sedation was unsuccessful without serious adverse event (SAE). This process was repeated until 6 consecutive patients reached adequate PS with a maximum of 1 SAE. The primary outcome was the optimal dose for adequate PS as per the PERC/PECARN consensus criteria. We subsequently conducted DosINK-2, a multicenter single-arm clinical trial. We enrolled a convenience sample of 30 children who all received the identified dose of IN ketamine from DosINK-1. The primary outcome was the proportion (95% CI) of patients who achieved adequate PS. Secondary outcomes included adverse events and parent, patient and physician satisfaction. Results In DosINK-1, 12 patients were recruited from April 2017 to March 2018 in one pediatric ED. Median age was 2.6 (interquartile range [IQR] 1.9, 3.7) years, 10 (85%) had facial laceration, and in 8 (67%) the laceration was &amp;gt;2 cm long. Sedation was adequate in 1/3 patients at doses of 3 and 4 mg/kg and in 3/3 patients at doses of 5 and 6 mg/kg, all without SAE. The identified dose of IN ketamine was 6 mg/kg. Nausea and vomiting in 4/12 (33%) patients were the only reported side effects. In DosINK-2, we recruited 30 patients from April 2018 to November 2019 in two pediatric EDs. The median age was 3.2 (IQR 1.9, 4.7) years; 21 (70%) had facial laceration, and in 20 (67%) the laceration was longer than 2 cm. Sedation was adequate in 18/30 (60% [95% CI 45, 80]) children, was suboptimal (procedure completed with minimal difficulties) in 6 (20%), was poor (struggle that interfered with procedure, competed with difficulty) in 3 (10%) and required additional sedative agents in 3 (10%) patients. Twenty-one (70%) physicians were willing to reuse IN ketamine at the same doses and 25 (83%) parents would agree to the same sedation in the future. Median time to return to baseline status was 58 min (IQR 33, 73). Two patients, including one who received supplemental IV ketamine, desaturated during the procedure and required oxygen by-mask and repositioning. After the procedure, 1(3%) patient had nausea, and 2(7%) vomited. Conclusion A single dose of 6 mg/kg of IN ketamine for PS during laceration repair by sutures in children in the ED was adequate in 60%(95% CI 45, 80). In an additional 20% PS was suboptimal, but procedures were completed with minimal difficulties only. IN ketamine, which saves painful IV insertion, was acceptable by most physicians and parents. An additional IN ketamine dose may further increase the proportion of adequate sedation, but its safety and efficacy should be examined.

Optimal Stopping of Adaptive Dose-Finding Trials

The primary objective of this paper is to develop computationally efficient methods for optimal stopping of an adaptive Phase II dose-finding clinical trial, where the decision maker may terminate the trial for efficacy or abandon it as a result of futility. We develop two solution methods and compare them in terms of computational time and several performance metrics such as the probability of correct stopping decision. One proposed method is an application of the one-step look-ahead policy to this problem. The second proposal builds a diffusion approximation to the state variable in the continuous regime and approximates the trial’s stopping time by optimal stopping of a diffusion process. The secondary objective of the paper is to compare these methods on different dose-response curves, particularly when the true dose-response curve has no significant advantage over a placebo. Our results, which include a real clinical trial case study, show that look-ahead policies perform poorly in terms of the probability of correct decision in this setting, whereas our diffusion approximation method provides robust solutions.

Safety and Efficacy of Lemborexant in Patients With Irregular Sleep-Wake Rhythm Disorder and Alzheimer\u2019s Disease Dementia: Results From a Phase 2 Randomized Clinical Trial

BACKGROUNDIrregular sleep-wake rhythm disorder (ISWRD) is a common sleep disorder in individuals with Alzheimer’s disease dementia (AD-D).OBJECTIVESThis exploratory phase 2 proof-of-concept and dose-finding clinical trial evaluated the effects of lemborexant compared with placebo on circadian rhythm parameters, nighttime sleep, daytime wakefulness and other clinical measures of ISWRD in individuals with ISWRD and mild to moderate AD-D.DESIGNMulticenter, randomized, double-blind, placebo-controlled, parallel-group study.SETTINGSites in the United States, Japan and the United Kingdom.PARTICIPANTSMen and women 60 to 90 years of age with documentation of diagnosis with AD-D and Mini-Mental State Exam (MMSE) score 10 to 26.INTERVENTIONSubjects were randomized to placebo or one of four lemborexant treatment arms (2.5 mg, 5 mg, 10 mg or 15 mg) once nightly at bedtime for 4 weeks.MEASUREMENTSAn actigraph was used to collect subject rest-activity data, which were used to calculate sleep-related, wake-related and circadian rhythm-related parameters. These parameters included least active 5 hours (L5), relative amplitude of the rest-activity rhythm (RA) and mean duration of sleep bouts (MDSB) during the daytime. The MMSE and the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) were used to assess for changes in cognitive function.RESULTSSixty-two subjects were randomized and provided data for circadian, daytime and nighttime parameters (placebo, n = 12; lemborexant 2.5 mg [LEM2.5], n = 12; lemborexant 5 mg [LEM5], n = 13, lemborexant 10 mg [LEM10], n = 13 and lemborexant 15 mg [LEM15], n = 12). Mean L5 showed a decrease from baseline to week 4 for LEM2.5, LEM5 and LEM15 that was significantly greater than with placebo (all p > 0.05), suggesting a reduction in restlessness. For RA, LS mean change from baseline to week 4 versus placebo indicated greater distinction between night and day with all dose levels of lemborexant, with significant improvements seen with LEM5 and LEM15 compared with placebo (both p > 0.05). The median percentage change from baseline to week 4 in MDSB during the daytime indicated a numerical decrease in duration for LEM5, LEM10 and LEM15, which was significantly different from placebo for LEM5 and LEM15 (p > 0.01 and p = 0.002, respectively).There were no serious treatment-emergent adverse events or worsening of cognitive function, as assessed by the MMSE and ADAS-Cog. Lemborexant was well tolerated. No subjects discontinued treatment.CONCLUSIONSThis study provides preliminary evidence of the potential utility of lemborexant as a treatment to address both nighttime and daytime symptoms in patients with ISWRD and AD-D.

Norursodeoxycholic acid versus placebo in the treatment of non-alcoholic fatty liver disease: a double-blind, randomised, placebo-controlled, phase 2 dose-finding trial

Norursodeoxycholic acid is an orally administered side chain-shortened homologue of ursodeoxycholic acid that undergoes hepatic enrichment with hepatoprotective, anti-inflammatory, and antifibrotic activity. We assessed the efficacy of two doses of norursodeoxycholic acid versus placebo for the treatment of non-alcoholic fatty liver disease. We did a multicentre, double-blind, placebo-controlled, randomised, phase 2 dose-finding clinical trial in tertiary referral hospitals and medical centres in Austria (n=6) and Germany (n=23) for patients with non-alcoholic fatty liver disease with or without diabetes. Patients with a clinical diagnosis of non-alcoholic fatty liver disease and serum alanine aminotransferase (ALT) concentrations of more than 0·8 times the upper limit of normal were randomly assigned (1:1:1) using a computer-generated central randomisation. Patients were randomly assigned to receive either norursodeoxycholic acid capsules at 500 mg per day or 1500 mg per day, or placebo, for 12 weeks with a subsequent 4-week follow-up period. All individuals involved in the trial were masked to treatment allocation. The primary efficacy endpoint was the mean relative percentage change in ALT concentrations between baseline and end of treatment assessed in the intention-to-treat population. This trial is registered with EudraCT, number 2013-004605-38. Between March 30, 2015, and Sept 20, 2016, of 198 individuals included in the analysis, 67 patients were randomly assigned to receive 500 mg norursodeoxycholic acid, 67 to 1500 mg norursodeoxycholic acid, and 64 to placebo. A dose-dependent reduction in serum ALT between baseline and end of treatment was observed with norursodeoxycholic acid versus placebo, with a significant effect in the 1500 mg group (mean change -27·8%, 95% repeated CI -34·7 to -14·4; p<0·0001). Serious adverse events (n=6) and treatment-emergent adverse events (n=314) were reported in a similar proportion of patients across groups. 112 treatment-emergent adverse events occurred in the 1500 mg group, 99 in the 500 mg group, and 103 in the placebo group. The most frequent adverse events were headache, gastrointestinal disorders, and infections (eg, diarrhoea, abdominal pain, or nasopharyngitis). Norursodeoxycholic acid at 1500 mg resulted in a significant reduction of serum ALT within 12 weeks of treatment when compared with placebo. Norursodeoxycholic acid was safe and well tolerated encouraging further studies. Dr Falk Pharma GmbH.

A phase II, dose finding, placebo-controlled, study of zuclomiphene citrate to amerliorate the frequency and severity of hot flashes caused by androgen deprivation in men with advanced prostate cancer.

TPS338 Background: Androgen deprivation therapy (ADT) is the mainstay of treatment for advanced prostate cancer. ADT not only lowers testosterone, but also decreases estrogen levels which can cause significant side effects including hot flashes, loss of bone and bone fractures, and decreases in libido. Up to 80% of the men on ADT report hot flashes and 30-40% of men have moderate to severe hot flashes. Concern over hot flashes make patients less likely to begin ADT and can lead to early discontinuation of ADT. While the off-label use of potent steroidal estrogens has demonstrated efficacy, the appropriate dose as well as dosing route or schedule of these potent estrogens, has not been established. Furthermore, the potential for safety issues with potent steroidal estrogens remains a significant limitation to their clinical utility. Zuclomiphene citrate, is novel weak nonsteroidal estrogenic agent that should ameliorate hot flashes caused by ADT, and as one of the isomers of clomiphene, has a 50 year safety history of being well tolerated in men. Methods: The Phase 2, placebo controlled, dose finding clinical trial (V72203) evaluating zuclomiphene citrate (VERU-944) capsules, oral daily dosing, for the treatment of moderate to severe hot flashes in men with prostate cancer on ADT is in progress. Men are randomized to daily doses of placebo or zuclomiphene 10mg, 50mg or 100mg. V72203 is enrolling approximately 36 men per arm in 10 sites in the United States. The primary efficacy endpoint is the mean change in frequency of moderate and/or severe hot flashes from baseline to week 4 and maintained until week 12. Secondary endpoints include changes from baseline in bone turnover markers, free and total testosterone, SHBG, PSA, and safety. Hot flashes are being measured in real time utilizing an electronic data capture device (ePRO) provided to each subject. We anticipate completion of enrollment by the end of 2018 with study results by second quarter of 2019. Clinical trial information: NCT03646162.

A double-blind, placebo-controlled, randomised, multicentre, proof-of-concept and dose-finding phase II clinical trial to investigate the safety, tolerability and efficacy of adrecizumab in patients with septic shock and elevated adrenomedullin concentration (AdrenOSS-2)

IntroductionSepsis remains a major health problem with an increasing incidence, high morbidity and high mortality. Apart from treatment with antibiotics and organ support, no approved specific adjunct therapies currently exist....

An algorithm for computing profile likelihood based pointwise confidence intervals for nonlinear dose-response models.

This study was inspired by the need to estimate pointwise confidence intervals (CIs) for a nonlinear dose-response model from a dose-finding clinical trial. Profile likelihood based CI for a nonlinear dose response model is often recommended. However, it is still not commonly used in dose-finding studies because it cannot generally be calculated explicitly. Most previous research has mainly focused on the performance of the profile likelihood based CI method compared with other common approaches. However, there are still no reports on computing profile likelihood based pointwise CIs for an entire dose-response curve. Based on a previous dose-finding trial with binary-response data, this present study proposed to calculate profile likelihood based pointwise CIs by using the bisection method with proper calculation order for doses in the curve plus crude search when the expected response is close to a boundary. The convergence could be improved by applying appropriate starting values for the optimization procedure with straightforward programming techniques. The algorithm worked well in most cases based on the simulation study and it can be applied more generally to other dose-response models, and other type of data like normally distributed response. It would indeed be great to be able to use profile likelihood approaches more routinely when constructing pointwise CIs for nonlinear dose-response models.

Bayesian Adaptive Design for Finding the Maximum Tolerated Sequence of Doses in Multicycle Dose-Finding Clinical Trials.

Statistical designs for traditional phase I dose-finding trials consider dose-limiting toxicity in the first cycle of treatment. In reality, patients often go through multiple cycles of treatment and may experience toxicity events in more than one cycle. Therefore, it is desirable to identify the maximum tolerated sequence of three doses across three cycles of treatment. Motivated by a three-cycle dose-finding clinical trial for a rare cancer with a JAK inhibitor, we proposed and implemented a simple Bayesian adaptive dose-cycle finding (BaSyc) design that allows intercycle and intrapatient dose modification. Because of the patient-specific dosing strategy over cycles, the BaSyc design is suited as a method in precision oncology. BaSyc is simple and transparent because its algorithm can be summarized as two tabulated decision rules before the trial starts, allowing physicians to visually examine these rules. In addition, BaSyc employs a time-saving enrollment scheme that speeds up the trial. Extensive simulation studies show that BaSyc has desirable operating characteristics in identifying the maximum tolerated sequence. The BaSyc design provides a first-of-kind multicycle approach for dose finding and will likely lead to better and safer patient care and drug development.

Data-Driven Prior Distributions for A Bayesian Phase-2 COPD Dose-Finding Clinical Trial

ABSTRACTThe prior distribution reflects knowledge and uncertainty of the modeled parameters. Determining the prior distribution for a dose-finding clinical trial can be influential in its design and analysis. Using the planning of a phase 2 trial for COPD with a dose-response curve as a case study, we illustrate the use of relevant historical data for the nonlinear curve mean-model parameters as well as consideration for terms to characterize between-trial and within-trial variability. Through a predictive inference exercise, a data-driven informative prior distribution is constructed for the future study. We share our strategies on how to obtain informative Bayesian priors for both design and analysis of dose-finding clinical trials using relevant historical data and deal with the associated issues.

A dose finding clinical trial of cabozantinib (XL184) administered in combination with abiraterone acetate in metastatic castration-resistant prostate cancer.

Cabozantinib can enhance the effect of abiraterone in preclinical prostate cancer models. This study aimed to define the recommended phase 2 dose (RP2D) and preliminary efficacy of abiraterone + cabozantinib in mCRPC. Patients with progressive mCRPC with 0-2 prior chemotherapy regimens but no prior CYP17A1 or MET inhibitor received abiraterone acetate at 1000 mg daily with prednisone 5 mg BID in combination with cabozantinib at 20, 40, or 60 mg daily in a dose-escalation 3 + 3 open-label phase 1 design (Part A). After tolerable doses were defined, cohorts were expanded to better define toxicity and efficacy (Part B). There were no dose-limiting toxicities (DLTs) in the first 4 weeks at any of the three dose levels in Part A. Two of the three patients at the 60 mg dose level required dose reductions beyond cycle 2 due to fatigue. In Part B, nine more patients were accrued to each of the 20 and 40 mg doses. Of the 12 patients treated at the 40 mg dose, only one DLT (grade 3 Lipase elevation) was observed in cycle 1. The median time to radiographic progression was 12.88 months (95% CI:5.42- not estimated [NE]) in the 20 mg cohort and 22.01 months (95% CI:15.44-NE) in the 40 mg cohort. Median overall survival was 23.29 months (95% CI:19.06-NE) in the 20 mg cohort and 39.08 months (95% CI:17.38-NE) in the 40 mg cohort. Based on tolerability and preliminary efficacy, 40 mg cabozantinib plus 1000 mg abiraterone daily is the RP2D.

ED50 of remifentanil for providing excellent intubating conditions when co-administered with a single standard dose of propofol without the use of muscle relaxants in children: dose-finding clinical trial.

Previous studies evidenced that orotracheal intubation without neuromuscular blockers is feasible in children and has some potential advantages. Remifentanil has favorable pharmacodynamic and pharmacokinetic properties as an opioid for orotracheal intubation, but its dose for excellent intubation conditions when co-administered with propofol has not been established. This study was designed to find the minimum effective dose of remifentanil for excellent intubation conditions of children when co-administered with propofol, without neuromuscular relaxant drugs. Blinded adaptive clinical trial, with sequential allocation of 27 children between 2 and 9 years-old, American Society of Anesthesiologists' physical status PI or PII, scheduled for elective surgery under general anesthesia. Remifentanil dose began at 2µg/kg and varied by 0.25µg/kg according to the sequential allocation up-and-down rule designed by Dixon and Massey. Remifentanil was infused in 30s and followed by propofol (3mg/kg) in 20s. Laryngoscopy and intubation were performed and assessed using Viby-Mogensen criteria, 90s after the end of opioid administration. Inclusion of patients stopped after six crossovers, and remifentanil effective dose was estimated using pooled adjacent-violators algorithm. Remifentanil effective dose for 50% was established in 3.04µg/kg (IC 95% 2.68-3.11, p < 0.05). The most frequent adverse effect was difficult positive pressure facial mask ventilation, which occurred in four children (15%). Minimum remifentanil effective dose for providing excellent intubating conditions when co-administered with a single standard dose of propofol without the use of neuromuscular blockers in children is 3.04µg/kg. NCT02454868.

Clinical trial simulations in paediatric oncology: A feasibility study from the Innovative Therapies for Children with Cancer Consortium

IntroductionPaediatric dose-finding studies are challenging to perform due to ethical reasons, the limited number of available patients and restricted number of blood samples. In certain cases, the adult pharmacokinetic (PK) exposure can be used as target for dose finding in paediatrics. The aim of this study was to investigate the performance of a paediatric phase I dose-finding clinical trial in silico. MethodsUsing an adult pharmacokinetic model, clinical trial simulations were performed to determine the power of a proposed clinical trial design. Power was defined as the fraction of 1000 trials with an area under the plasma concentration–time curve at steady-state (AUC0-24,SS) within ±20% of the adult geometric mean AUC0-24,SS. Different scenarios were compared to optimise the design of the trial. To show the potential of this framework for similar compounds, the current simulation method was also evaluated with adult and paediatric data from literature on sunitinib. ResultsAt the starting dose of 300 mg/m2, the power of the trial design was 66.9%. Power did not improve by dose escalation to 350 mg/m2 (65.3%). Power increased to 78.9% with inclusion of 10 patients per trial. Paediatric sunitinib PK data were adequately predicted from adult data with a mean prediction error of 1.80%. ConclusionThe performance of PK-based clinical trials in paediatrics can be predicted and optimised through PK modelling and simulation. Application of this approach enables clinical trials in paediatrics to be performed as efficiently as possible while protecting the child from unnecessary harm.

Implementing the EffTox dose-finding design in the Matchpoint trial

BackgroundThe Matchpoint trial aims to identify the optimal dose of ponatinib to give with conventional chemotherapy consisting of fludarabine, cytarabine and idarubicin to chronic myeloid leukaemia patients in blastic transformation phase. The dose should be both tolerable and efficacious. This paper describes our experience implementing EffTox in the Matchpoint trial.MethodsEffTox is a Bayesian adaptive dose-finding trial design that jointly scrutinises binary efficacy and toxicity outcomes. We describe a nomenclature for succinctly describing outcomes in phase I/II dose-finding trials. We use dose-transition pathways, where doses are calculated for each feasible set of outcomes in future cohorts. We introduce the phenomenon of dose ambivalence, where EffTox can recommend different doses after observing the same outcomes. We also describe our experiences with outcome ambiguity, where the categorical evaluation of some primary outcomes is temporarily delayed.ResultsWe arrived at an EffTox parameterisation that is simulated to perform well over a range of scenarios. In scenarios where dose ambivalence manifested, we were guided by the dose-transition pathways. This technique facilitates planning, and also helped us overcome short-term outcome ambiguity.ConclusionsEffTox is an efficient and powerful design, but not without its challenges. Joint phase I/II clinical trial designs will likely become increasingly important in coming years as we further investigate non-cytotoxic treatments and streamline the drug approval process. We hope this account of the problems we faced and the solutions we used will help others implement this dose-finding clinical trial design.Trial registrationMatchpoint was added to the European Clinical Trials Database (https://www.clinicaltrialsregister.eu/ctr-search/trial/2012-005629-65/GB) on 2013-12-30.