• The Korean Journal of Applied Statistics
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• v.35 no.2
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• pp.251-263
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• 2022

Phase I clinical trial is called 'Dose finding study'. It is first step of experimenting on humans with new drugs developed through animal experiments or vitro experiments. The important area of interest in designing Phase I clinical trial is determining the dose that acceptable level to the patients and provides the greatest efficacy. In this paper, we explain about methods to determine the maximum tolerated dose using various stopping rules. The SM3, NM, Rim, J3, BSM methods are compared through simulation. And we consider how the methods might be reformed. As a result of the simulation, BSM estimated the MTD closest to the target toxicity probability. J3 method required the least number of subjects. These results are due to the feature of the stopping rules of both methods. The BSM adds 2 or 1 subject at the same dose level when there is a toxic reaction. In addition, the J3 method has a smaller number of subjects than the other methods. If the methods are improved by combining these features, MTD can be estimated more efficiently. If the total number of subjects can be reduced while using the stopping rule of the BSM, accurate estimation is possible for a small number of subjects.

• Communications for Statistical Applications and Methods
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• v.16 no.1
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• pp.51-65
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• 2009

The purpose of a phase I clinical trial is to determine the maximum tolerated dose(MTD) of a new drug. This paper investigates the performance of standard method, continual reassessment method and accelerated titration designs in phase I clinical trials. Especially we study the precision and safety at the MTD of these methods. We utilize hyperbolic tangent function and power function to define dose-toxicity model. For each method, expected toxicity rate at MTD is computed and compared with target toxicity probability. We also suggest some modifications of these methods and show some improvements in performance.

• Biomolecules & Therapeutics
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• v.16 no.1
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• pp.40-45
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• 2008

The objective of this study was to investigate the single dose and 2-week repeated dose toxicity of Aceporol 330 in ICR mice following single intravenous administration and to compare its toxicity with a commercially available solubilizer of paclitaxel, Cremophor EL. In single dose toxicity test, $LD_{50}$ of Aceporol 330 in mice was estimated to be greater than maximum applicable dose, 4 ml/kg. However, $LD_{50}$ of Cremophor EL in male mice was determined to be 4 ml/kg. Maximum tolerated dose (MTD) of males and females in Aceporol 330-treated group and MTD of females in Cremophor EL-treated group were 3 ml/kg. MTD of males in Cremophor EL-treated group was less than 3 ml/kg. Characteristic toxic symptoms, and hematological and blood chemical changes were not observed after single dose and repeated dose of Aceporol 330 or Cremophor EL. No histopathological abnormalities were found in organs of all animal groups. Based on the linear pharmacokinetic property of paclitaxel and the higher $LD_{50}$ in mice, Aceporol 330 has a potential for use as a safer solubilizer for paclitaxel than Cremophor EL.

• Journal of Korean Society for Quality Management
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• v.39 no.2
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• pp.329-336
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• 2011

The purpose of Phase I clinical trial is to identify the maximum tolerated dose with specific toxicity rate. The standard TER design does not guarantee the pre-specified toxicity rate. It depends on the dose-toxicity curves. Therefore it is necessary to check the expected toxicity rate of various dose-toxicity curves before we conduct clinical trials. We developed TERAplusB library to help this situation, especially in cancer research. This package will help design the cancer clinical trial. We can compare the expected toxicity rates, the expected number of patients, and the expected times calculated with various dose-toxicity curves. This process will help find the best clinical trial design of the proposed drug.

• Journal of Pharmaceutical Investigation
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• v.30 no.1
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• pp.39-45
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• 2000

We have investigated the efficacy of liposome encapsulated N-(phosphonacetyl)-L-aspartic acid (PALA) for the treatment of the C-26 murine colon tumor in Balb/c mice, and have compared it in this regard to free PALA. Healthy female Balb/c mice and C-26 tumor inoculated mice were randomized for the maximum tolerated dose (MTD) study and the in vivo therapy study, and the survival was measured after a single intraperitoneal injection of the drug. The maximum tolerated dose for intraperitoneally administered drug was found to be 750 mg/Kg for free PALA, and was greater than the maximum dose possible (150 mg/Kg) for PALA encapsulated in both DSPC and DSPG liposomes. When drug was administered one day after tumor implantation, 150 mg/Kg of PALA in DSPG liposomes increased the percentage of tumor bearing mice surviving at day 36 from 8% (buffer control) to 88%. In contrast, 150 mg/Kg free PALA increased the day 36 surviving percentage to only 25%. A 150 mg/Kg dose of PALA in DSPC liposomes increased the surviving percentage to 50%, while a 75 mg/Kg dose of PALA in sterically stabilized liposomes increased the surviving percentage to 78%. These results show that PALA in negatively charged or sterically stabilized liposomes can exhibit considerably greater potency than free PALA in C-26 tumor bearing mice.

• Communications for Statistical Applications and Methods
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• v.29 no.4
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• pp.421-439
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• 2022

Phase I dose-finding trials are essential in drug development. By finding the maximum tolerated dose (MTD) of a new drug or treatment, a Phase I trial establishes the recommended doses for later-phase testing. The primary toxicity endpoint of interest is often a binary variable, which describes an event of a patient who experiences dose-limiting toxicity. However, there is a growing interest in dose-finding studies regarding non-binary outcomes, defined by either the weighted sum of rates of various toxicity grades or a continuous outcome. Although several novel methods have been proposed in the literature, accessible software is still lacking to implement these methods. This study introduces a newly developed R package, UnifiedDoseFinding, which implements three phase I dose-finding methods with non-binary outcomes (Quasi- and Robust Quasi-CRM designs by Yuan et al. (2007) and Pan et al. (2014), gBOIN design by Mu et al. (2019), and by a method by Ivanova and Kim (2009)). For each of the methods, UnifiedDoseFinding provides corresponding functions that begin with next that determines the dose for the next cohort of patients, select, which selects the MTD defined by the non-binary toxicity endpoint when the trial is completed, and get oc, which obtains the operating characteristics. Three real examples are provided to help practitioners use these methods. The R package UnifiedDoseFinding, which is accessible in R CRAN, provides a user-friendly tool to facilitate the implementation of innovative dose-finding studies with nonbinary outcomes.

• Journal of Gastric Cancer
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• v.21 no.4
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• pp.418-425
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• 2021

Purpose: We designed a new regimen by combining intraperitoneal (IP) paclitaxel (PTX) with systemic S-1 plus oxaliplatin (SOX) for the treatment of advanced gastric cancer with peritoneal metastasis. This dose-escalation study aimed to determine the maximum tolerated dose (MTD) and recommended dose (RD) of IP PTX administered weekly to patients. Materials and Methods: Eight cycles of IP PTX plus SOX regimen were administered to the patients. S-1 was administered orally twice daily at a dose of 80 mg/m²/day for 14 consecutive days, followed by 7 days of rest. Intravenous oxaliplatin was administered at a fixed dose of 100 mg/m² on day 1, while IP PTX was administered on days 1 and 8. The initial dose of IP PTX was 40 mg/m², and the dose escalation was set in units of 20 mg/m² up to 80 mg/m². Dose-limiting toxicities (DLTs) were defined as grade 3 non-hematologic toxicities, grade 4 leukopenia, grade 3 febrile neutropenia, and grade 3 thrombocytopenia. Results: Nine patients were included in the study. No DLTs were observed in any of the enrolled patients. Therefore, the MTD was not reached, and the RD of IP PTX was determined to be 80 mg/m². Four patients (44%) showed a decreased peritoneal cancer index score on second-look laparoscopic examination. Conclusions: The present study determined the dose for further clinical trials of IP PTX to be 80 mg/m², when combined with a systemic SOX regimen.

• Journal of the Korean Statistical Society
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• v.32 no.1
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• pp.33-46
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• 2003

The continual reassessment method (CRM) provides a Bayesian estimation of the maximum tolerated dose (MTD) in phase I clinical trials. The CRM has been proposed as an alternative design of the standard design. The CRM has been modified to improve practical feasibility and, recently, the likelihood approach CRM has been proposed. In this paper we investigate the consistency and asymptotic normality of the modified likelihood approach CRM in which the maximum likelihood estimate is used instead of the posterior mean. Small-sample properties of the consistency is examined using complete enumeration. Both the asymptotic results and their small-sample properties show that the modified CRML outperforms the standard design.

• Environmental Mutagens and Carcinogens
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• v.22 no.4
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• pp.255-258
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• 2002

In order to determine the safety of chemicals and pharmaceutical products, various methods can be used to evaluate the toxicity. In this study the genotoxic effect of the widely used industrial chemical, cadmium chloride, was assessed using the micronucleus test in peripheral blood of mice. The presence of micronucleated reticulocytes by microscopic observation following acridine orange staining indicated a potential genotoxic effect. The genotoxicity of intraperitoneally (i.p.) administered cadmium chloride (0.5, 1, 2 mg/kg) appeared to be dose dependent, with the maximum tolerated dose (MTD) found to be 2 mg/kg. Compared to the negative control (saline), cadmium chloride (2 mg/kg) exhibited statistically significant genotoxic potential (P<0.05) but was found to be less than the positive control of mitomycin C (0.5 mg/kg) and was not statistically significant compared to historical negative controls (P>0.05).

• Journal of Oriental Neuropsychiatry
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• v.24 no.1
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• pp.131-144
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• 2013

Objectives : To provide information on the safety of ACM, we carried out a single oral dose-increasing toxicity and 4-weeks repeated oral dose determining test of ACM in beagle dogs. Methods : In a single oral dose-increasing toxicity test, beagles were treated with ACM orally increasing dose level (1,000, 2,000, 5,000 mg/㎏) at interval of 3 days. After administration, signs of toxicity were observed for two weeks. In 4-weeks repeated oral dose determinating test, beagles were treated with ACM with oral dose 500, 1,000, 2,000 mg/kg for 4 weeks. Mortality, clinical signs, body weight changes, food consumption, urinalysis, hematological and biochemical parameters, organ weights, necropsy findings, and histological findings were monitored during the study period. Results : In a single oral dose-increasing toxicity test, we found no mortality, abnormalities in clinical signs, body weight, and necropsy findings during the study period. In 4-weeks repeated oral dose determinating test, we found no mortality, abnormalities in clinical signs, body weight, food consumption, urinalysis, hematological and biological parameters, gross findings, organ weights, necropsy findings, and histopathological findings in any of the beagles tested. Conclusions : The results obtained in these studies suggest that maximum tolerated dose (MTD) of ACM in male and female beagle dogs was supposed to be over 5,000 mg/kg. For the future studies of toxicity, it is advisable that high dose and low dose are set at 2000 mg/kg and 500 mg/kg, respectively.