Modified 3+3 design for phase I clinical trials

Phase I clinical trial is mainly designed to determine the maximum tolerated dose (MTD) of a new drug. Optimization of phase I trial design is crucial to minimize the number of enrolled patients exposed to unsafe dose levels and to provide reliable information to the later phases of clinical trials. Although it has been criticized about its inefficient MTD estimation, nowadays the traditional 3+3 method remains dominant in practice due to its simplicity and conservative estimation. There are many new designs that have been proven to generate more credible MTD estimation, such as the Continual Reassessment Method (CRM). Despite its accepted better performance, the CRM design is still not widely used in real trials. There are several factors that contribute to the difficulties of CRM adaption in practice. First, CRM is not widely accepted by the regulatory agencies such as FDA in terms of safety. It is considered to be less conservative and tend to expose more patients above the MTD level than the traditional design. Second, CRM is relatively complex and not intuitive for the clinicians to fully understand. Third, the CRM method take much more time and need statistical experts and computer programs throughout the trial. The current situation is that the clinicians still tend to follow the trial process that they are comfortable with. This situation is not likely to change in the near future. Based on this situation, we have the motivation to improve the accuracy of MTD selection while follow the procedure of the traditional design to maintain simplicity. We found that in 3+3 method, the dose transition and the MTD determination are relatively independent. Thus we proposed to separate the two stages. The dose transition rule remained the same as 3+3 method. After getting the toxicity information from the dose transition stage, we combined the isotonic transformation to ensure the monotonic increasing order before selecting the optimal MTD. To compare the operating characteristics of the proposed isotonic method and the other designs, we carried out 10,000 simulation trials under different dose setting scenarios to compare the design characteristics of the isotonic modified method with standard 3+3 method, CRM, biased coin design (BC) and k-in-a-row design (KIAW). The isotonic modified method improved MTD estimation of the standard 3+3 in 39 out of 40 scenarios. The improvement is much greater when the target is 0.3 other than 0.25. The modified design is also competitive when comparing with other selected methods. A CRM method performed better in general but was not as stable as the isotonic method throughout the different dose settings. The results demonstrated that our proposed isotonic modified method is not only easily conducted using the same procedure as 3+3 but also outperforms the conventional 3+3 design. It can also be applied to determine MTD for any given TTL. These features make the isotonic modified method of practical value in phase I clinical trials.^

Propagation of Cross-Section Uncertainties in Criticality Calculations in the Framework of UAM-Phase I Using MCNPX-2.7e and SCALE-6.1

In the framework of the OECD/NEA project on Benchmark for Uncertainty Analysis in Modeling (UAM) for Design, Operation, and Safety Analysis of LWRs, several approaches and codes are being used to deal with the exercises proposed in Phase I, “Specifications and Support Data for Neutronics Cases.” At UPM, our research group treats these exercises with sensitivity calculations and the “sandwich formula” to propagate cross-section uncertainties. Two different codes are employed to calculate the sensitivity coefficients of to cross sections in criticality calculations: MCNPX-2.7e and SCALE-6.1. The former uses the Differential Operator Technique and the latter uses the Adjoint-Weighted Technique. In this paper, the main results for exercise I-2 “Lattice Physics” are presented for the criticality calculations of PWR. These criticality calculations are done for a TMI fuel assembly at four different states: HZP-Unrodded, HZP-Rodded, HFP-Unrodded, and HFP-Rodded. The results of the two different codes above are presented and compared. The comparison proves a good agreement between SCALE-6.1 and MCNPX-2.7e in uncertainty that comes from the sensitivity coefficients calculated by both codes. Differences are found when the sensitivity profiles are analysed, but they do not lead to differences in the uncertainty.

Influence of crude protein content, ingredient complexity, feed form, and duration of feeding of the phase I diets on productive performance and nutrient digestibility of Iberian pigs.

The influence of CP content and ingredient complexity, feed form, and duration of feeding of the Phase I diets on growth performance and total tract apparent digestibility -TTAD- of energy and nutrients was studied in Iberian pigs weaned at 28 d of age. There were 12 dietary treatments with 2 type of feeds -high-quality, HQ; and low-quality, LQ-, 2 feed forms -pellets vs. mash-, and 3 durations -7, 14, and 21 d- of supply of the Phase I diets.

Tenerife South Airport (Phase I)

In collaboration with Arsenio Pérez Amaral, Antonio Corona and Eustaquio Martínez

Immunization of metastatic breast cancer patients with a fully synthetic globo H conjugate: A phase I trial

The carbohydrate antigen globo H commonly found on breast cancer cells is a potential target for vaccine therapy. The objectives of this trial were to determine the toxicity and immunogenicity of three synthetic globo H-keyhole limpet hemocyanin conjugates plus the immunologic adjuvant QS-21. Twenty-seven metastatic breast cancer patients received five vaccinations each. The vaccine was well tolerated, and no definite differences were observed among the three formulations. Serologic analyses demonstrated the generation of IgM antibody titers in most patients, with minimal IgG antibody stimulation. There was significant binding of IgM antibodies to MCF-7 tumor cells in 16 patients, whereas IgG antibody reactivity was observed in a few patients. There was evidence of complement-dependent cytotoxicity in several patients. Affinity column purification supported the specificity of IgM antibodies for globo H. On the basis of these data, globo H will constitute one component of a polyvalent vaccine for evaluation in high-risk breast cancer patients.

Results of a phase-I/II randomized, masked, placebo-controlled trial of recombinant human interleukin-11 (rhIL-11) in the treatment of subjects with active rheumatoid arthritis

Interleukin-11 (IL-11) is a pleiotropic cytokine that regulates the growth and development of hematopoietic stem cells and decreases the proinflammatory mediators of cytokine and nitric oxide production. In animal models of arthritis, treatment with recombinant human IL-11 (rhIL-11) reduces both the level of synovitis and the histologic lesion scores in the joints.

Additional traffic assignment options for the TASSIM model. Phase I. Final report.

Transportation Department, Washington, D.C.

Integrated traffic simulation model - phase I. Volume 4: revisions to the UTCS-1 traffic simulation model to enhance operational efficiency. Final report.

Federal Highway Administration, Washington, D.C.

Statewide pedestrian study. Phase I report: Maryland's overall pedestrian accident situation. Interim report.

Mode of access: Internet.

Integrated traffic simulation model, phase, I. Volume 1: executive summary. Final report.

Federal Highway Administration, Washington, D.C.

Integrated traffic simulation model - phase I. Volume 2: design of the TRAF system (TOS). Final report.

Federal Highway Administration, Washington, D.C.

Strategic Defense Initiative : funding needs through completion of Phase I System.

GAO/NSIAD-90-79-FS.

Integrated motorist information system (IMIS) feasibility and design study. Phase I: feasibility study. Volume 2 - appendices. Final report.

Federal Highway Administration, Office of Research and Development, Washington, D.C.

Eastern lake survey-phase II : national stream survey-phase I : processing laboratory operations report.

Mode of access: Internet.