BackgroundThis study describes the development of Response Surface Pathway (RSP) design, assesses its performance and effectiveness in estimating LD50, and compares RSP with Up and Down Procedures (UDPs) and Random Walk (RW) design.MethodsA basic 4-level RSP design was used on 36 male ICR mice given intraperitoneal doses of Yessotoxin. Simulations were performed to optimise the design. A k-adjustment factor was introduced to ensure coverage of the dose window and calculate the dose steps. Instead of using equal numbers of mice on all levels, the number of mice was increased at each design level. Additionally, the binomial outcome variable was changed to multinomial. The performance of the RSP designs and a comparison of UDPs and RW were assessed by simulations. The optimised 4-level RSP design was used on 24 female NMRI mice given Azaspiracid-1 intraperitoneally.ResultsThe in vivo experiment with basic 4-level RSP design estimated the LD50 of Yessotoxin to be 463 μg/kgBW (95% CI: 383–535). By inclusion of the k-adjustment factor with equal or increasing numbers of mice on increasing dose levels, the estimate changed to 481 μg/kgBW (95% CI: 362–566) and 447 μg/kgBW (95% CI: 378–504 μg/kgBW), respectively. The optimised 4-level RSP estimated the LD50 to be 473 μg/kgBW (95% CI: 442–517). A similar increase in power was demonstrated using the optimised RSP design on real Azaspiracid-1 data. The simulations showed that the inclusion of the k-adjustment factor, reduction in sample size by increasing the number of mice on higher design levels and incorporation of a multinomial outcome gave estimates of the LD50 that were as good as those with the basic RSP design. Furthermore, optimised RSP design performed on just three levels reduced the number of animals from 36 to 15 without loss of information, when compared with the 4-level designs. Simulated comparison of the RSP design with UDPs and RW design demonstrated the superiority of RSP.ConclusionOptimised RSP design reduces the number of animals needed. The design converges rapidly on the area of interest and is at least as efficient as both the UDPs and RW design.

An anti-cancer agent containing benzene-poly-carboxylic acids complex with cis-diammineplatinum (II) dichloride (BP-C1) was developed to establish a low toxic and cost effective treatment of breast cancer. The study was aimed to investigate if BP-C1 could be given continuously without rest periods and to estimate Maximum Tolerated (MTD) and Minimum Efficient Dose (MED) in metastatic breast cancer (MBC) treatment. A non-randomized, multicentre trial with 3-level Response Surface Pathway design was performed. Five MBC patients were included at each of the three design levels. BP-C1 was daily administrated intramuscularly during 32 days. The first five patients were given a cumulative dose of 0.64 mg/kg bodyweight. Based on the obtained results, the dose was increased /decreased for the next five patients in the next design level. The main variable was the National Cancer Institute Common Toxicity Criteria (NCI-CTC). Cumulative doses of 0.96 mg/kg or higher were defined as high-dose. One moderate and one mild increase in maximum NCI-CTC were found on 0.64 mg/kg, one mild increase occurred on 0.96 mg/kg and no changes were detected on 1.12 mg/kg. The Sum NCI-CTC increased (p=0.07) in the low-dose group, but reduced (p=0.09) in the high-dose group. In the high-dose group, 62.5% of the patients were classified as responders including one complete responder compared to 28.6% in the low-dose group. In conclusion, BP-C1 can safely be administrated continuously during 32 days. The MTD is larger than 1.12 mg/kg and MED estimated to 0.96 mg/kg.

Background: The most commonly used escalation methods in dose-finding studies have obvious weaknesses, and the Bayesian approach is difficult for clinicians to understand and to apply. The study aims were to introduce and assess the performance of clinically based response surface pathway (RSP) design for dose-finding studies, exemplified by one between-patient study, one within-patient study, and simulation studies. Methods: The between-patient study consisted of 15 women suffering from stage IV breast cancer, while the within-patient study consisted of seven female dogs with metastatic mammary cancer. The studies were conducted to determine the maximum tolerated dose (MTD) of a new anticancer agent named BP-C1 using three-level RSP designs. Adjustment of the dose from one design level to the next was based on a k-adjustment factor estimated to ensure coverage of the entire predefined dose window. Patient sequences with an equal number of patients as design levels were included in the between-patient design, whereas the same patients were included in all the design levels in the within-patient design. Results: Four of the five patient sequences in the between-patient study and all seven dogs in the within-patient study reached the upper limit of the dose windows without any increase in toxicity. The MTD of BP-C1 was thus found to be higher than the predefined cumulative dose window for both patient groups. In all three scenarios, the RSP design estimated MTDs better than the traditional 3+3 design; however, the toxicity rates were found to be higher when the target MTD was under the starting dose. Conclusion: The RSP designs do not need an assumed statistical model, and may be useful in estimating MTD, using a minimal sample size. The k-adjustment factor ensures complete dose window coverage and the design utilizes more information by allowing multinomial outcomes.

Background:Response surface pathway (RSP) design has been recently developed and described for dose-finding studies. The aim of this paper was to introduce and demonstrate additional procedures to strengthen and generalize the design and combine RSP with classical study design. Materials and methods: Nine bull calves and six heifer calves were included in an unbalanced 2 × 2 Latin Square (LSQ) designed study with large and small aperture bottle teats. The two LSQ sequences were performed with independent randomized three-level between-patient RSP design with an odd number of response classifications. The milk temperature window was 8°C-38°C with a mid temperature of 23°C. X-rays of the abdominal cavity were taken before, during, and immediately after intake of milk and recorded as "milk", "trace", or "no milk". Based on the results of the first design level, the milk temperatures for five calves in the second design level were obtained by a randomization procedure. A similar procedure was performed for seven calves in the third design level. Adjustment of the dose from one design level to the next was based on a k-adjustment factor estimated to ensure coverage of the entire predefined dose window. Results: Starting with a low number of subjects and increasing this number with increasing design levels reduces the sample size without reducing the power. The suggested randomization procedure worked as expected. No milk in Rumen was recorded and minimum milk temperature (MMT) was estimated to be ≤8°C for both teats. The odd number of response categories increases the flexibility of RSP, enabling category redefinition in hindsight from "trace" to "uncertain". After category redefinition, MMT for large bottle teat was estimated to be 14.3°C (95% confidence interval: 8.3-20.3°C), but 8°C for small. Conclusion:The suggested changes and additional procedures increase the strength and flexibility of the RSP design. Keywords: k-adjustment factor, Latin Square design, patient reduction in clinical trials, randomized response surface pathway design BackgroundDuring the first few weeks of life, milk is the primary source of nutrition for the dairy calf. Over the milk feeding period, the calf has an anatomical feature called the esophageal groove or sulcus reticuli. The groove, when activated, turns into a tube allowing the milk to pass by the reticulorumen straight into the abomasum where the milk is digested.1 Activation of the reticular groove is caused by many factors, including the smell and taste of milk, milk temperature, sucking behavior, and body posture while drinking.2 If the esophageal groove is not properly closed, milk can enter Rumen, the

The pharmacokinetic profile, tolerability and efficacy of benzene-poly-carboxylic acids complex with cis-diammineplatinum (II) dichloride (BP-C1) were studied in dogs with mammary cancer. A three-level response surface pathway designed trial was performed on seven dogs. At each level BP-C1 was administered subcutaneously daily for 7 days followed by a 7-day rest period in a dose escalating manner. Adverse events according to VCOG-CTCAE, performance status and tumour progression were recorded. The pharmacokinetic profile followed a two-compartment model with rapid absorption, short distribution, and a slow elimination phase. The overall elimination half-life was 125 h. The maximum tolerated dose of BP-C1 was estimated to be above 0.46 mg kg −1 . A significant reduction in VCOG-CTCAE toxicity which correlated negatively with increasing dose was found. The dogs' general performance status remained unchanged. No decrease in total tumour burden was found, although temporary tumour reduction was seen in some target tumours.