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Clinical Trial
. 2018 May;7(5):1766-1773.
doi: 10.1002/cam4.1436. Epub 2018 Mar 25.

Determination of a radotinib dosage regimen based on dose-response relationships for the treatment of newly diagnosed patients with chronic myeloid leukemia

Hayeon Noh  1 , Su Young Jung  2   3 , Jae-Yong Kwak  4 , Sung-Hyun Kim  5 , Suk Joong Oh  6 , Dae Young Zang  7 , Suhyun Lee  2   3 , Hye Lin Park  8 , Dae Jin Jo  8 , Jae Soo Shin  8 , Young Rok Do  9 , Dong-Wook Kim  10 , Jangik I Lee  2   3
Affiliations
Clinical Trial

Determination of a radotinib dosage regimen based on dose-response relationships for the treatment of newly diagnosed patients with chronic myeloid leukemia

Hayeon Noh et al. Cancer Med. 2018 May.

Abstract

Radotinib is a second-generation BCR-ABL1 tyrosine kinase inhibitor approved for the treatment of chronic myeloid leukemia in chronic phase (CP-CML). Here, using the data from a Phase 3 study conducted in patients with newly diagnosed CP-CML, the dose-efficacy as well as dose-safety relationship analyses were performed to determine a safe and effective initial dosage regimen of radotinib. A significant positive association was detected between the starting dose of radotinib adjusted for body weight (Dose/BW) and the probability of dose-limiting toxicity (≥grade 3 hematologic and nonhematologic toxicity) (P = 0.003). In contrast, a significant inverse association was discovered between Dose/BW and the probability of major molecular response (BCR-ABL1/ABL1 ≤ 0.1%) when controlled for sex (P = 0.033). Moreover, frequent dose interruptions and reductions secondary to radotinib toxicities occurred in the Phase 3 study, resulting in nearly half (44%) of patients receiving a reduced dose at a 12-month follow-up. In conclusion, the results of this study demonstrate the need for initial radotinib dose attenuation to improve the long-term efficacy and safety of radotinib. Hence, the authors suggest a new upfront radotinib dose of 400 mg once daily be tested in patients with newly diagnosed CP-CML.

Keywords: Chronic myeloid leukemia; dose determination; dose-response relationship; radotinib; tyrosine kinase inhibitor.

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Figures

Figure 1
Figure 1
Logistic regression curve that predicts the probability of major molecular response (MMR) at 12 months in relation to the daily dose of radotinib adjusted for patients’ baseline body weight (Dose/BW), when controlled for sex. P indicates the probability that a patient achieves MMR.
Figure 2
Figure 2
Box plots showing distributions of time to first dose‐limiting toxicity (DLT) categorized by DLT manifestations. The vertical line across the box is the median, and the box represents the interquartile range (IQR; 25th to 75th percentile). The bars extend to the minimum and the maximum values. Black dots indicate the individual data points.
Figure 3
Figure 3
Logistic regression curve that predicts the probability of first dose‐limiting toxicity (DLT) by 12 months in relation to the daily dose of radotinib adjusted for patients’ baseline body weight (Dose/BW). P indicates the probability that a patient experiences DLT.
Figure 4
Figure 4
Kaplan–Meier curves for the time to first dose‐limiting toxicity (DLT) by 12 months (A) in all patients (n = 160) treated with radotinib in Phase 3 study, and (B) in the patients who received a daily dose of radotinib adjusted for patients’ baseline body weight (Dose/BW) ≥13 mg/kg/day compared with those who received a Dose/BW <13 mg/kg/day.
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