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EXPAND: 48-week follow-up analysis
Figure 1. Study design. Dark arrows represent escalation from a given dose level to the following one, only if both that dose level and the previous one have been deemed safe. Dotted arrows represent each dose level in stratum 2, which will open to patients only if both that dose level and the following one have been deemed safe in stratum 1. Per protocol amendment, new patients enrolled in stratum 1 in the safety-expansion phase will be given the 10 mg twice-daily (bid) dose instead of the 15 mg bid dose level previously evaluated as the maximum safe starting dose (MSSD). The MSSD cohort (10 mg bid) in stratum 1 included 3 patients from the dose-escalation and 17 patients from the safety-expansion phases. In stratum 2, the MSSD cohort included 8 patients from the dose-escalation and 10 patients from the safety-expansion phases.
enrolled in S1 in the safety-expansion phase (Online Supplementary Appendix). Patients who were already receiving the 15 mg bid dose continued to take their assigned dose.
The end of the study will occur after all study patients complete their last assessment as per protocol (follow-up visit 30 days after the end of the treatment visit) (Online Supplementary Appendix). Details of the statistical analyses are presented in the Online Supplementary Appendix.
The study was approved by the institutional review boards of the respective institutions prior to patient enrollment and was conducted in accordance with the principles of the Declaration of Helsinki. All patients provided written informed consent. The trial is registered at clinicaltrials.gov identifier: 01317875.
Assessments
In the dose-escalation phase, the primary objective was to determine the MSSD (incidence rate of DLTs) of ruxolitinib. The key secondary objectives included safety [frequency, duration, and severity of adverse events (AEs) and serious AEs] and efficacy (spleen response: proportion of patients achieving ≥50% of reduc- tion in palpable measurement of spleen length at week 48 data cutoff relative to day 1). The key exploratory objectives included patient-reported outcomes [change in the Total Symptom Score (TSS) as assessed by the modified Myelofibrosis Symptom Assessment Form (MFSAF) v.2.0 diary].31-33
Results
Results from the interim analysis (week 24 data cutoff: January 20, 2015) of the study have been presented at the 2015 American Society of Hematology meeting.29 At that data cutoff, 46 patients (S1, n=27; S2, n=19) had received treatment.
Overall study cohort
At week 48 data cutoff (December 7, 2017), the final enrollment for EXPAND included 69 patients (S1, n=44; S2, n=25) (Online Supplementary Table S2). Overall, 31.8% (14 out of 44) of patients in S1 and 12.0% (3 out of 25) of patients in S2 were still receiving ruxolitinib treatment (Online Supplementary Table S3). The median exposure to ruxolitinib was 51.4 weeks (range, 0.9-210.0 weeks) in S1 and 67.4 weeks (range, 4.4-161.1 weeks) in S2.
The AEs (in ≥20% of patients in either stratum, regardless of study drug relationship) reported in the overall cohort are presented in Online Supplementary Table S4. Reasons for on-treat- ment death included acute myeloid leukemia (1 patient), cardiac arrest (1 patient), and unknown (1 patient, not suspected to be related to study drug) in S1 and complications following gastroin- testinal ulcer (1 patient) and multiple organ failure (1 patient) in S2 (Online Supplementary Table S5). Hemoglobin levels and platelet counts over time are presented in Figure 2. An initial decrease in the blood count parameters was observed in the first few weeks; however, the parameters stabilized with time. Spleen response at week 48 was achieved in 7 out of 22 patients [31.8% (95%CI: 13.9, 54.9)] in S1 and 5 out of 14 patients [35.7% (95%CI: 12.8, 64.9)] in S2. A spleen response at any time point was observed in 22 out of 43 patients [51.2% (95%CI: 35.5, 66.7)] in S1 and 17 out of 25 patients [68.0% (95%CI: 46.5, 85.1)] in S2 (Online Supplementary Figure S1).
Maximum safe starting dose cohort
Patients’ characteristics. Baseline patients’ characteristics (S1, n=20; S2, n=18) were indicative of an advanced disease stage (Online Supplementary Table S6). In the MSSD cohort, 70.0% (14 out of 20) of patients in S1 and 16.7% (3 out of 18) of patients in S2 were still receiving ruxolitinib treatment (Table 1). The primary reasons for the end of treatment included AEs [S1, n=1 (5.0%); S2,
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