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A.M. Vannucchi et al.
COMFORT-II (n=219; clinicaltrials.gov identifier: 00934544).9-12 In both COMFORT studies, ruxolitinib demonstrated marked and sustained clinical benefits in spleen size and improvement in symptom burden, and was generally well tolerated.9-12
Patients with MF may present with thrombocytopenia (platelet counts, <100x109/L) owing to the nature of the disease.13,14 Across various studies, approximately 16-26% of patients with MF were found to be thrombocytopenic at diagnosis.15-19 In addition, patients with MF may also experience treatment-emergent thrombocytopenia while on ruxolitinib therapy (owing to its mechanism of action).9,12,20 The Study 251 (n=153; clinicaltrials.gov identifi- er: 00509899) identified thrombocytopenia as a dose-lim- iting toxicity (DLT) for ruxolitinib.21 Patients in the COM- FORT studies had baseline platelet counts ≥100x109/L, limiting the safety and efficacy data in patients with lower platelet counts.14,18,21
To date, only a few treatment options have been evaluated for patients with MF and thrombocytopenia. The safety and efficacy of JAK inhibitors in thrombocy- topenic patients with MF have also not been adequately explored.15,22 Evidence from clinical trials evaluating the use of ruxolitinib in patients with MF with baseline thrombocytopenia (platelet counts <100x109/L) is limited.14,23-25
The Study 258 (n=50; clinicaltrials.gov identifier: 01348490) evaluated the efficacy and safety of low-dose ruxolitinib [5 mg twice daily (bid)] with subsequent dose escalation in patients with low platelet counts (50 to <100x109/L).14 Ruxolitinib was generally well tolerated and provided efficacy benefits, suggesting that a starting dose of 5 mg bid with escalation to 10 mg bid may be suit- able for the low platelet count population.14
The JUMP study (n=2233; clinicaltrials.gov.identifier: 01493414), a phase IIIb expanded- access study, was amended to enroll patients with base- line platelet counts ≥50x109/L to gather additional safety and efficacy data in patients with low platelet counts.23-25 In the JUMP study, the safety profile of ruxolitinib in the low-platelet patient cohort was consistent with that observed in patients with platelet counts ≥100x109/L. Spleen and symptom responses achieved with low-dose ruxolitinib (5 mg bid) were within the expected range based on the COMFORT studies.23
The recommended starting dose of ruxolitinib (prescribing information) is based on the platelet count.26 The maximum recommended starting dose in patients with platelet counts between 50x109/L and 100x109/L is 5 mg bid, and the dose should be titrated with caution.26,27 However, the findings from the COMFORT-I and the Study 258 demonstrated that the final titrated doses of ≥10 mg bid resulted in larger improvements in spleen vol- ume and MF-related symptoms compared to titrated doses of ≤5 mg bid.14,28
The purpose of the EXPAND study (clinicaltrials.gov iden- tifier: 01317875: open-label, phase Ib, dose-finding study) was to establish the maximum safe starting dose (MSSD) of ruxolitinib in patients with MF with baseline platelet counts between 50x109/L and 100x109/L. The study also intended to assess the safety and tolerability of ruxolitinib in this patient population.
The preliminary findings from the dose-escalation and safety-expansion phases of EXPAND at the preplanned interim analysis [day 168 (week 24)] were previously
reported.29 Guided by the occurrence of protocol-defined DLTs during the first cycle of treatment (28 days), 15 mg bid was initially declared as the MSSD for patients enrolled in stratum 1 (S1; platelet counts: 75-99×109/L) of the study, whereas 10 mg bid was declared as the MSSD for patients in stratum 2 (S2; platelet counts: 50-74×109/L). However, based on the safety and efficacy findings from the interim analysis, the MSSD for S1 was subsequently lowered to 10 mg bid (as per the protocol amendment). Here, we present the results from the 48-week follow up of EXPAND for the MSSD cohorts.
Methods
Patient population
Eligible patients: i) were aged ≥18 years; ii) had been diagnosed with intermediate-1, intermediate-2, or high-risk MF (primary MF, post-polycythemia vera MF, or post-essential thrombocythemia MF);30 iii) had a palpable spleen (≥5 cm from the costal margin); and iv) fulfilled the platelet count criteria at screening or study day 1 (S1: <100x109/L and ≥75x109/L; S2: <75x109/L and ≥50x109/L). An Eastern Oncology Cooperative Group performance status of ≤2 was required at screening. The key exclusion criteria included: i) patients with any history of platelet counts <45x109/L within 30 days prior to screening; ii) platelet transfu- sion within 14 days prior to screening; iii) history or predisposi- tion to clinically significant bleeding; iv) history of platelet dys- function and/or bleeding diathesis; and v) regular use of drugs inhibiting platelet function.
Study design
EXPAND was a phase Ib, open-label, multicenter, dose-finding study of ruxolitinib in patients with intermediate- or high-risk primary MF, post-polycythemia vera MF, or post-essential throm- bocythemia MF who had baseline platelet counts between ≥50x109/L and <100x109/L. The study design is shown in Figure 1.
The study period consisted of 2 phases: dose escalation and safety expansion. The successive cohorts of newly enrolled patients received increasing doses of ruxolitinib until the MSSD was determined in the dose-escalation phase. The MSSD was defined as the dose level most closely associated with a posterior probability of DLT between 16% and 33% that did not also have >25% probability of excessive toxicity. A DLT was defined as the occurrence of any treatment-related toxicity occurring through study day 28 (Online Supplementary Table S1). A preplanned interim analysis was conducted when the last patient enrolled in the dose-escalation phase completed week 24.29
An adaptive Bayesian logistic regression model guided by escalation with overdose control was used to allocate patients into each cohort (5 dose levels) in the dose-escalation phase (Treatment Dose Levels) (Online Supplementary Appendix). The patients in the dose-determining set (DDS) enrolled in the dose-finding part of the study were assessed to determine the MSSD. The DDS consisted of all patients from the safety set who met the minimum exposure criterion and had sufficient safety evaluations or who experienced a DLT. The safety set consisted of all patients who received at least 1 dose of ruxolitinib. The DDS definition, mini- mum exposure criterion, and planned enrollment are provided in the Online Supplementary Appendix.
The safety-expansion phase was conducted after determination of the MSSD to further evaluate the safety and tolerability of the MSSD, and establish that the dose was suitable for use in patients with MF with low platelet counts. Per protocol amendment, 10 mg bid was evaluated as the starting dose for all new patients
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haematologica | 2019; 104(5)