ADORE: an open platform study of ruxolitinib in combination with other novel therapies in patients with myelofibrosis

Abstract

Ruxolitinib, a Janus kinase (JAK)1/JAK2 inhibitor, is the standard of care for symptomatic patients with myelofibrosis (MF). However, ∼70% of patients discontinue ruxolitinib after ∼5 years, a third of whom report suboptimal splenic response. ADORE was a phase 1b/2 study with an innovative open platform design that assessed the safety, efficacy, and pharmacokinetics of novel compounds in combination with ruxolitinib in patients with MF who had a suboptimal response to ruxolitinib alone. A total of 44 patients were enrolled in part 1 of the study of ruxolitinib in combination with siremadlin, rineterkib, sabatolimab, crizanlizumab, or NIS793. Most patients were allocated to receive ruxolitinib plus siremadlin (N = 23). The most frequent adverse events with siremadlin were gastrointestinal (nausea and diarrhea) and hematological (thrombocytopenia, anemia, and neutropenia). Siremadlin 30 mg orally once daily on days 1 to 5 of a 28-day cycle was selected as the recommended phase 2 dose. The most robust spleen volume reduction (SVR) at 24 weeks was observed with ruxolitinib plus siremadlin 30 mg. Reductions in percent JAK2V617F allele burden at week 24 were observed, notably in several patients with SVR. An increase in growth differentiation factor 15 protein levels in patients receiving siremadlin demonstrated the on-target modulation of downstream p53 targets. Overall, available data from ADORE suggest the feasibility and benefits of combining novel agents with ruxolitinib in patients with suboptimal response to ruxolitinib alone. This trial was registered at www.clinicaltrials.gov as #NCT04097821.

Graphical abstract

Figure 1.

Study design.^aPatients were enrolled with earlier versions of the protocol with the following differences in key inclusion criteria: Hb level <10 g/dL (protocol amendment 4, 25 August 2020); treated with ruxolitinib for ≥24 weeks and at a stable dose for ≥8 weeks before study entry (protocol amendment 6, 20 July 2021). ^bAs the enrollment was permanently halted, based on protocol amendment, an extension treatment phase was added to part 1 for eligible and benefitting patients from part 1. ^cDose escalation to determine the phase 2 dose for the siremadlin and rineterkib arms (already known for other agents). ^dThe NIS793 arm had a 21-day cycle; all other arms had a 28-day cycle. ^ePatients were to be treated with combination therapy for 12 weeks, followed by novel agent monotherapy. ^fThe ruxolitinib dose was to be neither escalated nor de-escalated and should have remained fixed at the stable dose during part 1 of the study. ^gRineterkib was tested only at 200 mg in the actual study, but the study design had other potential options stated in the event of dose escalation or reduction. BID, twice daily; C1D15, cycle 1 day 15; CT, computed tomography; Hb, hemoglobin; MRI, magnetic resonance imaging; PET-MF, post–essential thrombocythemia myelofibrosis; PMF, primary myelofibrosis; PPV-MF, post–polycythemia vera myelofibrosis; QD, once daily; Q3W, every 3 weeks; Q4W, every 4 weeks.

Figure 2.

Change in spleen volume (CT/MRI) from baseline at week 24. n = number of patients with both baseline and week 24 MRI/CT spleen volume assessment. N = number of patients treated. $Shown for patients with both baseline and end of week 24 MFSAF TSS assessment and baseline TSS ≥10. #From BL to week 24 or at EOT assessment if the EOT visit is within the week 24 assessment window (169 ± 28 days). BL, baseline; CT, computed tomography; EOT, end of treatment; MRI, magnetic resonance imaging; NA, not available; RUX, ruxolitinib; SVR, spleen volume reduction; TSS, total symptom score; W24, week 24.

Figure 3.

Change in MFSAF TSS from baseline at week 24 when the baseline score is ≥10. n = number of patients with both baseline and week 24 TSS assessment and baseline TSS of ≥10. N = number of patients treated. Change in TSS assessed by MFSAF v4 7-day recall. BL, baseline; NA, not available; TSS, total symptom score.

Figure 4.

Change in JAK2V617F allele burden from baseline at week 24. n = number of patients with Week 24 JAK2V617 allele burden assessment. N = number of patients treated. #From BL to week 24 or at EOT assessment if the EOT visit is within the week 24 assessment window (169 ± 28 days). The JAK2V617 detection threshold is the assay limit of detection (0.5%). JAK2V617 mutational status (−) may have the allele burden at an undetectable or negligible level. High-risk mutation genes include ASXL1, SRSF2, EZH2, IDH1, IDH2, and U2AF1; the mutational status is considered positive if any one of these genes demonstrates a mutation at a given time point. BL, baseline; EOT, end of treatment; NA, not available; W24, week 24.