Only Modest Benefit Seen in Combining Ruxolitinib, Buparlisib

A study combining ruxolitinib and buparlisib in myelofibrosis (MF) showed only a modest benefit compared with ruxolitinib alone, and further studies to see if there is a synergistic effect between the 2 agents will not continue, according to a study published recently in Haematologica.

MF is a myeloproliferative neoplasm characterized by bone marrow fibrosis, cytopenias, splenomegaly, and elevated proinflammatory cytokine levels. Janus kinase (JAK) 1/2 inhibitors in patients with MF are a mainstay treatment for myeloproliferative neoplasms, although they are not a cure.

Ruxolitinib, a JAK1/2 inhibitor, is approved for treatment of MF and polycythemia vera after an inadequate response or intolerance to hydroxyurea.

Buparlisib is an inhibitor of the pan-class I phosphatidylinositol 3-kinase (PI3K) family of lipid kinases with potential anticancer activity; the PI3K/AKT pathway is also dysregulated in MF. The idea behind the study was to target multiple signaling pathways involved in MF.

HARMONY, a phase 1B, 2-arm, open-label, multicenter, dose-finding study, investigated the safety and efficacy of ruxolitinib and buparlisib in adult patients with intermediate/high-risk primary MF, post—polycythemia vera MF, or post–essential thrombocythemia MF. The maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) was established at 15 mg twice daily (bid) for ruxolitinib and 60 mg once daily (qd) for buparlisib. The dose-limiting toxicity (DLT) and adverse event (AE) profile of the combination was similar to the safety profile of the individual drugs.

Patients with and without prior JAK1/2 treatment were enrolled simultaneously into the 2 arms of the study. The study consisted of 2 periods, namely the treatment period (cycle 1 day 1 to cycle 7 day 1 [C7D1]) and treatment extension period (C7D1 to cycle 12 day 28 [C12D28]). The treatment period comprised 6 cycles of 28 days per cycle. A follow-up visit was scheduled 30 days after the end-of-treatment visit (C7D1, C12D28, or premature discontinuation).

The study comprised dose-escalation and expansion phases. In the dose-escalation phase, successive cohorts of a minimum 3 patients received increasing doses of ruxolitinib (5 mg bid to 40 mg bid) and buparlisib (40 mg qd to 100 mg qd) until the MTD/RP2D was reached. An additional 6 patients were enrolled to determine a dose level as the MTD/RP2D.

The primary objective was to establish the MTD/RP2D of the combination of ruxolitinib and buparlisib in each arm as assessed by the incidence rate of DLTs. The key secondary objective was to evaluate safety.

Sixty-three patients (46% with primary MF, 31.7% with post—polycythemia vera MF, and 22.2% with post–essential thrombocythemia MF) were enrolled in the study (treatment naïve, n = 33; prior treatment, n = 30).

AEs (33.3%) were the primary reason for end of treatment. Primary AEs leading to study drug discontinuation in the MTD population included thrombocytopenia (n = 3), anxiety (n = 2), and depression (n = 2) in the treatment-naïve arm and progression to acute myeloid leukemia (n = 2) in the prior treatment arm.

The researchers said HARMONY is the first study presenting safety and efficacy data on ruxolitinib and buparlisib combination in patients with MF. The MTD for the combination was determined to be 15 mg bid for ruxolitinib and 60 mg qd for buparlisib in both arms of the study.

Approximately 40% of the patients had a spleen volume reduction of 35% or greater with the combination in the expansion phase. With ruxolitinib alone in previous studies, 41.9% of patients at week 24 and 28% of patients at week 48 achieved spleen volume reduction of 35% or greater.

But in this study, the anticipated synergistic effect of the combination in spleen volume was not observed. Only a few patients had improvement or stabilization in bone marrow fibrosis.

Reference

Durrant ST, Nagler A, Guglielmelli P, et al. Results from HARMONY: an open-label, multicentre, 2-arm, phase 1b, dose-finding study assessing the safety and efficacy of the oral combination of ruxolitinib and buparlisib in patients with myelofibrosis [published online May 7, 2019]. Haematologica. doi:10.3324/haematol.2018.209965.