A dose-finding phase Ib study successfully evaluated a combined regimen of oral ruxolitinib and buparlisib in adult patients with intermediate- or high-risk primary or secondary myelofibrosis for safety and efficacy.
Simon T. Durrant, MBBS, MRCS
A dose-finding phase Ib study successfully evaluated a combined regimen of oral ruxolitinib (Jakafi) and buparlisib in adult patients with intermediate- or high-risk primary or secondary myelofibrosis (MF) for safety and efficacy.
The study, which was recently published inHaematologica, determined that the combination was well tolerated at low doses of the 2 agents and demonstrated modest efficacy. However, the investigators decided not to advance the combination for further testing due to the modest benefit seen.
“The dose-limiting toxicity [DLT] and adverse event [AE] profile of the combination was similar to the safety profile of the individual drugs and resulted in an overall moderate clinical benefit compared with ruxolitinib monotherapy,” wrote the authors, led by Simon T. Durrant, MBBS, MRCS, of Royal Brisbane Hospital, Herston, Australia. “Based on [this] modest, overall benefit-risk profile and efficacy, the ruxolitinib and buparlisib combination will not be progressed at this time.”
The treatment period in the HARMONY trial consisted of 6 cycles of 28 days followed by a treatment-extension period consisting of 6 additional cycles. Participants were eligible to continue into the extension period if they showed no evidence of disease progression at the end of the treatment period.
HARMONY’s main objective was to establish the maximum-tolerated dose (MTD)/recommended phase II dose (RP2D) of the combination of ruxolitinib and buparlisib in patients who had received prior treatment with a JAK inhibitor and patients who had not. The incidence rate of DLTs was used to assess each arm. The secondary objective was to evaluate the combined regimen’s safety.
In all, the investigators enrolled 33 JAK inhibitor-naïve patients and 30 who had received prior JAK inhibitor treatment. The disease breakdown was 46% with primary MF, 31.7% with post-polycythemia vera MF, and 22.2% with post-essential thrombocythemia MF. Notably, patients in the prior JAK inhibitor group had lower hemoglobin and platelet counts and a higher white blood cell count compared with JAK inhibitor-naïve patients at baseline.
In the dose-escalation phase, dose levels for the ruxolitinib/buparlisib combination were: 10 mg of ruxolitinib and 60 mg of buparlisib (dose level 1; n = 15), 15 mg of ruxolitinib and 60 mg of buparlisib (dose level 2; n = 42), 15 mg of ruxolitinib and 80 mg of buparlisib (dose level 3; n = 3), and 20 mg of ruxolitinib and 80 mg of buparlisib (dose level 4; n = 3).
Among the 42 patients treated at the MTD, 70.6% of patients in each group achieved ≥50% reduction in total symptom scores by week 24. Additionally, several patients demonstrated improvement in bone marrow fibrosis (1 in each arm) or stabilization (2 in JAK inhibitor-naïve arm and 4 in prior JAK inhibitor arm).
At the MTD, the median duration of exposure to ruxolitinib was 79.5 weeks (range, 12-167.6) in the JAK inhibitor-naïve arm and 54.6 weeks (range, 8-151.3) in the prior JAK inhibitor arms. The median duration of buparlisib was 79.4 weeks (range, 2.4-167.4) in the JAK inhibitor-naïve arm and 54.5 weeks (range, 7.1-151.1) in the prior treatment arm.
In the JAK inhibitor-naïve arm, 75% of patients (12 of 16) achieved ≥50% reduction in spleen length by the beginning of the treatment extension period. This number rose to 13 patients (86.7%) by the end of the extension period. In the prior JAK inhibition arm, only about one-third of patients achieved this level of response (35.3%, 6 of 17 before extension period; 36.4%, 4 of 11 by the end of the extension period). Additionally, the proportion of MTD patients in the expansion phase who achieved ≥35% of reduction in spleen volume was 5 of 9 (55.6%) in the JAK inhibitor-naïve arm and 3 of 7 (42.9%) in the prior JAK inhibition arm.
There were 5 DLTs during the first cycle, 3 in JAK inhibitor-naïve patients, and 2 in the prior therapy group. Three patients experienced thrombocytopenia, including 2 who were JAK inhibitor-naïve and 1 who was pretreated with a JAK inhibitor, all at different dose levels. One JAK inhibitor-naïve patient treated at dose level 2 experienced anxiety and 1 JAK inhibitor pretreated patient treated at dose level 4 experienced depression.
The MTD/RP2D was established as 15 mg twice daily for ruxolitinib and 60 mg once daily for buparlisib.
Overall, one-third of patients in both groups ultimately discontinued treatment due to AEs and every patient experienced at least 1 AE. Among nonhematologic AEs, anxiety, depression, dizziness, dyspnea, and stomatitis were the most common in the MTD population (n = 42). Thrombocytopenia and anemia were the most frequent all-grade hematologic AEs. These AEs occurred in 63.6% and 50% of the JAK inhibitor-naïve group, respectively. Among those who had received prior JAK inhibition, 55% developed thrombocytopenia or anemia.
More pretreated patients developed grade 3/4 thrombocytopenia than treatment-naïve patients (35.0% vs 22.7%). The most common serious AEs were pneumonia (JAK inhibitor-naïve, 9.1%; JAK inhibitor pretreated, 15%) and pyrexia (4.5% and 10%, respectively). Ten percent of pretreated patients progressed to acute myeloid leukemia compared with 4.5% of the JAK inhibitor-naïve patients.
Turrant et al found that the frequency of infections, thrombocytopenia, and psychiatric disorders were similar or slightly higher in the prior JAK inhibition arm compared with the JAK inhibitor-naïve arm. They also found that 7 on-treatment deaths occurred, but determined that none of these were related to the study treatment.
The investigators noted that no unexpected DLTs were observed with the combination regimen and that the incidence of thrombocytopenia, anxiety, and depression were consistent with the known profile of both drugs. They found the combination to be well- tolerated with a manageable safety profile and clinically relevant efficacy. No new safety signals were observed compared with prior reports for each of the agents.
“In our study, the anticipated synergistic effect of the combination was not observed on spleen response. The combination demonstrated a modest effect inJAKallele burden in both the arms, and only a few patients had improvement or stabilization in bone marrow fibrosis,” Turrant et al wrote. “However, 2 factors have to be taken into account before interpreting this data; the small sample size and short duration of the study.”
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 9, 2019].Haematologica.doi: 10.3324/haematol.2018.209965.