Part 1 (Phase 1b) includes a dose-escalation arm to determine the recommended Phase 2 dose
(RP2D) for the combination of siremadlin and ruxolitinib, and two safety run-in arms to
confirm the doses of crizanlizumab plus ruxolitinib and sabatolimab plus ruxolitinib.
Ruxolitinib will be administered at the same stable dose used prior to study entry. A Bayesian
logistic regression model will be used to identify the maximum tolerated dose and/or RP2D
for the siremadlin and ruxolitinib combination. Patients will be treated for ≥6 cycles (24
weeks). The combination treatments evaluated as safe and tolerable in Part 1 will proceed to
Part 2.
In Part 2 (Phase 2; early efficacy assessment, Selection), patients will be randomized to one of
the selected combinations or ruxolitinib monotherapy and treated for ≥12 cycles (48 weeks).
After all Part 2 patients have completed 24 weeks of treatment, an interim analysis will
determine which treatment should be dropped for futility or considered in Part 3 (Phase 2;
efficacy, Expansion).
In Part 3, patients will be randomized 2:1:1 to the combination treatment arm, ruxolitinib
cessation arm (novel agent monotherapy), or ruxolitinib monotherapy arm and treated for
≥12 cycles. Patients in the ruxolitinib cessation arm will be treated with ruxolitinib
combination therapy for 12 weeks, followed by tapering of ruxolitinib.
The study will end 24 months after the last patient has initiated Part 3. Enrollment is currently
ongoing.