Title: PROMise: Investigation into the combination of a Plexxikon BETi with ruxolitinib in patients with high or intermediate-2 risk myelofibrosis not receiving an adequate response with ruxolitinib alone
Funder: Cancer Research UK

Abstract: Background Myelofibrosis (MF) is a chronic Philadelphia chromosome-negative myeloproliferative neoplasm associated with progressive bone marrow fibrosis and extramedullary haematopoiesis, which may develop as primary MF (PMF) or evolve from polycythemia vera (PV) or essential thrombocythaemia (ET). MF pathogenesis is characterised by dysregulation of JAK-STAT signalling, in most patients caused by activating mutation of JAK2, CALR and MPL. The JAK1 and JAK2 inhibitor ruxolitinib is currently the only therapy with an approved indication in MF. Results from previous studies demonstrated that ruxolitinib induced rapid reductions in splenomegaly and symptom burden, however the majority of patients failed to achieve a 35% reduction in spleen volume (approximately 50% reduction in spleen length). Furthermore, complete responses are uncommon and significant clonal responses are rare. Thus, there is a major unmet need to improve therapeutic approaches for MF patients, including rational use of JAK2-inhibitor treatment in combination with other therapies. Bromodomain and extra-terminal (BET) inhibitors have shown preclinical efficacy in combination with JAK2 inhibition, and in JAK2-inhibitor resistant cell lines. Co-treatment of BETi with ruxolitinib has been shown to have synergistic efficacy in a mouse model of MF, with reversal of fibrosis and splenomegaly. Aims To determine the recommended phase 2 dose (RP2D) of a Plexxikon BETi administered in combination with ruxolitinib at standard individual dosing, and investigate the safety and efficacy of the combination in patients with high or intermediate-2 risk MF. Methods This is a phase I trial with a dose finding component to establish the RP2D followed by a dose expansion component at the RP2D. Up to 60 eligible patients will be registered to a dose (starting dose ‘level 0’) of BETi, administered in combination with their current dose of ruxolitinib. Patients will be classified as either low-, mid- or high-dose ruxolitinib and, as the ruxolitinib dose-toxicity relationship is unknown, dose-escalation will occur within each category using independent continual re-assessment methods. The target toxicity level in each arm is 25% and a RP2D will be identified in each category. Investigations into relationships between categories will be carried out. The main activity outcome of interest is 50% reduction in palpable spleen length after 6 cycles of treatment. Spleen length will also be assessed using ultrasound and measurements will be compared. The results of this research will be used to guide future treatments for MF. If the results of this trial are positive this combination may be taken forward in a phase II trial.

Lay abstract: Background Myelofibrosis (MF) is a chronic Philadelphia chromosome-negative myeloproliferative neoplasm associated with progressive bone marrow fibrosis and extramedullary haematopoiesis, which may develop as primary MF (PMF) or evolve from polycythemia vera (PV) or essential thrombocythaemia (ET). MF pathogenesis is characterised by dysregulation of JAK-STAT signalling, in most patients caused by activating mutation of JAK2, CALR and MPL. The JAK1 and JAK2 inhibitor ruxolitinib is currently the only therapy with an approved indication in MF. Results from previous studies demonstrated that ruxolitinib induced rapid reductions in splenomegaly and symptom burden, however the majority of patients failed to achieve a 35% reduction in spleen volume (approximately 50% reduction in spleen length). Furthermore, complete responses are uncommon and significant clonal responses are rare. Thus, there is a major unmet need to improve therapeutic approaches for MF patients, including rational use of JAK2-inhibitor treatment in combination with other therapies. Bromodomain and extra-terminal (BET) inhibitors have shown preclinical efficacy in combination with JAK2 inhibition, and in JAK2-inhibitor resistant cell lines. Co-treatment of BETi with ruxolitinib has been shown to have synergistic efficacy in a mouse model of MF, with reversal of fibrosis and splenomegaly. Aims To determine the recommended phase 2 dose (RP2D) of a Plexxikon BETi administered in combination with ruxolitinib at standard individual dosing, and investigate the safety and efficacy of the combination in patients with high or intermediate-2 risk MF. Methods This is a phase I trial with a dose finding component to establish the RP2D followed by a dose expansion component at the RP2D. Up to 60 eligible patients will be registered to a dose (starting dose ‘level 0’) of BETi, administered in combination with their current dose of ruxolitinib. Patients will be classified as either low-, mid- or high-dose ruxolitinib and, as the ruxolitinib dose-toxicity relationship is unknown, dose-escalation will occur within each category using independent continual re-assessment methods. The target toxicity level in each arm is 25% and a RP2D will be identified in each category. Investigations into relationships between categories will be carried out. The main activity outcome of interest is 50% reduction in palpable spleen length after 6 cycles of treatment. Spleen length will also be assessed using ultrasound and measurements will be compared. The results of this research will be used to guide future treatments for MF. If the results of this trial are positive this combination may be taken forward in a phase II trial.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS