Promise: Investigation into the Combination of a Potent Beti with Ruxolitinib in Patients with High or Intermediate-2 Risk Myelofibrosis Not Receiving an Adequate Response with Ruxolitinib Alone

ISRCTN: 12451433

Background:

Myelofibrosis (MF), a chronic myeloproliferative neoplasm (MPN), often results in progressive splenomegaly and cytopenia (1). Acute myeloid leukaemia develops in 10-20% of patients, and median survival with intermediate-2 disease is four years (2). Stem cell transplant can be curative, but is only suitable for younger, comorbidity-free patients (median MF diagnosis is 73.6 years) (3).

Janus Kinase 2 (JAK2) mutation is common in MPN, and the JAK1/2 inhibitor ruxolitinib was approved in 2011 (4). However, patients still experience high disease burden, with a clear need for further treatments.

Research has now focused on bromodomain and extra terminal (BET) inhibitors (5), in particular the role these have in disease associated inflammation (6). Preclinical data suggests BETi disrupts this inflammation leading to anti-fibrotic activity within MPN models. BETi with ruxolitinib eliminates fibrosis in MF mouse models thus overcoming a limitation of ruxolitinib monotherapy (7).

OPN-2853 (previously PLX2853) is potent against isolated bromodomains from multiple BET proteins with rapid drug absorption, high Cmax, and short half-life differentiating it from other BETi. Preclinical efficacy has been demonstrated across a range of hematologic malignancies. PROMise is evaluating OPN-2853 in combination with ruxolitinib to identify the recommended phase 2 dose (RP2D).

Methods:

Primary Objectives:

• To assess the RP2D of OPN-2853 in combination with ruxolitinib that is safe and tolerable

• To assess the efficacy of the combination of OPN-2853 and ruxolitinib for reduction in spleen size

PROMise is a single country (UK) multicentre study, recruiting up to 60 patients with high or intermediate-2 risk MF who are not receiving an adequate response on ruxolitinib alone. Patients must have been treated with ruxolitinib for at least 24 weeks, on a stable dose for at least 4 weeks, and have ongoing splenomegaly.

PROMise is split into three ruxolitinib dose categories based on platelet count which are assessed independently, Low Dose (5mg-20mg daily), Mid Dose (25mg-45mg daily) and High Dose (≥50mg daily). These are evaluated in combination with three OPN-2853 dose levels, Level 1 (20mg OD Decreased Dose), Level 2 (40mg OD Starting Dose) and Level 3 (80mg OD Increased Dose).

Cohorts of patients (n=2-4) receive up to eight 21-day cycles of OPN-2853 and ruxolitinib. Patients are closely monitored for Dose Limiting Toxicities in cycle 1.

The Trial Safety Committee (TSC) meets following cycle 1 to establish the dose recommendations of OPN-2853 for each dose category using the continual reassessment method (CRM). The CRM is utilised independently for each dose category, as such it is possible for the low, mid and high doses to be allocated to different OPN-2853 doses. Following cycle 8, patients may continue to receive OPN-2853 if experiencing clinical benefit and are followed up annually.

Peripheral blood, bone marrow aspirate and bone marrow trephine samples are taken from all patients to measure the proportion who achieve a molecular response, and to determine the on target transcriptional response in myeloid cells. Additionally, pharmacokinetic samples are taken at specified timepoints pre and post dose to establish PK properties of OPN-2853 in combination with ruxolitinib.

Current Status:

To date PROMise has recruited 14 patients across all dose categories, and two TSC meetings have taken place.

References:

• O'Sullivan, J.M. and C.N. Harrison, Myelofibrosis: clinicopathologic features, prognosis, and management. Clin Adv Hematol Oncol, 2018. 16(2): p. 121-131.

• Lussana, F. and A. Rambaldi, Inflammation and myeloproliferative neoplasms. J Autoimmun, 2017. 85: p. 58-63

• McLornan, D.P., et al., Allogeneic stem cell transplantation for myelofibrosis in 2012. Br J Haematol, 2012. 157(4): p. 413-25.

• Vainchenker, W., et al., JAK inhibitors for the treatment of myeloproliferative neoplasms and other disorders. F1000Res, 2018. 7: p. 82.

• Delmore, J.E., et al., BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell, 2011. 146(6): p. 904-17.

• Brown, J.D., et al., NF-kappaB directs dynamic super enhancer formation in inflammation and atherogenesis. Mol Cell, 2014. 56(2): p. 219-231.

• Kleppe, M., et al., Dual Targeting of Oncogenic Activation and Inflammatory Signaling Increases Therapeutic Efficacy in Myeloproliferative Neoplasms. Cancer Cell, 2018. 33(4): p. 785-787.