Pelabresib (CPI-0610) Monotherapy in Patients with Myelofibrosis – Update of Clinical and Translational Data from the Ongoing Manifest Trial

Background: Pelabresib (CPI-0610) is a potent, first-in-class, selective, oral small-molecule inhibitor of bromodomain and extraterminal domain (BET) proteins which is able to modify the expression of genes involved in nuclear factor kappa B (NFκB) signaling in patients with myelofibrosis (MF). Here we present results from MANIFEST (NCT02158858), an ongoing, global, open-label Phase 2 study investigating pelabresib monotherapy in patients with advanced MF who are intolerant/refractory to, or ineligible for ruxolitinib (RUX) and typically have very poor prognosis.

Methods: Eligibility criteria are MF patients intolerant/refractory to or ineligible for JAKi, Dynamic International Prognostic Scoring System (DIPSS) risk category of ≥intermediate-2, platelets ≥75 × 10⁹/L, and ≥2 symptoms measurable (score ≥1) per Myelofibrosis Symptom Assessment Form (MFSAF) v4.0. Additional criteria include red blood cell (RBC) transfusion dependent (TD) per Gale criteria in TD cohort or spleen volume of ≥450 cc by computed tomography/magnetic resonance imaging in non-TD cohort. Patients were enrolled as TD (defined as ≥2 U RBCs/month over 12 wks) and non-TD if TD criteria are not met. The primary endpoint in TD cohort is RBC transfusion independence (TI; defined as no transfusion for ≥12 wks), and ≥35% spleen volume reduction (SVR35) at wk 24 in the non-TD cohort. Secondary endpoints include number of patients with ≥50% total symptom score reduction (TSS50) per MFSAF v4.0 at wk 24, and safety. Additional exploratory endpoints include changes in plasma levels of proinflammatory cytokines and bone marrow (BM) morphology/fibrosis. Patients with assessment at wk ≥24 and those discontinuing after wk 12 are included in the analysis of the corresponding endpoint; these were the evaluable patients.

Results: As of 29 September 2020, 27 pts were treated in the non-TD cohort for a median duration of 51 wks (2, 147 wks). At wk 24, 30% (7/23) evaluable pts achieved SVR35 (median change: –29%), and 48% (10/21) pts achieved TSS50 (median change: –56%). In the TD cohort, 19 pts were treated for a median duration of 32 wks (5, 78 wks). 21% (3/14) evaluable TD pts achieved RBC TI for ≥12 wks. Updated 24-wk data with a larger data set and new long-term data at 48 wks will be presented.

Pt subgroup analyses revealed evidence of activity of pelabresib in a subset of pts who were ineligible to receive RUX, a patient population that generally has few therapeutic options. Clinical benefits observed with pelabresib included achievement of SVR35 and TSS50, improvements in bone marrow fibrosis, and increases in hemoglobin levels.

A panel of 68 cytokines, including those known to be nuclear factor kappa B (NF-κB) targets linked to inflammation and elevated in MF pts, were evaluated in plasma samples obtained at baseline (BL) and during therapy. Cytokines were clustered to show different patterns of change during treatment with pelabresib. Overall, pelabresib significantly reduced plasma levels of several cytokines in RUX naïve or experienced pts (Figure). Cytokine changes with pelabresib in cluster 3 (which includes IL-6, CRP, RANTES, TNFa and IL-18, and is characterized by higher BL values and bigger decreases over time) and in cluster 5 (which includes EPO, TARC, ICAM-1 and IL-8, and is characterized by relatively lower BL values and less profound decreases over time) were more pronounced in RUX-naïve pts.

46 pts were evaluable for safety. The most common hematological treatment emergent adverse events (TEAEs) of any grade were thrombocytopenia (30%; ≥Grade 3: 15%) and anemia (15%; ≥Grade 3: 13%). The most common (≥20%) nonhematological TEAEs were nausea (39%; no ≥Grade 3), diarrhea (37%; ≥Grade 3: 4%), dysgeusia and asthenic conditions (30% each; no ≥Grade 3 for either), respiratory tract infections (28%; ≥Grade 3: 2%), cough (26%; no ≥Grade 3) and constipation and weight decrease (22% each; ≥Grade 3: 2% each).

Conclusions: Preliminary data suggested pelabresib monotherapy was generally well tolerated and demonstrated signals of clinical activity in MF pts intolerant/refractory to or ineligible for JAKi, who have limited treatment options and poor outcomes.