CPI-0610, a Bromodomain and Extraterminal Domain Protein (BET) Inhibitor, As Monotherapy in Advanced Myelofibrosis Patients Refractory/Intolerant to JAK Inhibitor: Update from Phase 2 MANIFEST Study

CPI-0610 is a unique, first-in-class, oral, small-molecule inhibitor of bromodomain and extraterminal domain (BET) proteins, designed to promote disease-modifying activity through selective gene regulation of key oncogenic, fibrotic, and inflammatory factors with potential to transform the standard of care in myelofibrosis (MF). Many MF patients (pts) have suboptimal responses or are resistant to the JAK inhibitor (JAKi) ruxolitinib (rux) or develop anemia and transfusion dependence (TD), which may lead to discontinuation. Here we present results from Arm 1 of MANIFEST, an ongoing, global, open-label Phase 2 study investigating CPI-0610 monotherapy in advanced MF pts refractory/intolerant to JAKi.

Pts are stratified as transfusion-dependent (TD, defined as ≥2U RBCs/month over 12 wks, IWG-MRT criteria) and non-transfusion-dependent (non-TD). Eligibility: MF pts intolerant/resistant/refractory/lost response to or ineligible for JAKi, DIPSS ≥Int-2, platelets ≥75 x 10⁹/L, ≥2 symptoms measurable (score ≥ 1) per MFSAF v4.0, RBC TD per IWG-MRT criteria in TD cohort or spleen volume of ≥ 450 cc by CT/MRI in non-TD cohort. 1° endpoints-TD cohort: TD to TI (transfusion independence) [defined as no transfusion for 12 wks per IWG-MRT]; non-TD cohort: SVR35 (≥35% spleen volume reduction) at wk 24. 2° endpoints: TSS50 (≥50% total symptom score reduction) per MFSAF v4.0 at wk 24, safety and PK. Exploratory: changes in plasma levels of proinflammatory cytokines and bone marrow (BM) morphology/fibrosis. Pts with assessment at or post wk 24 and those discontinued after wk 12 are included in the analysis of the corresponding endpoint.

As of 17 Apr 2020, 27 pts were treated in non-TD cohort (median: 34.4 wks, range: 2, 123.3). Baseline characteristics: mean age 68.3 years old (yo) (SD: 9.0), 51.9% male, 81.4% with DIPSS ≥Int-2, 63.0% with hemoglobin <10g/dL, 70.4% with primary MF, 51.9% with high molecular risk, 63.0% with JAK2, 22.2% with CALR, and 7.4% with MPL mutations. Median time since MF diagnosis: 5.5 yrs (range: 0.0-19.7). Median number of prior lines of therapies: 2 (range: 1-5). Median time since last rux dose: 9.2 months (range: 0.5, 45.8). At wk 24, 23.8% (5/21) pts achieved SVR35 (median change: -28.2%, range: -51.0%, 14.4%), 47.4% (9/19) pts achieved TSS50 (median change: -55.6%, range: -100%, 24.7%). At wk 12, 17.4% (4/23) pts achieved SVR35 (median change: -19.9%, range: -62.8%, 18.0%), 30.0% (6/20) pts achieved TSS50 (median change: -26.2%, range: -100%, 23.2%). 57.9% (11/19) pts achieved ≥1.5 g/dL increase in hemoglobin (Hgb) levels without transfusion during the previous 12 wks. Improvements in BM fibrosis were also observed.

In TD cohort, 16 pts were treated (median: 28.9 wks, range: 7.9, 62.6). Baseline characteristics: mean age 71.9 yo (SD: 8.7), 68.8% male, 93.8% with DIPSS ≥Int-2, 93.8% with Hgb <10g/dL, 62.5% with primary MF, 56.3% with high-molecular-risk, 68.8% with JAK2, 18.8% with CALR, and 12.5% with MPL mutations. Median time since MF diagnosis: 4.1 yrs (range: 0.3-33.8). Median number of prior lines of therapies: 2 (range: 1-6). 43.8% of the patients received erythropoietin stimulating therapy prior to enrollment. 21.4% (3/14) of TD pts converted to TI. At wk 24, median spleen volume change is -17.4% (range: -33.8%, 64.7%); 0/10 achieved SVR35. 8.3% (1/12) pts achieved TSS50 (median change: -5.8%, range: -69.9%, 31.7%) at 24 wks. At wk 12, 28.6 % (4/14) pts achieved SVR35 (median change: -15.3%, range: -73.7%, 51.6%), 42.9% (6/14) pts achieved TSS50 (median change: -30.7%, range: -100%, 37.0%).

43 pts were evaluable for safety across cohorts. Median exposure was 34.4 wks. The most common hematological treatment-emergent adverse events (TEAEs) of any grade were thrombocytopenia (25.6%, ≥Gr3: 14%) and anemia (11.6%, ≥Gr3: 9.3%). The most common non-hematological TEAEs were nausea (32.6%, no ≥Gr3), diarrhea (30.2%, ≥Gr3: 4.7%), respiratory tract infections (27.9%, ≥Gr3: 2.3%), dysgeusia and cough (27.9% each, no ≥Gr3), and fatigue (20.9%, no ≥Gr3). 6 pts discontinued treatment because of TEAEs. There were no Gr5 TEAEs.

The results indicate that CPI-0610 monotherapy is generally well-tolerated and provides clinical benefits in MF pts refractory/intolerant to rux. SVR35 and symptomatic improvement were observed. Majority of non-TD pts demonstrated ≥1.5 g/dL increase in Hgb, a potential disease-modifying effect of CPI-0610. Conversion to TI was observed in the TD cohort.