Pelabresib (CPI-0610) is an investigational selective small-molecule designed to promote anti-tumor activity by inhibiting the function of bromodomain and extra-terminal domain (BET) proteins to decrease the expression of abnormally expressed genes in cancer. The compound has demonstrated a wide therapeutic window, with activity seen at a 48 mg dose in a lymphoma study and with a maximum tolerated dose of 225 mg. Constellation Pharmaceuticals, a MorphoSys company, is using a starting dose of 125 mg in MANIFEST, our global, multicenter, open-label Phase 2 study of pelabresib in patients with Myelofibrosis (MF). Preclinical studies and translational insights from our first-in-human study of pelabresib led us to prioritize the clinical development of pelabresib in MF.
Phase II MANIFEST trial is testing pelabresib:
- as monotherapy in MF patients who are refractory to or intolerant of/ineligible for, and are no longer on, ruxolitinib (Arm 1);
- as add-on to ruxolitinib in MF patients who have had a suboptimal response to ruxolitinib or have experienced disease progression (Arm 2);
- in combination with ruxolitinib in MF patients as 1L therapy who are JAK-inhibitor-naïve (Arm 3)
- as monotherapy in patients with high-risk essential thrombocythemia who are intolerant of, or refractory to, hydroxyurea (Arm 4)
We have also initiated MANIFEST-2, a global, double-blind, randomized Phase 3 clinical study with pelabresib in combination with ruxolitinib versus placebo plus ruxolitinib in JAK-inhibitor-naïve patients with primary myelofibrosis or post-ET or post-PV myelofibrosis who have splenomegaly and symptoms requiring therapy. We are randomizing patients to receive pelabresib + ruxolitinib or the placebo + ruxolitinib. The primary endpoint of the study is a ≥35% reduction in spleen volume (SVR35) from baseline at 24 weeks. A key secondary endpoint of the study is 50% or greater improvement in Total Symptom Score (TSS50) from baseline at 24 weeks. Other endpoints include bone marrow fibrosis grade improvements, duration of transfusion independence, rate of red-blood-cell transfusion for the first 24 weeks, and hemoglobin response.
If you are a US healthcare provider and would like to learn more about MANIFEST-2, click here.