MANIFEST-2, A GLOBAL, PHASE 3, RANDOMIZED, DOUBLE-BLIND, ACTIVE-CONTROL
POSTER 15
STUDY OF CPI-0610 AND RUXOLITINIB VS. PLACEBO AND
RUXOLITINIB IN JAKI-TREATMENT-NAIVE MYELOFIBROSIS PATIENTS
John Mascarenhas1, Claire Harrison2, Aaron Gerds3, Katarina Luptakova4, Jessica Christo4, Jing Wang4,
Gozde Colak4, James Shao4, Suresh Bobba4, Patrick Trojer4, Jeffrey Humphrey4 and Srdan Verstovsek5
(1)Division of Hematology/Medical Oncology, Icahn School of Medicine at Mount Sinai, New York
(2)Guy’s and St Thomas’ NHS Foundation Trust, London, United Kingdom
(3)Cleveland Clinic, Cleveland
(4)Constellation Pharmaceuticals, Cambridge
(5)The University of Texas, MD Anderson Cancer Center, Houston
The bromodomain and extraterminal domain (BET) family of proteins bind to chromatin to
regulate the transcription of target genes involved in multiple pro-fibrotic pathways and is a
potential novel therapeutic target for reducing fibrosis in myelofibrosis (MF). CPI-0610 is a
unique, first-in-class, oral, small-molecule inhibitor of BET (BETi) 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 MF.
Janus kinase 1/2 inhibitors (JAKi) are currently approved for treatment of MF, including
ruxolitinib (rux) and fedratinib. Approximately one third of JAKi naïve MF patients treated with
rux (35%; 106 of 301) or fedratinib (37%; 35 of 96) achieved a spleen volume reduction ≥ 35%
(SVR35) at 6-12 months. CPI-0610, a potential disease-modifying therapeutic agent with a
novel mechanism of action may improve the outcome in MF pts. Blocking BET activity with
CPI-0610 altered megakaryocyte differentiation and decreased cytokine production in
preclinical studies. In addition, synergistic therapeutic effect of BETi and JAKi combination was
observed in preclinical MF models. Clinical activity of CPI-0610 in combination with rux in JAKi-naïve
MF patients observed in the phase 2 MANIFEST study was higher (SVR35 at wk 24: 67%)
than that observed with rux alone in historical phase 3 trials (Mascarenhas, ASH 2020).
MANIFEST-2 is designed as a global, phase 3, 1:1 randomized, double-blind, active-control
study of CPI-0610 + rux vs. placebo + rux in JAKi treatment-naïve patients with primary MF,
post-polycythemia-vera MF, or post-essential-thrombocythemia MF. Key eligibility criteria:
DIPSS score ≥Int-1; platelet ≥100 x 109/L; spleen volume ≥ 450 cc by CT/MRI; ≥2 symptoms
measurable (score ≥3) or a total symptom score (TSS) of ≥10 using the MFSAF v4.0; peripheral
blast count <5%, ECOG ≤2. Approximately 310 patients (155 in each arm) will be enrolled in
the study. Patient randomization will be stratified by DIPSS risk category (Intermediate-1 vs.
Intermediate-2 vs. High), platelet count (> 200 × 109/L vs. 100 – 200 × 109/L), and spleen
volume (≥ 1800 cm3 vs. < 1800 cm3). Double-blind treatment (CPI-0610 or matching placebo)
will be administered once daily (QD) for 14 consecutive days followed by a 7-day break, which
is considered 1 cycle of treatment (1 cycle = 21 days). Rux will be administered twice daily
(BID) for all 21 days within each cycle. Primary endpoint: SVR35 response (≥35% reduction in
spleen volume) at wk 24; key secondary endpoint: TSS50 response (≥50% reduction in TSS) at
wk 24; other secondary endpoints: safety, PK, PD, changes in bone marrow fibrosis and
myeloid differentiation during treatment, duration of SVR35 response, duration of TSS50
response, PFS, OS, conversion from transfusion dependence to independence, rate of RBC
transfusion for the first 24 wks, hemoglobin response, peripheral proinflammatory cytokines.