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Investigational BET Inhibitor, CPI-0610, Promotes Responses in Myelofibrosis

February 2020 Vol 13, Special Issue: Payers' Perspectives in Oncology
Wayne Kuznar

Orlando, FL—A potent, oral small-molecule bromodomain and extraterminal domain (BET) inhibitor—CPI-0610—improves spleen volume and symptoms when added to the Janus kinase (JAK) inhibitor ruxolitinib (Jakafi) in ruxolitinib-naïve patients with myelofibrosis. Ruxolitinib is the only FDA-approved treatment for myelofibrosis.

Preliminary data from MANIFEST, a phase 2 clinical trial, showed that 80% of patients with myelofibrosis had a spleen volume reduction of ≥35% and 71.4% of patients had a total symptom score improvement of ≥50% at 12 weeks after initiating CPI-0610 and ruxolitinib, reported Claire N. Harrison, DM, Deputy Director, Haematology/Oncology and Cellular Pathology, Guy’s and St Thomas NHS Foundation Trust, London, England, at ASH 2019.

“Whilst ruxolitinib, the first approved therapy for myelofibrosis, as shown in the COMFORT 1 study, delivers significant spleen volume and symptom improvement in approximately 40% of patients, the symptomatic improvement occurs in the setting of cytopenias in some agents, and additional agents with a different mechanism of action are postulated to be needed in order to deepen symptomatic responses and modify the disease in an unmet-need patient population,” said Dr Harrison.

Previous findings released from the MANIFEST study were from 2 cohorts of patients with myelofibrosis who received treatment with the JAK inhibitor ruxolitinib or with the BET inhibitor CPI-0610. As monotherapy (Arm 1) or as add-on therapy to ruxolitinib (Arm 2), CPI-0610 was generally well-tolerated and reduced spleen size, alleviated myelofibrosis symptoms, improved hemoglobin levels, and reduced transfusion burden, as well as suppressed proinflammatory cytokine and improved bone marrow fibrosis, in patients with myelofibrosis.

Dr Harrison presented preliminary data from Arm 3 of the MANIFEST study, a global, multicenter, open-label study of CPI-0610 in combination with ruxolitinib in JAK inhibitor–naïve patients.


As of October 17, 2019, 30 treatment-naïve patients were enrolled in Arm 3, and 15 (50%) of them have received the study treatment for at least 12 weeks. Dose modification of ruxolitinib or of CPI-0610 was required in 40% of the patients. A total of 53.3% of the patients had primary myelofibrosis, 10% had post–polycythemia vera myelofibrosis, and 33.3% had post–essential thrombocythemia myelofibrosis. At baseline, the median platelet count was 369.5 × 109/L, the median spleen volume was 1637 cm3, and the median total symptom score was 16. Overall, 50% of the patients had a high molecular-risk profile at baseline.

Patients received treatment with CPI-0610 on a pattern of 14 days on, 7 days off cycle, with a starting dose of ruxolitinib according to the patient’s baseline platelet count. The ruxolitinib dose was increased by 5 mg twice daily per cycle, from cycle 3 day 1 or thereafter, to a maximum dose of 20 mg twice daily. All patients continue to receive treatment for a median duration of 4 cycles (12 weeks).

The median reduction in spleen ­volume at week 12 was 49.7%. The benchmark for spleen volume reduction for ruxolitinib alone at full dose, as indicated, is 28.5% to 41.9%, noted Dr Harrison.

Responses were seen in patients who were considered to be high risk, including 86.7% of patients with a Dynamic International Prognostic Scoring ­System score ≥intermediate-2, 80% of ­patients with hemoglobin values <10 g/dL, and 53.3% of patients who had high-risk molecular characteristics. The median change in the total symptom score at week 12 was –60.3%.

In the 7 patients with elevated levels of proinflammatory cytokines at baseline, the median C-reactive protein level was reduced by 57.1% and the median interleukin-18 level was reduced by 85.7%.

Safety Data

Thrombocytopenia, which occurred in 16.7% of patients, was reversible and asymptomatic. In all, 3 patients had grade 3 anemia and 1 had grade 4 thrombocytopenia, which was the only grade 4 adverse event, and which required a 3-week dose interruption.

The most common nonhematologic adverse events were diarrhea (26.7%), nausea (20%), constipation (20%), and mouth ulceration (20%), all of which were grade 1 or 2. No new or unexpected infections were reported.

“Based on these preliminary data, this cohort has been expanded in the MANIFEST study, and a phase 3 trial is being planned,” said Dr Harrison.

Last modified: August 30, 2021