CPI-0610 Shows Strong Efficacy Signals for Advanced Myelofibrosis

CPI-0610 showed promising spleen volume responses and a meaningful reduction in total symptom score as monotherapy and in combination with ruxolitinib (Jakafi) for patients with refractory or intolerant advanced myelofibrosis.

John Mascarenhas, MD

The BET inhibitor CPI-0610 demonstrated promising spleen volume responses (SVR) and a meaningful reduction in total symptom score (TSS) as monotherapy and when added to ongoing treatment with ruxolitinib (Jakafi) for patients with refractory or intolerant advanced myelofibrosis, according to updated findings from the phase II MANIFEST trial presented at the 2019 ASH Annual Meeting.1

For CPI-0610 added on to ongoing treatment with ruxolitinib, there was a 24.9% median reduction in spleen volume at 24 weeks and a 58.8% median improvement in TSS for transfusion dependent (TD) patients with myelofibrosis. Additionally, 43% of patients converted from being TD to transfusion independent (TI) following treatment with the combination. Promising improvements in TSS and SVR were also seen for CPI-0610 monotherapy.

"CPl-0610 as monotherapy or add-on to ruxolitinib in relapsed/refractory population demonstrated antitumor activity, as evidenced by spleen and symptom improvements, along with improvements in hemoglobin and bone marrow fibrosis," John Mascarenhas, MD, Tisch Cancer Institute, Division of Hematology/Medical Oncology, Icahn School of Medicine at Mount Sinai, said during a presentation of the results. "Among evaluable patients who were transfusion dependent on ruxolitinib, 6 of 14 patients converted to transfusion independence after the addition of CPl-0610 in the study."

CPI-0610 is thought to reduce and suppress the differentiation of myeloid cells into megakaryocytes in the bone marrow, potentially leading to disease modification for patients with myelofibrosis. In addition to this mechanism, the inhibition of BET proteins further halts the creation of pro-inflammatory cytokines, such as IL-8, TGFβ, and NFκB.

The MANIFEST trial included multiple treatment arms, each looking at cohorts of TD and TI patients. Arm 1 of the study examined single-agent CPI-0610 for patients no longer on ruxolitinib (n = 36). In arm 2 of the study, CPI-0610 was added to ruxolitinib for patients already receiving the JAK/STAT inhibitor for at least 6 months (n = 54). Arm 1 of the study included cohort 1A, in which patients were TD. Cohort 1B within this same group included those who were TI. In arm 2, patients included in cohort 2A of this group were TD and cohort 2B were TI.

In arm 2 looking at the combination of CPI-0610 and ruxolitinib, an SVR with at least 35% reduction in spleen size (SVR35) at week 24 was experienced by 25% of TD patients. Additionally, a TSS reduction of ≥50% (TSS50) at week 24 was experienced by 54% of TD patients. Seventy-five percent of patients noted an improvement in overall status by patient global impression of change (PGIC) scores. Sixty-one percent of patients said their status was much or very much improved.

In TI patients treated with the combination, the SVR35 rate was 0 and the TSS ≥50% response was 38% at 24 weeks. In this group, there was a 69% improvement in PGIC score, with 46% of patients saying their overall status was much or very much improved.

In TD patients in arm 1, which looked at CPI-0610 monotherapy, the SVR35 was 0 and there was a median reduction in spleen size of 3.2% in TD patients. TSS ≥50% was 0 with the single agent, with a mean reduction from baseline of 18.4%. The PGIC score improved by 50%. In TI patients in arm 1, the SVR35 was 0 and the median change in spleen reduction was 26%. TSS ≥50% occurred in 60% of patients, with a median reduction of 53.5%. At 24 weeks, there was a 100% improvement in PGIC scores, with more than half of patients saying they were much improved (57%).

In the CPI-0610 monotherapy and add-on groups, respectively, 55% and 13% of patients had improvements of ≥1.5 g/dL in hemoglobin counts. Bone marrow fibrosis was improved from baseline to subsequent bone marrow biopsy for 22.2% and 43.5% of patients in the monotherapy and add-on groups, respectively. Both hemoglobin and bone marrow fibrosis improvements were seen in 22.2% and 17.4% of patients, in the single-agent and add-on arms, respectively.

Of those who transitioned from TD to TI, 36.4% in the add-on arm had bone marrow improvement. A 1 grade improvement in bone marrow fibrosis was seen in 38% of patients analyzed, with most of these occurring within 6 months of treatment (83%).

Across both groups, 83.3% of patients continued on the study at the time of the analysis. The primary reason for discontinuation was progressive disease (5.6%) or death (5.6%). The median treatment duration was 16.2 weeks, and 41.1% of patients have been on treatment for 24 weeks or longer.

The most common all-grade, all-cause adverse events (AEs) were diarrhea (32.2%), thrombocytopenia (23.3%), nausea (22.2%), cough (16.7%), vomiting (14.4%), fatigue (14.4%), and upper respiratory tract infection (14.4%). Non-hematologic AEs were primary grade 1/2 in severity, Mascarenhas noted.

The most common grade ≥3 AEs were thrombocytopenia (10%), anemia (6.7%), diarrhea (4.4%), and fatigue (3.3%). None of the grade ≥3 cases of thrombocytopenia were deemed serious, Mascarenhas noted. Across the 90 patients enrolled in the study, 8 experienced a grade 4 AE (8.9%). There were 3 grade 5 events (3.3%), which were not considered related to CPI-0610. These events all occurred in arm 2 of the study.

"CPl-0610 as monotherapy and as add-on was generally well tolerated. Thrombocytopenia was observed and asymptomatic. It was generally reversible and manageable and there were no additional unanticipated safety concerns observed," said Mascarenhas.

Based on findings from the first arms of the study, cohort 2A was expanded to enroll an additional 60 patients for the combination of CPl-0610 and ruxolitinib. Additionally, arm 3 of the study, which was not presented as part of this presentation, is looking at the combination of CPI-0610 with ruxolitinib in untreated patients with myelofibrosis.

In this group of 15 patients,2 the SVR35 response rate was 80% at 12 weeks. The median change from baseline in spleen size was 49.7%. This response was seen in a high-risk population, including in those with DIPSS intermediate-2 or higher disease (86.7% response) and those with HMR-positive disease (53.3% response).

Based on these preliminary findings, cohort 3 of the study is being expanded to enroll up to 101 patients (NCT02158858).


  1. Mascarenhas J, Kremyanskaya M, Hoffman R, et al. MANIFEST, a phase 2 study of CPI-0610, a Bromodomain and Extraterminal Domain inhibitor (BETi), as monotherapy or “add-on” to ruxolitinib, in patients with refractory or intolerant advanced myelofibrosis. Presented at: 2019 ASH Annual Meeting; December 7-10, 2019; Orlando, FL. Abstract 670. bit.ly/2YyH3IH.
  2. Harrison CN, Patriarca A, Mascarenhas J, et al. Preliminary report of MANIFEST, a phase 2 study of CPI-0610, a Bromodomain and Extraterminal Domain inhibitor (BETi), in combination with ruxolitinib, in JAK inhibitor (JAKi) treatment naïve myelofibrosis patients. Presented at: 2019 ASH Annual Meeting, Orlando, FL, December 7-10, 2019. Abstract 4164. bit.ly/2LCVQNi.

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