The following article features coverage from the American Society of Hematology 2019 meeting. Click here to read more of Cancer Therapy Advisor‘s conference coverage.

The investigational epigenetic drug CPI-0610, a selective small-molecule bromodomain and extraterminal domain inhibitor (BETi), is clinically active against refractory myelofibrosis (MF), according to findings from the multicenter, open-label phase 2 MANIFEST trial ( Identifier: NCT02158858), presented during the 61st American Society of Hematology (ASH) Annual Meeting and Exposition in Orlando, Florida.

“Preliminary data indicate that CPI-0610 alone or ‘add-on’ to rux is generally well tolerated and provides clinical benefits in MF patients with inadequate responses or who are refractory to rux,” reported lead study author John Mascarenhas, MD, of the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, NYC, and coauthors, in the study abstract. “Improvement in BM fibrosis and anemia responses indicate the potential for meaningful disease modification.”

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Ruxolitinib is a kinase inhibitor that reduces spleen volume. It was approved in 2011 and for a while, was the only option on the market with an indication in myelofibrosis — that was, until 2019, when fedratinib was approved for intermediate-2 or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis.

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To study the safety and clinical activity of CPI-0610, the authors enrolled 90 patients with refractory MF and MF that exhibited suboptimal responses to ruxolitinib (rux). Patients with rux-refractory disease or for whom rux was not tolerated were given CPI-0610 monotherapy (study arm 1; 36 patients). Those with suboptimal responses to rux were given CPI-0610 plus rux (study arm 2; 54 patients). Patients were stratified for transfusion dependence status (transfusion dependent [TD], defined as an average of ≥2 units per month over 12 weeks, or non-TD). The CPI-0610 starting daily dose was 125 mg, 2 weeks on, 2 weeks off.

In the monotherapy group, TD patients had a spleen volume response (SVR) of 25%, while in the non-TD group, SVR was 0%. In the drug combination group, SVR was 29%, whereas in the non-TD group, SVR was 0%

Overall total symptom score (TSS) was 21 across the cohorts.

With CPI-0610 used as a monotherapy, 55% (6/11) patients had at least a 1.5 g/dL increase in hemoglobin, whereas with CPI-0610 used in combination with rux, 13% (2/15) patients had at least a 1.5 g/dL increase in hemoglobin. With the monotherapy, bone marrow fibrosis (BMF) improvement was 22.2%, whereas with CPI-0610 plus rux, BMF improvement was 43.5%.

The most common hematologic AE was thrombocytopenia. And, 8 of 90 (8.9%) patients reported grade 4 adverse events (AEs); all of these were resolved. Lastly, 3 out of 90 (3.3%) patients reported grade 5 AEs, but the sponsor did not consider these related to CPI-0610.

“CPI-0610 as monotherapy or as add-on to ruxolitinib in R/R/I MF patients demonstrated antitumor activity as evidenced by SVR35 and TSS50 responses, along with improvements in hemoglobin and bone marrow fibrosis.” the authors noted. “Among evaluable patients who were transfusion dependent on ruxolitinib, 6 of 14 patients converted to transfusion independence after the addition of CPI-0610.”

“Based on the results of this study, the cohort with transfusion-dependent R/R/I MF patients was expanded to enroll up to 60 patients to further investigate the antitumor activity of CPI-0610 as an add-on to ruxolitinib, and a cohort 3 assessing CPI-0610 and ruxolitinib combination in ruxolitinib-naive patients has also been expanded to enroll up to 101 patients,” the investigators added.

Disclosure: Some of the authors disclosed financial relationships with the pharmaceutical industry. For a full list of disclosures, please refer to the original abstract.

Read more of Cancer Therapy Advisor‘s coverage of ASH’s annual meeting by visiting the conference page.


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: 61st American Society of Hematology (ASH) Annual Meeting and Exposition; December 7-10, 2019; Orlando, FL. Abstract 670.