Constellation Pharmaceuticals announced that two abstracts highlighting the MANIFEST clinical trial of CPI-0610 for myelofibrosis – one in association with the American Society for Clinical Oncology (ASCO) annual meeting and the other in association with the European Hematology Association (EHA) annual meeting – have been published online. The abstracts include an analysis based on a data cutoff of January 17, 2019, from 18 enrolled patients.
MANIFEST is an open-label Phase 2 clinical trial of CPI-0610 in patients with myelofibrosis (MF). The trial was designed to evaluate is evaluating CPI-0610, either as a monotherapy or in combination with ruxolitinib, in a second-line setting in patients with MF who are refractory to or intolerant of or have relapsed or lost response to ruxolitinib. Patients in the two second-line arms are being stratified based on transfusion dependent status. The primary endpoint for the cohorts with transfusion-dependent patients is conversion to transfusion independence for 12 consecutive weeks. The primary endpoint for the patients who were non-transfusion dependent at baseline is spleen volume reduction. In addition, a third arm was added, designed to evaluate treatment with CPI-0610 in combination with ruxolitinib as a first-line therapy in JAK 1/2-inhibitor-naïve MF patients.
Highlights of data on second-line patients in the ASCO and EHA abstracts, which published on May 15 and May 16, respectively, are as follows:
- Of 10 evaluable patients, spleen volume reductions as measured by MRI occurred in all 10 and ranged from 6% to 44%.
- Symptom improvements were observed.
- Out of the four patients who received bone marrow assessments, three had a one-grade improvement in bone marrow fibrosis and had hemoglobin increases of ≥1.5 g/dL for ≥12 weeks without transfusions. The fourth patient had a one-grade improvement in the bone marrow reticulin score. All of these score improvements were based on a scale of 0-3.
- Two of the four patients with bone marrow assessments were transfusion dependent at baseline, and both of these patients became transfusion independent.
- Hemoglobin increases of ≥1.5 g/dL occurred in both of two evaluable patients on monotherapy and three of nine patients on the combination with ruxolitinib.
- CPI-0610, both as monotherapy and in combination with ruxolitinib, was generally well tolerated. The most common side effects were Grade 1/2 diarrhea, nausea/vomiting, and reversible and non-cumulative thrombocytopenia.
Upcoming presentations at ASCO and EHA will reflect an analysis of a larger patient population (n=44) based on a data cutoff of April 17, 2019.
Myelofibrosis is an uncommon type of bone marrow cancer that disrupts the body’s normal production of blood cells. Myelofibrosis is considered a chronic leukemia — a cancer that affects the blood-forming tissues in the body – and belongs to a group of diseases called myeloproliferative disorders. Myelofibrosis causes extensive scarring in bone marrow, leading to severe anemia that can cause weakness and fatigue. It can also cause a low number of blood-clotting cells called platelets, which increases the risk of bleeding. Myelofibrosis also often causes an enlarged spleen.
CPI-0610 is a potent and selective small molecule designed to promote anti-tumor activity by selectively inhibiting the function of BET proteins to decrease the expression of abnormally expressed genes in cancer. Abnormal BET function has been implicated in cancer through several means, including chromosomal translocation, gene amplification and overexpression whereby oncogenic and inflammatory signals are turned on in cancer cells through altered BET activity.