On May 16, 2019 Constellation Pharmaceuticals, Inc. (Nasdaq: CNST) reported that two abstracts relating to the MANIFEST clinical trial of CPI-0610 for myelofibrosis – one in association with the American Society for Clinical Oncology (ASCO) (Free ASCO Whitepaper) annual meeting and the other in association with the European Hematology Association (EHA) (Free EHA Whitepaper) annual meeting – published online (Press release, Constellation Pharmaceuticals, MAY 16, 2019, View Source [SID1234536407]). The abstracts include an analysis based on a data cutoff of January 17, 2019, from 18 enrolled patients. Upcoming presentations at ASCO (Free ASCO Whitepaper) and EHA (Free EHA Whitepaper) will reflect an analysis of a larger patient population based on a data cutoff of April 17, 2019.
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MANIFEST is an open-label Phase 2 clinical trial of CPI-0610 in patients with myelofibrosis (MF), a rare cancer of the bone marrow that disrupts the body’s normal production of blood cells. Constellation 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, the Company added a third arm designed to evaluate treatment with CPI-0610 in combination with ruxolitinib as a first-line therapy in JAK 1/2-inhibitor-naïve MF patients.
Data Highlights From Abstracts
Below are highlights of data on second-line patients in the ASCO (Free ASCO Whitepaper) and EHA (Free EHA Whitepaper) abstracts, which published on May 15 and May 16, respectively.
Spleen volume reductions as measured by MRI occurred in all ten evaluable patients 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.
"Interim data from the MANIFEST trial indicate that CPI-0610 has been generally well-tolerated, with promising therapeutic activity for the treatment of myelofibrosis," said Adrian Senderowicz, Chief Medical Officer at Constellation Pharmaceuticals. "In addition to spleen and symptom improvement in these refractory patients, we are pleased to see an array of clinical data suggesting the potential for disease-modifying effects, such as improved hematopoietic function, conversion to transfusion independence, and improvement in bone marrow fibrosis. We look forward to providing further updates of the MANIFEST trial at both ASCO (Free ASCO Whitepaper) and EHA (Free EHA Whitepaper)."
ASCO Poster Presentation
TITLE: A Phase 2 Study of CPI-0610, a Bromodomain and Extraterminal Protein Inhibitor (BETi) alone or with Ruxolitinib (RUX), in Patients with Myelofibrosis (MF)
Poster Session: Hematologic Malignancies—Leukemia, Myelodysplastic Syndromes, and Allotransplant
Date and Time: Monday, June 3, 2019, 8:00 AM CDT (9:00 AM EDT)
Dr. Marina Kremyanskaya of the Mount Sinai School of Medicine, an investigator in the MANIFEST clinical trial, will present a poster with updated details of interim data at the American Society for Clinical Oncology (ASCO) (Free ASCO Whitepaper) annual meeting. The data to be presented in the poster were gathered from 44 patients enrolled as of April 17, 2019. Twelve patients received 24-week assessments and 16 patients received 12-week assessments. Among the parameters being assessed were spleen volume reduction, total symptom scores, transfusion dependence, bone marrow fibrosis, and safety.
EHA Oral Presentation
TITLE: CPI-0610, A Bromodomain and Extraterminal Domain (BET) Inhibitor, Reduces Proinflammatory Cytokines, Bone Marrow Fibrosis and the Number of Transfusions in Myelofibrosis Patients
Session: New Agents in MPN
Date and Time: June 15, 12:15 PM CEST (6:15 AM EDT)
Dr. Ronald Hoffman of Mt. Sinai Health System, an investigator in MANIFEST, will make an oral presentation on these updated interim data at the European Hematology Association (EHA) (Free EHA Whitepaper) annual meeting on June 15 at 12:15 PM CEST.
Investor Event. Constellation will also host an investor meeting and conference call to discuss these interim data on June 4 at 7:00 AM CDT. This event will include participation by Dr. Srdan Verstovsek, a medical oncologist at the University of Texas MD Anderson Cancer Center who is an investigator in the MANIFEST trial, and Dr. Raajit Rampal, hematologic oncologist at Memorial Sloan Kettering Cancer Center. Details will be announced later.