, Blum K. Disease-Modifying Potential of BET Inhibitor Pelabresib (CPI-0610) as Demonstrated by Improvements in Bone Marrow Function and Clinical Activity in Patients With Myelofibrosis - Preliminary Data Poster #2568 Date: Sunday, December 12, 2021 Presentation Time: 6:00 PM - 8:00 PMCPI-0610 significantly delayed tumor growth and increased the survival of MM-bearing SCID mice. (Nasdaq: CNST) today announced that two oral. CPI-0610 induces apoptosis and G 1 cell cycle arrest associated with MYC downregulation. , et al. Pelabresib is a small molecule inhibitor of bromodomain and extra-terminal (BET) proteins. We further show that CPI-0610 inhibits MM cell growth in the presence of cytokines and when co-cultured with bone marrow stromal cells. gov identifier: NCT02158858 ), a global, open-label, nonrandomized, multicohort, phase II study, includes a cohort of JAKi-naïve patients with myelofibrosis treated with pelabresib and ruxolitinib. For a discussion of other risks and uncertainties, any of which could cause the Company’s actual results to differ from those contained in the forward-looking statements, see the “Risk Factors” section. It has potential applications in the treatment of various forms of cancer . CPI-0610 demonstrated activity, both as a monotherapy and as add on to ruxolitinib, in second-line or later settings; Translational data supports potential disease-modifying effects of CPI-0610;CPI-0610, CPI-1205 and CPI-0209 are investigational therapies and have not been approved by the FDA (or any other regulatory authority). / Mascarenhas, John; Kremyanskaya, Marina; Patriarca, Andrea et al. CPI-0610 is still valuable to pursue with a larger group of patients who are more diverse in baseline characteristics to get a better idea of the response to this agent. Pelabresib (CPI-0610) is an investigational, selective oral bromodomain and extraterminal domain inhibitor (BETi). Interim data from the trial demonstrated reduction in spleen volume, BM fibrosis, anemia and blood transfusions, as well as total. , Dec. Over the past decade, numerous pan-BET inhibitors have been generated, and some of them are currently in clinical trials, such as OTX-015, CPI-0610, and I-BET762. Pelabresib is currently being investigated as a monotherapy and in combination with the JAK inhibitor (JAKi) ruxolitinib (RUX), in. For a discussion of other risks and uncertainties, any of. Keywords: CPI-0610; JAKi treatment-naive; MANIFEST-2; myelofibrosis; pelabresib; ruxolitinib. 2015; 126:1491. Delaney has a track. A phase 1 study evaluating CPI-0610 in patients with progressive lymphoma: NHL or Hodgkin's lymphoma: Secondary outcome: Changes in the expression of MYC and other genes in tumor tissue: Phase 2 NCT02674750: Study to evaluate the efficacy and safety of CUDC-907 in patients with RR DLBCL, including patients with MYC alterationsFor this reason, the compounds that reached clinical trials (Fig. CPI-0610, CPI-1205 and CPI-0209 are investigational therapies and have not been approved by the FDA (or any other regulatory authority). Modify: 2023-11-04. FRANCESCA PALANDRI via Scopus - Elsevier. With more data on the agent expected to be released from trials in this space toward the end of the year, Joseph M. 3 weeks in the monotherapy arm and 25. Pelabresib (CPI-0610), a first-in-class, oral, small-molecule inhibitor of BET proteins (BETi), has potential to promote disease-modifying activity through altered gene regulation of key oncogenic, fibrotic, and inflammatory factors in the clonal disease cells of origin in MF. CPI-0610 is a unique, first-in-class, oral, small-molecule inhibitor of BET proteins, designed to promote disease-modifying activity through selective gene regulation of key oncogenic, fibrotic, and inflammatory factors with potential to transform the standard of care in MF. About CPI-0610. An early signal of clinical activity was seen in the phase 1 portion of the MANIFEST study (NCT02158858) that. Patients in the two second-line arms are being stratified based on transfusion dependent status. Pelabresib (CPI-0610) is a potent, first-in-class, selective, oral small-molecule BET inhibitor, which is able to modify the expression of genes involved in nuclear factor kappa B (NFκB) signaling in pts with MF. The 14 days of CPI-0610 dosing and the 7-day break together constitute 1 cycle of treatment. CPI-0610 can become a part of the standard of care and even expand the overall addressable market in myelofibrosis indication. 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. ” The data were gathered from 44 patients. However, toxicity studies. Abramson JS, Blum KA, Flinn IW, Gutierrez M, Goy A, Maris M, et al. CPI-0610 showed signals of clinical activity, both as a monotherapy and in combination with ruxolitinib, in refractory myelofibrosis (MF) patients. The utilization of pelabresib (CPI-0610) monotherapy demonstrated signals of clinical activity in the form of spleen volume reduction, symptom reduction, and hemoglobin benefit in patients with. CPI-0610 displays potent cytotoxicity against MM cell lines and patient-derived MM cells through G1 cell cycle arrest and caspase. The Grade 3 and 4 TEAEs were mostly hematological with anemia being the most commonly recorded Grade 3 TEAE. Pacritinib in Patients With Primary Myelofibrosis, Post Polycythemia Vera Myelofibrosis, or Post-Essential Thrombocythemia Myelofibrosis. CPI-0610, CPI-1205 and CPI-0209 are investigational therapies and have not been approved by the FDA (or any other regulatory authority). . CPI-0610 showed encouraging action in JAK inhibitor-naive anemic MF patients, a population with a poor prognosis, as well as ruxolitinib-refractory MF patients. However, protein levels of BCL2, NF- κ B and MCL1 remain unchanged. MPN-375 BET inhibitor Pelabresib (CPI-0610) combined with ruxolitinib in patients with myelofibrosis—JAK inhibitor-Naïe or with suboptimal response to ruxolitinib—preliminary data from the MANIFEST study. In the monotherapy group, TD patients had a spleen volume response (SVR) of 25%, while in the non-TD group, SVR was 0%. Context CPI-0610 is a unique, first-in-class, oral, small-molecule inhibitor of BET proteins, designed to promote disease-modifying activity through selective gene regulation of key oncogenic. CPI-0610-mediated BET inhibition overcomes the protective effects conferred by cytokines and bone marrow stromal cells. CPI-0610 is a unique, first-in-class, oral, small-molecule inhibitor of BET proteins, designed to promote disease-modifying activity through selective gene regulation of key oncogenic, fibrotic, and inflammatory factors with potential to transform the standard of care in MF. The. It strongly and selectively binds to the bromodomains of all four BET proteins and inhibits their interaction with acetylated lysine residues on chromatin, disrupting chromatin remodelling and gene expression [2•]. (Nasdaq: CNST), a clinical-stage. Kremyanskaya M, Mascarenhas J, Palandri F, et al. Placebo and Ruxolitinib in JAKi Treatment Naive MF Patients. A Phase 3, randomized, blinded study comparing pelabresib (CPI-0610) and ruxolitinib with placebo and ruxolitinib in myelofibrosis (MF) patients that have not been previously treated with Janus kinase inhibitors (JAKi). In Arm 2, which examined CPI-0610 in combination with ruxolitinib in ruxolitinib-experienced patients, 29% of evaluable non-TD subjects achieved SVR35 at 24 weeks. Besides CPI-0610, these include the phosphatidylinositol-3-kinase delta isoform inhibitors parsaclisib 20 and umbralisib, 21 the BH3-mimetic navitoclax, the heat shock protein 90 antagonist PU-H71, etc. 05, 2020 (GLOBE NEWSWIRE) -- Constellation Pharmaceuticals, Inc. Pts can experience intolerance, inadequate response or loss of response to first-line cytoreductive therapies (hydroxyurea [HU] or interferon alfa-2a). Treatment with a therapeutic antibody less than 4 weeks before the first dose of CPI-0610. We are currently conducting MANIFEST, a Phase 2 clinical trial of CPI-0610 as a monotherapy and in combination with ruxolitinib (marketed as Jakafi ® /Jakavi ®) in patients with myelofibrosis, or MF, a progressive hematological cancer. CPI-0610 is a small molecule inhibitor of bromodomain and extra-terminal (BET) proteins. HemaSphere 2022;6:99-100). An additional cohort is recruiting JAKi naïve patients to receive CPI-0610/ruxolitinib combination, and showed encouraging preliminary activity [Citation 33]. 06, 2020 (GLOBE NEWSWIRE) -- Constellation Pharmaceuticals, Inc. D, A STRING network, which is used to model known or predicted protein–protein interactions from custom gene lists, was seeded with significant hits from both the CPI-0610 and JQ1 CRISPR screens, and identifies a concordant network of enriched hits of interest across both JQ1 and CPI-0610 CRISPR screens centered on hematopoietic TFs, AHR, and. Arms 1 and 2 are studying CPI-0610 as a monotherapy or in combination with ruxolitinib in. This study is exploring either CPI-0610 alone or in combination with ruxolitinib (Janus kinase 1/2 inhibitor). Here, we review preclinical and clinical data on Pelabresib (CPI-0610), an investigational oral small-molecule potent BET-inhibitor being explored in MF. Article. Pelabresib (CPI-0610) is a first-in-class, oral, small-molecule inhibitor of the tandem amino-terminal bromodomains (BD1 and BD2) of bromodomain and extraterminal domain (BET) proteins, which regulate gene expression pathways. Pelabresib (CPI-0610) is a potent, first-in-class, selective, oral small-molecule BET inhibitor, which is able to modify the expression of genes involved in nuclear factor kappa B (NFκB) signaling in pts with MF. Pelabresib (CPI-0610) is a potent and selective benzoisoxazoloazepine BET bromodomain inhibitor with an IC50 of 39 nM for BRD4-BD1 in TR-FRET assay and currently undergoing human clinical trials for hematological malignancies. CPI-0610 is a potent, selective, and cell-active BET inhibitor. CPI-0610 is a unique, first-in-class, oral, small-molecule inhibitor of BET (BETi) proteins, designed to promote disease-modifying activity through selective gene regulation of key oncogenic, fibrotic, and inflammatory factors with potential to transform the standard of care in MF. Pelabresib (CPI-0610) Monotherapy in Patients With High-Risk Essential Thrombocythemia Refractory or Intolerant to Hydroxyurea: Preliminary Results From MANIFEST Study pdf | 552. Spleen response rates in first-line patients at 12 weeks and 24 weeks in line with previously reported data and differentiated from standard of ca. So, combinations with Navitoclax which is Bcl-xL cell inhibitor, CPI-0610, which is BET inhibitor, Luspatercept which is anemia drug. Authors Jigar Raythatha 1 , Lauren Arnold 1 Affiliation 1 Constellation Pharmaceuticals. Methods: MANIFEST (ClinicalTrails. Adis is an information provider. About CPI-0610. 17, 2019. – Amends second-line trial design to stratify for transfusion dependence based on positive preliminary data –– Expands study to include an additio. D, A STRING network, which is used to model known or predicted protein–protein interactions from custom gene lists, was seeded with significant hits from both the CPI-0610 and JQ1 CRISPR screens, and identifies a concordant network of enriched hits of interest across both JQ1 and CPI-0610 CRISPR screens centered on. Nonetheless, five patients showed objective response, which included two complete responses (CRs) and three PRs; five patients had prolonged (>6 months) SD, indicating that CPI-0610 was a well-tolerated drug with clinical activity in patients with advanced. The Phase 1 portion of the CPI-0209 Phase1/2 clinical trial is an open label, dose escalation study in patients with advanced tumors. Abramson JS, Blum KA, Flinn IW, et al. The rate of 63% was still a good response for this therapy since, in similar patient populations, the response rate is usually about 50% to 60%. CPI-0610 displays potent cytotoxicity against MM cell lines and patient-derived MM cells through G 1 cell cycle arrest and caspase-dependent apoptosis. The first-generation BET bromodomain inhibitors tested in the clinic, including GSK525762 (I-BET762), OTX-015, and CPI-0610, are thienotriazolodiazepine or benzodiazepine compounds and have. Figure 2. Tolerability and Efficacy of Navitoclax Alone or in Combination With Ruxolitinib in Participants With Myelofibrosis. We are also exploring other novel cancer epigenetics targets in preclinical testing to fuel a sustainable pipeline of innovative small-molecule product candidates. Background: Pelabresib (CPI-0610) is a potent, first-in-class, selective, oral small-molecule inhibitor of bromodomain and extraterminal domain (BET) proteins which is able to modify the expression of genes involved in nuclear factor kappa B (NFκB) signaling in patients with myelofibrosis (MF). CPI-0610 is a first-in-class inhibitor of bromodomain and extraterminal domain (BET) proteins, which regulate gene transcription in numerous pro-fibrotic pathways. Mascarenhas served as lead author of a study presented at the 2022 European Hematology Association (EHA) Congress, titled, “BET inhibitor pelabresib (CPI-0610) combined with ruxolitinib in. In ruxolitinib treatment-naïve and previously treated patients with myelofibrosis, pelabresib combined with ruxolitinib resulted in splenic and symptom responses and BM fibrosis improvement and was generally well tolerated. CPI-0610 is a unique, first-in-class, oral, small-molecule inhibitor of BET (BETi) proteins, designed to promote disease-modifying activity through selective gene regulation of key oncogenic, fibrotic, and inflammatory factors with potential to transform the standard of care in MF. Pelabresib - MorphoSys. e. Pelabresib (CPI-0610) is an investigational selective small-molecule designed to promote anti-tumor activity by inhibiting the function of bromodomain and extra-terminal domain (BET) proteins to decrease the expression of abnormally expressed genes in cancer. In one of. Substitution on the amide nitrogen was not required for potency, as illustrated by 10 (CPI-0610), which also demonstrated greater in vitro metabolic stability than the secondary amides. Constellation developed pelabresib (CPI-0610) which inhibits members of the BET family of chromosome-binding. Doses (mg) of 6 12, 24, 48, 80, 120, 170, 230, 300 (capsules) and 125 and 225. To make progress in CPI studies on this disease, herein, we review and summarize the mechanisms of activation of the PD-L1. Browse Publications Technical Papers 2020-01-0610. 2f), supporting the potential for BETi to be used for ovarian cancer. In preclinical studies, pelabresib downregulated NF-κB signaling and demonstrated antitumor activity in vitro. 8% median improvement in TSS for transfusion dependent (TD. The future of epigenetic therapy: CPI-0610 for the treatment of myeloidfibrosis Epigenomics. Guidelines differ from study to study, and identify who can or cannot participate. Methods: We retrieved and reviewed published reports on the clinical trials of twelve BET inhibitors including AZD5153, ABBV-075, BMS-986158, CPI-0610, GSK525762, OTX-015, PLX51107, INCB054329, INCB057643, FT-1101, CC-90010, and ODM-207 for patients with hematological malignancies and solid tumors and summarized their published target genes. As previously reported at ASH 2020, 42 of 63 evaluable patients (67%) achieved a ≥35%. CPI-0610 inhibits the expression of Nuclear receptor binding SET domain protein 3 (NSD3) target genes. Products with only one mechanism of action are approved. CPI-0610 7. Confirmation of the preliminary results in a larger number of patientsResponses produced in patients with myelofibrosis who received pelabresib (CPI-0610) in combination with ruxolitinib (Jakafi) were durable beyond week 24 according to data from the phase 2. Pelabresib (CPI-0610) is an oral, small-molecule, investigational BET inhibitor that downregulates NF-κB gene expression and other relevant genes involved in MF disease pathways. Royalty Pharma will purchase the rights to receive 3% of future net sales of CPI-0209. Constellation is driving development of the BET inhibitor CPI-0610 for the treatment of myelofibrosis as well as the EZH2 inhibitors CPI-1205 and CPI0209 for the treatment of metastatic castration. 21 of 29 evaluable patients (72%) achieved SVR35 at 12 weeksCPI-0610 demonstrated activity, both as a monotherapy and as add on to ruxolitinib, in second-line or later settings; Translational data supports potential disease-modifying effects of CPI-0610; CAMBRIDGE, Mass. We look forward to the continued evaluation of CPI-0610 in this ongoing Phase 2 trial and to providing additional data from MANIFEST later this year. BET inhibitor CPI-0610 is well tolerated and induces responses in diffuse large B-cell lymphoma and follicular. 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. Pelabresib (CPI-0610) Selective benzoisoxaoloazepine BET bromodomain inhibitor for BRD4-BD1 : NSD3 NSD3: AZD 5153 6-hydroxy 2-naphthoic acid ZEN-3694: Orally available BET-BRD4 bromodomain inhibitor Orally available pan-BET bromodomain inhibitor Context: Pelabresib (CPI-0610), a first-in-class, oral, small-molecule inhibitor of BET proteins (BETi), has potential to promote disease-modifying activity through altered gene regulation of key oncogenic, fibrotic, and inflammatory factors in MF. CPI-0610 is a small molecule inhibitor of bromodomain and extra-terminal (BET) proteins. The isoxazole derivative CPI-0610, which exhibits an IC 50 of 120 nM for BRD4 in the MV4-11 xenograft tumour model [96, 100], was developed by Constellation Pharmaceuticals. 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. CPI-0610 is a unique, first-in-class, oral, small-molecule inhibitor of BET (BETi) proteins, designed to promote disease-modifying activity through selective gene regulation of key oncogenic, fibrotic, and inflammatory factors with potential to transform the standard of care in MF. Constellation Pharmaceuticals Provides Updates of MANIFEST Study for CPI-0610 and EZH2 Franchise. MPN-375 BET Inhibitor Pelabresib (CPI-0610) Combined With Ruxolitinib in Patients With Myelofibrosis – JAK Inhibitor-Naïe or With Suboptimal Response to Ruxolitinib – Preliminary Data From the MANIFEST Study. Contact Ronald AldridgePelabresib (CPI-0610) is an investigational selective small molecule designed to promote anti-tumor activity by inhibiting the function of bromodomain and extra-terminal domain (BET) proteins to decrease the expression of abnormally expressed genes in cancer. CPI-0610 is a well-tolerated, potent, selective BET inhibitor that is currently evaluated as a monotherapy and in combination with ruxolitinib in patients with MF, in a global phase 2 study (MANIFEST, NCT02158858). In Arm 2, CPI-0610 is used in combination with ruxolitinib for second-line patients, and in Arm 3, CPI-0610 is used as a first-line treatment in patients who are JAKi naive, also in combination. Phase 2 Part: Open-label study of CPI-0610 with and without Ruxolitinib in patients with Myelofibrosis. 9 Inhibiting BET may modify critical MF pathways, including. CPI-0209, a second-generation enhancer of zeste homolog 2 (EZH2) inhibitor, in Phase 2 development for hematological malignancies and solid tumors by Constellation. Pelabresib (CPI-0610), a first-in-class, oral, small-molecule inhibitor of bromodomain and extraterminal domain (BET) proteins, has the potential to promote disease-modifying activity through altered gene regulation of key oncogenic, fibrotic, and inflammatory factors in the clonal disease cells of origin in myelofibrosis (MF). 40) were amide or urea analogs such as RO6870810 (TEN-010), birabresib (OTX015, MK-8628), CPI-0610 137, and BAY-1238097 (Fig. CPI-0610 treatment resulted in MM cytotoxicity in vitro by inducing G 1 cell cycle arrest and caspase-dependent apoptosis. Mascarenhas J, Harrison C, Luptakova K, et al. Preclinical and clinical data on Pelabresib (CPI-0610), an investigational oral small-molecule potent BET-inhibitor being explored in MF, suggest it offers a much-needed innovative treatment approach for patients with MF. Targets. , Goy A. This CPI-0610-induced dose-dependent maturation of aberrant immature MK cells may play a role in reducing MF disease manifestations. Pelabresib (CPI-0610) is a small molecule inhibitor of bromodomain and extra-terminal (BET) proteins. and ABBV-07 5 (6). gov identifier: NCT02158858 ), a global, open-label, nonrandomized, multicohort, phase II study, includes a cohort of JAKi-naïve patients with myelofibrosis treated with pelabresib and ruxolitinib. Severe. ” The data were gathered from 44 patients. CPI-0610 is a small molecule inhibitor of BET proteins with a novel mechanism of action and potential for disease-modifying effects in MF. CPI-0610, CPI-1205 and CPI-0209 are investigational therapies and have not been approved by the FDA (or any other regulatory authority). METHODS MANIFEST (ClinicalTrails. METHODS MANIFEST (ClinicalTrails. Plain language summary Myelofibrosis (MF) is a rare type of blood cancer that interferes with the process of blood cell production by the bone marrow. , et al. Pelabresib is a small molecule inhibitor of bromodomain and extra-terminal (BET) proteins. The CPI-0610 starting daily dose was 125 mg, 2 weeks on, 2 weeks off. Overall, the use of CPI-0610 induced a significant reduction in spleen volume of at least 35% and total symptom score reduction of at least 50%. The dose will not be adjusted for body weight or. Constellation’s two lead product candidates, pelabresib (CPI-0610), a BET inhibitor, and CPI-0209, a second-generation EZH2 inhibitor, are in mid- to late-stage clinical trials and have broad. It is designed to downregulate BET target genes and modify nuclear factor kappa B. Study Description. Phone Number: 1-877-MDA-6789. Contact Ronald AldridgeJohn O. The novel BET inhibitor CPI-0610 demonstrated clinical activity with or without ruxolitinib (Jakafi) in patients with JAK inhibitor-naïve and JAK inhibitor-exposed or -intolerant myelofibrosis. and Cote, Alexandre and Leblanc, Yves and Nasveschuk, Christopher G. Pelabresib (CPI-0610) is a synthetic, small-molecule inhibitor of the tandem amino-terminal bromodomains (BD1 and BD2) of BET proteins currently in clinical development. 2019 Nov;11(14):1553-1555. About CPI-0610. A. In preclinical studies, pelabresib treatment results in downregulation of NF-κB signaling activity, accompanied by loss of viability in ABC- diffuse large B-cell lymphoma. The Phase 3 MANIFEST-2 study is evaluating pelabresib combined with ruxoliti. The maximum decline in the platelet count occurs around day 14, with recovery over the following 1-2 week break from treatment. MANIFEST is an open-label Phase 2 clinical trial of pelabresib (CPI-0610) in patients with myelofibrosis (MF), a rare cancer of the bone marrow that disrupts the body's normal production of blood. , Flinn I. As the inhibition of individual BET bromodomains will lead to different. “There is a dose-dependent and concentration-dependent inhibition of IL8 and CCR1, and both are NF-kB dependent genes,” Senderowicz said. Constellation is evaluating CPI-0610 in combination with ruxolitinib in JAK-inhibitor-naïve MF patients (Arm 3), with a primary endpoint of the proportion of patients with a ≥35% spleen volume. 9 weeks in the combination arm. METHODS MANIFEST (ClinicalTrails. A. In solution, store at -20ºC and use within 3 months to prevent loss of potency. A phase I study of Cpi-0610, a Bromodomain And Extra Terminal Protein (BET) inhibitor in patients with relapsed or refractory lymphoma. Description. Constellation is driving development of the BET inhibitor pelabresib (CPI-0610) for the treatment of myelofibrosis as well as its EZH2 inhibitor CPI-0209 for the treatment of other cancers. CPI-0610 rapidly suppressed expression of both proinflammatory cytokines. However, only a single failed study has been published in treating Ph(-) myeloproliferative neoplasm (MPN). ConclusionsPelabresib (CPI-0610), a first-in-class, oral, small-molecule inhibitor of BET proteins (BETi), has potential to promote disease-modifying activity through altered gene regulation of key oncogenic, fibrotic, and inflammatory factors in MF. Findings from the phase 2 MANIFEST trial showed that at 12 weeks, the BET inhibitor CPI-0610 in combination with ruxolitinib demonstrated a 72. , May 14, 2020 (GLOBE NEWSWIRE) -- Constellation Pharmaceuticals, Inc. Royalty Pharma will purchase the rights to receive 3% of future net sales of CPI-0209. The novel targeted agent CPI-0610 enhanced responses to ruxolitinib in patients with myelofibrosis enrolled in the global phase II MANIFEST-2 trial, investigators reported at the 2020 American Society of Hematology (ASH) Annual Meeting & Exposition. Preclinical studies have shown that CC-90010 has significant. Pelabresib (CPI-0610) is an oral small-molecule investigational inhibitor of BET protein bromodomains currently being developed for the treatment of patients with MF. Pelabresib (CPI-0610), a first-in-class, oral, small-molecule inhibitor of BET proteins (BETi), has potential to promote disease-modifying activity through altered gene regulation of key oncogenic, fibrotic, and inflammatory factors in MF. There is no guarantee that. Phase 2 Part: Open-label study of CPI-0610 with and without Ruxolitinib in patients with Myelofibrosis. 2f). Constellation's two lead product candidates, pelabresib (CPI-0610), a BET inhibitor, and CPI-0209, a second-generation EZH2 inhibitor, are in mid- to late-stage clinical trials and have broad therapeutic potential to offer meaningful benefits to patients with various hematological and solid tumors. CPI-0209, a second-generation enhancer of zeste homolog 2 (EZH2) inhibitor, in Phase 2 development for hematological malignancies and solid tumors by Constellation. Aliquot to avoid multiple freeze/thaw cycles. If these preliminary data are confirmed in further testing, CPI-0610 may have the potential for disease modification and could become part of a new standard of care in myelofibrosis. For research use only. CPI-0610 in MANIFEST, both as monotherapy and in combination with ruxolitinib and in both JAK-inhibitor-naïve and JAK-inhibitor-experienced and -ineligible patients, was generally well tolerated. 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. For CPI-0610 added on to ongoing treatment with ruxolitinib, there was a 24. CPI-0610 induces apoptosis and G 1 cell cycle arrest associated with MYC downregulation. Storage. Finally, in Arm 3, which looked at CPI-0610 in combination with ruxolitinib in JAK-inhibitor-naïve patients, 67% of subjects achieved a ≥35% reduction in SVR35 at the 24. We would like to show you a description here but the site won’t allow us. Constellation's two lead product candidates, pelabresib (CPI-0610), a BET inhibitor, and CPI-0209, a second-generation EZH2 inhibitor, are in mid- to late-stage clinical trials and have broad therapeutic potential to offer meaningful benefits to patients with various hematological and solid tumors. Keywords: MPN, SVR35, TSS50, ruxolitinib, fedratinib, momelotinib MPN-379 Matching-Adjusted Indirect Comparison (MAIC) of Pelabresib (CPI-0610) in Combination With Ruxolitinib vs. Pelabresib (CPI-0610) in Myelofibrosis: Pelabresib is an oral small-molecule BET inhibitor currently under investigation for the treatment of MF. Masarova says that CPI-0610, a bromodomain, and extra-terminal (BET) inhibitor holds promise in patients with myelofibrosis since it could alter the transcription factors and potentially overcome the patient’s resistance to ruxolitinib (Jakafi). The combined use of pelabresib (CPI-0610) and ruxolitinib (Jakafi) demonstrated durable responses beyond week 24 in patients with myelofibrosis who experienced a suboptimal response to ruxolitinib and. We are enrolling MF patients who are Janus-kinase-1/2, or JAK1/JAK2-, inhibitor-naïve, a first. Methods: We retrieved and reviewed published reports on the clinical trials of twelve BET inhibitors including AZD5153, ABBV-075, BMS-986158, CPI-0610, GSK525762, OTX-015, PLX51107, INCB054329, INCB057643, FT. The body weights of the. We are also exploring other novel cancer epigenetics targets in preclinical testing to fuel a sustainable pipeline of innovative small-molecule product candidates. Furthermore, the use of CPI-0610 in combination with suberoylanilide. 2217/epi-2019. MANIFEST-2, A GLOBAL, PHASE 3, RANDOMIZED, DOUBLE-BLIND, ACTIVE-CONTROL STUDY OF CPI 0610 AND RUXOLITINIB VS. , CPI-0610 added onto existing treatment with ruxolitinib) have been treated for over 16 months. MOR210/TJ210/HIB210 is a human antibody directed against C5aR1, the receptor of the complement factor C5a, currently in Phase 1 clinical development. Initial studies indicated that CPI-0610 offers some improvement in terms of selectivity for (i) BRD4 (2-fold over other BET family members), and (ii) between BRD4. Constellation is evaluating CPI-0610 in combination with ruxolitinib in JAK-inhibitor-naïve MF patients (Arm 3), with a primary endpoint of the proportion of patients with a ≥35% spleen volume. There is a high unmet need for a treatment that can potentially delay or reverse BM fibrosis in patients (pts) with MF. Confirmation of the preliminary results in a. BET proteins regulate key oncogenic pathways, including NFκB and TGFβ signaling which are important drivers of pro-inflammatory cytokine (Ck) expression and bone marrow. Keywords: CPI-0610 •JAKitreatment-naive MANIFEST-2 myelofibrosis pelabresib ruxolitinib Myelofibrosis (MF) is a clonal myeloproliferative neoplasm (MPN) that includes primary MF as well as MF that develops after a diagnosis of polycythemia vera or essential thrombocythemia [1,2]. CPI-0610, CPI-1205 and CPI-0209 are investigational therapies and have not been approved by the FDA (or any other regulatory authority). Menu icon A vertical stack of three evenly. Two abstracts with preliminary data from the MANIFEST clinical trial from 59 enrolled patients as of June 27, 2019, the data cutoff date, were published today in association with ASH. Methods: Phase 2 trial with 3 arms: CPI-0610 monotherapy (Arm 1) or RUX + CPI-0610 “add-on. The study. MANIFEST Trial of CPI-0610. 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. Kremyanskaya, M, Mascarenhas J, Palandri F, et al. CPI-0610 is a unique, first-in-class, oral, small-molecule inhibitor of bromodomain and extraterminal domain (BET) proteins, designed to promote disease-modifying activity. Constellation’s epigenetics platform includes a deep understanding of the biological contexts in which BET proteins operate. Modify: 2023-11-04. Cross-trial comparisons with JAKi monotherapy have limitations due to. Arm 1 (2L) – CPI-0610 monotherapy in JAK-inhibitor-experienced or -ineligible patients . 1491. In preclinical studies, pelabresib downregulated NF-κB signaling and demonstrated antitumor activity in vitro. , Maris M. cpi 0610 Experimental: Continuous Treatment Period Unblinded, open label drug will be administered once daily for 14 consecutive days followed by a 7 day break, which is considered 1 cycle of treatment (1 cycle = 21 days). Pelabresib (CPI-0610) monotherapy in patients with myelofibrosis – update of clinical and translational data from the ongoing manifest trial. Context: Pelabresib (CPI-0610) combined with ruxolitinib showed encouraging spleen and symptom responses in Janus kinase inhibitor (JAKi)-naïve patients with intermediate or high-risk. Pelabresib (CPI-0610; PELA) is an oral, small-molecule, investigational BET inhibitor that downregulates NF-κB signaling and other relevant genes involved in MF disease pathways (Mascarenhas J, et al. MANIFEST-2, a global, phase 3, randomized, double-blind, active-control study of CPI-0610 and ruxolitinib vs. and Bellon, Steve and Bergeron,. CPI-0610 (0-1500 nM; 72 hours; Multiple myeloma cell lines and primary MM cells) treatment reduces the viability of MM cells in a dose-dependent manner [2]. 1,2. ”Mr. placebo and ruxolitinib in JAK. 07) Dates. An additional cohort is recruiting JAKi naïve patients to receive CPI-0610/ruxolitinib combination, and showed encouraging preliminary activity [33]. The novel targeted agent CPI-0610 enhanced responses to ruxolitinib in patients with myelofibrosis enrolled in the global phase II MANIFEST-2 trial, investigators reported at the 2020 American Society of Hematology (ASH) Annual Meeting & Exposition. Background: CPI-0610, a selective and potent small molecule BETi, has shown clinical activity and a wide therapeutic window in a Phase 1 lymphoma study (Blum KA, 2018). Ruxolitinib is the only FDA-approved treatment for myelofibrosis. Both the CPI-0610 and navitoclax combinations with ruxolitinib are also being studied in the JAK inhibitor-naïve setting; early results with the former are promising (10 of 15 (66. ABBV-075 and JQ1 were tested. We previously evaluated CPI-0610 in three Phase 1 clinical trials in an aggregate of 138 patients with hematological malignancies. their clin ical invest igation s are focused on cancer therapies. Pelabresib (CPI-0610) is a potent and selective benzoisoxazoloazepine BET bromodomain inhibitor. Article. However, the thrombocytopenia was reversible and not cumulative. Data from pacritinib in the first line setting, seen here, cannot be compared to any arm of the MANIFEST trial. CPI-0610 data was 29% and 38%, which also compares favorably with the above data. In addition, the first dose of CPI-0610 should not occur before a period equal to or greater than 5 half-lives of the small molecule investigational agent has elapsed. Taken together, these paired BM biopsy and in vitro myeloid maturation results demonstrated an effect. Like ruxolitinib failure, there is also no uniformly accepted. A Phase 1/2 Study of CPI-0610, a Small Molecule Inhibitor of BET Proteins: Phase 1 (Dose Escalation of CPI-0610 in Patients With Hematological Malignancies) and Phase 2 (Dose Expansion of CPI-0610 With and Without Ruxolitinib in Patients With Myelofibrosis and Essential Thrombocytopenia)Here we describe the identification and characterization of a potent and selective benzoisoxazoloazepine BET bromodomain inhibitor that attenuates BET-dependent gene expression in vivo, demonstrates antitumor efficacy in an MV-4-11 mouse xenograft model, and is currently undergoing human clinical trials for hematological. The benzoisoxazoloazepine CPI-0610 decreased MYC transcripts in vivo and reduced leukemia xenograft tumor growth, which was synergistic with doxorubicin treatment [117]. Arm 3 (1L) – CPI-0610 + ruxolitinib interim efficacy subgroup analysis in JAK-inhibitor-naïve patients. Create: 2012-07-23. Here we present results from MANIFEST. Of the 36 patients who received CPI-0610 monotherapy, 34 were still receiving the treatment as of Oct. Conclusions: CPI-0610 is a well-tolerated, and an effective therapeutic agent for the treatment of MF. Constellation is evaluating CPI-0610 in combination with ruxolitinib in JAK-inhibitor-naïve MF patients (Arm 3), with a primary endpoint of the proportion of patients with a ≥35% spleen volume. There has been significant progress in immune checkpoint inhibitor (CPI) therapy in many solid tumor types. (C)-JQ1, I-BET762, OTX015, I-BET151, CPI203, PFI-1, MS436, CPI-0610 chemical structures are shown. Although CPI-0610 was tested at doses as high as 400 mg PO QD, the maximum tolerated dose was 225 mg PO QD for 2 weeks on, 1 week off. Garner ,Optional tumor biopsy will be obtained prior to Day 1 of CPI-0610 administration. 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. 05. CPI-0610 has been evaluated in 3 Phase 1 studies in > 140 patients with lymphoma, multiple myeloma and acute leukemias/myelodysplastic syndrome/MF. CPI-0610 is a unique, first-in-class, oral, small-molecule inhibitor of BET (BETi) proteins, designed to promote disease-modifying activity through selective gene regulation of key oncogenic, fibrotic, and inflammatory factors with potential to transform the standard of care in MF. Two abstracts with preliminary data from the MANIFEST clinical trial from 59 enrolled patients as of June 27, 2019, the data cutoff date, were published today in association with ASH. We would like to show you a description here but the site won’t allow us. 2018; 29:Pelabresib (CPI-0610) is an investigational, orally administered, small molecule BET inhibitor that reduces expression of BET target genes and modulates NF-κB signaling. The ProSTAR study is evaluating CPI-1205, Constellation’s potent and highly selective small-molecule EZH2 inhibitor, in combination with either enzalutamide or abiraterone / prednisone. gov identifier: NCT02158858 ), a global, open. and Vaswani, Rishi G. If these preliminary data are confirmed in further testing, CPI-0610 may have the potential for disease modification and could become part of a new standard of care in myelofibrosis. Pelabresib (CPI-0610) is an investigational selective small-molecule designed to promote anti-tumor activity by inhibiting the function of bromodomain and extra-terminal domain (BET) proteins to decrease the expression of abnormally expressed genes in cancer. Pelabresib (CPI-0610) is a synthetic, small-molecule inhibitor of the tandem amino-terminal bromodomains (BD1 and BD2) of BET proteins currently in clinical. As in Arm 2, the TEAEs recorded for Arm 3 were generally mild and showed the combination was well tolerated (Table 3). 21 of 29 evaluable patients (72%) achieved SVR35 at 12 weeksCAMBRIDGE, Mass. Arm 2 (2L) – CPI-0610 + ruxolitinib in ruxolitinib-experienced patients. CPI-0610 is a selective and potent oral BETi, being evaluated in the first study of a BETi in MF. at UCLA. V126. Ann Oncol. Methods: We retrieved and reviewed published reports on the clinical trials of twelve BET inhibitors including AZD5153, ABBV-075, BMS-986158, CPI-0610, GSK525762, OTX-015, PLX51107, INCB054329, INCB057643, FT-1101, CC-90010, and ODM-207 for patients with hematological malignancies and solid tumors and summarized their. Treatment with an investigational small molecule less than 2 weeks before the first dose of CPI-0610. HemaSphere 2022;6:99-100). 3), and the WEE1 inhibitor adavosertib a moderate response (SPM score 84). CPI-0610 is a potent, selective, and cell-active BET inhibitor. A Phase 3, randomized, blinded study comparing pelabresib (CPI-0610) and ruxolitinib with placebo and ruxolitinib in myelofibrosis (MF) patients that have not been previously treated with Janus kinase inhibitors (JAKi). In the MANIFEST-2 phase 3 study, CPI-0610 plus ruxolitinib will be compared to placebo plus ruxolitinib in JAK inhibitor–naïve MF patients with at least DIPSS intermediate-1 disease, splenomegaly by imaging, and symptomatic MF. Products with only one mechanism of action are approved. The MANIFEST trial investigating this drug had 3 arms; the second arm combined ruxolitinib. 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. Participant eligibility includes age, gender, type and stage of disease, and previous treatments or health concerns. CPI-0610 significantly delayed tumor growth and increased theCPI-0610 is an effective BET inhibitor in multiple myeloma (MM) and is currently being tested in phase I clinical trial [84]. The results provide evidence of synergy between CPI-0610 and rux in these myelofibrosis patients, and the spleen and symptom benefits are. 18 μM for MYC. 9% median reduction in spleen volume at 24 weeks and a 58. CPI-0610 will be administered 200mg orally once a daily for 14 consecutive days followed by a 7-day break. (B) Comparison of average IC 50 s of BET inhibitors from patient-derived samples. Pelabresib (CPI-0610) is an investigational, oral, small-molecule bromodomain and extraterminal (BET) domain inhibitor. . Interim data from this study have shown promising results,. erated CPI-0610 well; thrombocytopenia was the only overlapping toxicity with ruxolitinib but was non-cumulative and reversible. CPI-0610 demonstrated activity, both as a monotherapy and as add on to ruxolitinib, in second-line or later settings; Translational data supports potential disease-modifying effects of CPI-0610; CAMBRIDGE, Mass. Background: Pelabresib (CPI-0610; PELA) is a bromodomain and extraterminal domain (BET) inhibitor in development for the treatment of myelofibrosis. We further show that CPI-0610 inhibits MM cell growth in the presence of cytokines and when co-cultured with bone marrow stromal cells. The two patients treated with a combination of CPI-0610 and ruxolitinib (i. We do not sell or distribute actual drugs. gov, NCT04603495) trial, which will evaluate the efficacy and safety of pelabresib (CPI-0610) and ruxolitinib versus placebo and ruxolitinib in patients with JAKi treatment-naive MF. Optional tumor biopsy will be obtained prior to Day 1 of CPI-0610 administration. 5,6 Analysis of. Clear anti-tumor activity was observed in. The combined use of pelabresib (CPI-0610) and ruxolitinib (Jakafi) demonstrated durable responses beyond week 24 in patients with myelofibrosis who experienced a suboptimal response to ruxolitinib and in those who were JAK inhibitor naïve, according to preliminary data from arms 2 and 3 of the phase 1/2 MANIFEST trial (NCT02158858). Double-blind treatment (CPI-0610 or matching placebo) will be administered daily for 14 consecutive days followed by a 7-day break, which is considered 1 cycle of treatment (1 cycle = 21 days). PLACEBO AND RUXOLITINIB IN JAK INHIBITOR-TREATMENT-NAIVE MYELOFIBROSIS PATIENTS. A phase I study of CPI-0610, a bromodomain and extra terminal protein (BET) inhibitor in patients with relapsed or refractory lymphoma. However, protein levels of BCL2, NF- κ B and MCL1 remain unchanged in MM cells upon BET inhibition. Alternative Names: CPI-0610. The Phase 3 MANIFEST-2 study is evaluating pelabresib combined with ruxoliti. Assessing the Impact of Lubricant and Fuel Composition on LSPI and Emissions in a Turbocharged Gasoline Direct Injection Engine 2020-01-0610. CPI 0610 ; View More. The BET inhibitor CPI-0610 binds to the acetylated lysine recognition motifs on the bromodomain of BET proteins, thereby preventing the interaction between the BET proteins and acetylated histone peptides. BET Inhibitor CPI-0610 is well tolerated and induces responses in diffuse large B-cell lymphoma and follicular lymphoma: preliminary analysis of an ongoing. 365. Pelabresib (CPI-0610) is an investigational selective small molecule designed to promote anti-tumor activity by inhibiting the function of bromodomain and extra-terminal domain (BET) proteins to decrease the expression of abnormally expressed genes in cancer. These findings indicate that BET inhibition not only results in a robust reduction of MYC transcription and activity but also suppresses the expression of. Pelabresib (CPI-0610) is an investigational, selective oral bromodomain and extraterminal domain inhibitor (BETi). In July 2012, LLS began its partnership with Constellation to support three first-in-human Phase 1 clinical trials for blood cancer patients and is currently supporting "A Phase 3, Randomized, Double-blind, Active-Control Study of CPI-0610 and Ruxolitinib vs. Strategic Funding PartnershipWe look forward to the continued evaluation of CPI-0610 in this ongoing Phase 2 trial and to providing additional data from MANIFEST later this year. Abramson J. (Nasdaq: CNST) today announced that three abstracts relating to the MANIFEST clinical trial of CPI-0610 in myelofibrosis were published online in association with the European Hematology Association (EHA) annual meeting. JAK Inhibitor Monotherapy in Patients With Intermediate or High-Risk Myelofibrosis Vikas Gupta PhD1, John Mascarenhas MD2, Marina Kremyanskaya MD,. 45 Although small-molecule pan-BET inhibitors show promising effects in clinical evaluation, there are still problems and challenges to overcome, such as the moderate clinical. We plan to provide a further update on CPI-0610 in oral and poster presentations and at an investor event at the ASH meeting on December 9. Constellation has aligned with the FDA on the design of MANIFEST-2, the pivotal Phase 3 clinical trial for CPI-0610 expected to begin in 2H20; Constellation plans to explore additional indications for CPI-0610; CAMBRIDGE, Mass. The recommended Phase 2 dose of CPI-0610 in the MANIFEST study is 125 mg once daily (may be titrated up), which is below the maximum tolerated dose of 225 mg once daily. 9%. W. CPI-0610 is thought to reduce and suppress the differentiation of myeloid cells into megakaryocytes in the bone marrow, potentially leading to disease modification. Spleen response rates in first-line patients at 12 weeks and 24 weeks in line with previously. The. When CPI-0610 was added to ongoing treatment with Ruxolitinib, 22% of patients achieved SVR at 24 weeks, and 34% had converted from TD, to TI. Myelofibrosis is characterized by the presence of bone marrow fibrosis, increased cytokine production and inflammation, over activation of the JAK-STAT. A Phase 3, randomized, blinded study comparing pelabresib (CPI-0610) and ruxolitinib with placebo and ruxolitinib in myelofibrosis (MF) patients that have not been previously treated with Janus kinase inhibitors (JAKi). 22, 10. This study is evaluating CPI-0610 in two parts: Phase 1 Part (Complete): Open-label, sequential dose escalation study of CPI-0610 in patients with previously A Phase 1/2 Study of CPI-0610, a Small Molecule Inhibitor of BET Proteins: Phase 1 (in Patients With Hematological Malignancies) and Phase 2 (Dose Expansion of CPI-0610 With and. CPI-1205, CPI-0610, CPI-0209, and other product candidates are investigational in nature and have not yet been approved by the FDA or other regulatory authorities. MANIFEST-2, a global, phase 3, randomized, double-blind, active-control study of CPI-0610 and ruxolitinib vs. 31 Pharmacokinetic parameters were dose-proportional for the evaluated doses. 37. 2217/epi-2019-0274. Pelabresib (CPI-0610) Selective benzoisoxaoloazepine BET bromodomain inhibitor for BRD4-BD1 : NSD3 NSD3: AZD 5153 6-hydroxy 2-naphthoic acid ZEN-3694: Orally available BET-BRD4 bromodomain inhibitor Orally available pan-BET bromodomain inhibitor : Open in a separate window. Pelabresib is being investigated as a treatment for myelofibrosis and has not. , Goy A. CPI-0610 is a selective and potent oral BETi, being evaluated in the first study of a BETi in MF. The combination was well-tolerated. The benefits yielded with the BET inhibitor pelabresib (formerly CPI-0610) in patients with myelofibrosis are multifold, and the agent’s potential to improve disease biology and overcome. - Mechanism of. Mascarenhas, MD. doi: 10. A minimum 2-week period between the last treatment with a therapeutic antibody and the. In preclinical studies, pelabresib treatment results in downregulation of NF-κB signaling activity, accompanied by loss of viability in ABC- diffuse large B-cell lymphoma.