It has potential applications in the treatment of various forms of cancer . CPI-0610 Add-on to Ruxolitinib in Transfusion-Dependent Patients (Cohort 2A) SVR35: At 24 weeks, SVR35 was achieved in 3 out of 12 (25%) evaluable patients, with a median percent change of -24. MANIFEST-2, a global, phase 3, randomized, double-blind, active-control study of CPI-0610 and ruxolitinib vs. 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. Additionally, we have begun planning for a randomized. 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. 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. Abramson JS, Blum KA, Flinn IW, et al. A. 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. at UCLA. 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. Arm 1 (2L) – CPI-0610 monotherapy in JAK-inhibitor-experienced or -ineligible patients . 1 (PubChem release 2021. Molecular studies to further our understanding of the underlying mechanisms of CPI-0610 treatment are ongoing. CPI-0610, CPI-1205 and CPI-0209 are investigational therapies and have not been approved by the FDA (or any other regulatory authority). We also confirmed the in vivo efficacy of CPI-0610 in a MM xenograft mouse. 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 was generally well tolerated in MANIFEST, both as monotherapy and in combination with ruxolitinib, and in both JAK-inhibitor-naïve and -ineligible as well as JAK-inhibitor-experienced patients. Pelabresib is currently being investigated as a treatment for myelofibrosis and. 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. Products with only one mechanism of action are approved. CPI-203 and CPI-0610 were obtained from Constellation Pharmaceuticals and kept as a solid powder at room temperature (RT). Pelabresib is a small molecule inhibitor of bromodomain and extra-terminal (BET) proteins. 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. A minimum 2-week period between the last treatment with a therapeutic antibody and the first dose of CPI-0610 may be permitted in patients with rapidly progressive or aggressive subtypes of lymphoma following discussion with the medical monitor. Certain more-dramatic changes, such as incorporation of an amide isostere ( 11 ) or removal of the acetamide methylene linker ( 12 ), led to a substantial loss. 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 selective and potent oral BETi, being evaluated in the first study of a BETi in MF. Kremyanskaya M, Mascarenhas J, Palandri F, et al. 8. Arms 1 and 2 are studying CPI-0610 as a monotherapy or in combination with ruxolitinib in. CPI-0610-mediated BET inhibition overcomes the protective effects conferred by cytokines and bone marrow stromal cells. With 63 myelofibrosis patients now treated and evaluable in the company’s mid-stage study, the 24-week spleen response rate to its oral drug, CPI-0610 — when used on top of Jakafi, Incyte’s. 22, 10. Brief Summary: A Phase 3, randomized, blinded study comparing pelabresib (CPI-0610) and ruxolitinib with placebo and ruxolitinib in. “We are excited about the emerging profile of CPI-0610,” said Jigar Raythatha, Chief Executive Officer of Constellation Pharmaceuticals. CPI-0610 and CPI-1205 are each in Phase 2 clinical trials, and a third program, CPI-0209, is expected to begin a Phase 1 clinical trial in mid-2019. Phase 2 Part: Open-label study of CPI-0610 with and without Ruxolitinib in patients with Myelofibrosis. PLACEBO AND RUXOLITINIB IN JAK INHIBITOR-TREATMENT-NAIVE MYELOFIBROSIS PATIENTS. Buy Profile. 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%. 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. 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. The primary endpoint of each trial was to establish the safety of CPI-0610 as a single agent by evaluating the frequency of dose-limiting toxicities associated with treatment with CPI-0610 for 21 days. CPI-0610 is a drug which acts as a BET inhibitor, mainly acting at the BRD2 and BRD4 subtypes. 2022, p. 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. Pelabresib (CPI-0610) is an oral small-molecule investigational inhibitor of BET protein bromodomains currently being developed for the treatment of patients with MF. 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. CPI-0610 is a small molecule inhibitor of bromodomain and extra-terminal (BET) proteins. 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. The BET Inhibitor, CPI-0610, Promotes Myeloid Differentiation in Myelofibrosis Patient Bone Marrow and Peripheral CD34+ Hematopoietic Stem Cells. The Grade 3 and 4 TEAEs were mostly hematological with anemia being the most commonly recorded Grade 3 TEAE. We would like to show you a description here but the site won’t allow us. The dose will not be adjusted for body weight or. Downsized turbocharged gasoline direct injection (TGDI) engines with high specific power and torque can enable reduced fuel. 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. CPI-0610 discontinuation due to TEAEs occurred in 12% of patients, and six Grade 5 TEAEs were recorded. CPI-0610 is a selective and potent oral BETi, being evaluated in the first study of a BETi in MF. Dose increase by 25 mg was allowed from Cycle 3 onwards to a maximum dose of 225 mgThe combination of pelabresib (CPI-0610) and ruxolitinib (Jakafi) produced responses that proved to be durable beyond week 24 in patients with myelofibrosis who experienced a suboptimal response. We further show that CPI-0610 inhibits MM cell growth in the presence of cytokines and when co-cultured with bone marrow stromal cells. 2217/epi-2019-0274. Myelofibrosis is characterized by the presence of bone marrow fibrosis, increased cytokine production and inflammation, over activation of the JAK-STAT. Arm 3 (1L) – CPI-0610 + ruxolitinib interim efficacy subgroup analysis in JAK-inhibitor-naïve patients. 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. Phase 1 Part (Complete): Open-label, sequential dose escalation study of pelabresib in patients with previously treated Acute Leukemia, Myelodysplastic. MANIFEST TrialCPI-0610 (4), 35. CPI-0610, CPI-1205 and CPI-0209 are investigational therapies and have not been approved by the FDA (or any other regulatory authority). BET inhibitors in clinical development (ABBV-075, I-BET762, CPI-0610) are variably effective in limiting CTCL cell viability (A) Representative dose-response curves of CTCL cells derived from patient 11 to different BET inhibitors. , Aug. 2018; 29 (Abstract 41O) Google Scholar; CC-90010 is a novel, oral, reversible, small-molecule inhibitor of BET proteins. Mascarenhas J, Harrison C, Luptakova K, et al. The CPI-0610 is a selective small molecule which promotes anti-tumor activity by inhibiting the function of BET proteins, which normally enhances target gene expression. 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). The two patients treated with a combination of CPI-0610 and ruxolitinib (i. Storage. The therapeutic potential of CPI-0610, an inhibitor of BET proteins, currently in Phase I testing in multiple myeloma (MM), is investigated and a synergistic cytotoxic effect in the cell lines tested is observed, due in part to suppression of MYC, IKZF1 and IRF4 . Products with only one mechanism of action are approved. METHODS. Spleen response rates in first-line patients at 12 weeks and 24 weeks in line with previously. 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. Severe. CPI-0610 is a small molecule inhibitor of bromodomain and extra-terminal (BET) proteins. 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). Download scientific diagram | BET bromodomain inhibitor molecules. and Vaswani, Rishi G. 1,2 “Preliminary data demonstrate the. 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. 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; Arm 3 (1L) – CPI-0610 + ruxolitinib interim efficacy subgroup analysis in JAK-inhibitor-naïve patients As previously reported at ASH 2020, 42 of 63 evaluable patients (67%) achieved a ≥35% reduction in spleen volume (SVR35) at 24 weeks (the primary endpoint for Arm 3). Pelabresib (CPI-0610) is a potent and selective benzoisoxazoloazepine BET bromodomain inhibitor. 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) Actual Study Start Date : July 29, 2014 Arm 3 (1L) – CPI-0610 + ruxolitinib in JAK-inhibitor-naïve patients. Placebo and Ruxolitinib in JAKi Treatment Naive MF Patients. (Nasdaq: CNST) today announced that two oral. 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. 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. However, protein levels of BCL2, NF- κ B and MCL1 remain unchanged in MM cells upon BET inhibition. Phase 2 Part: Open-label study of CPI-0610 with and without Ruxolitinib in patients with Myelofibrosis. 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). 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. 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. S. Pelabresib is a small molecule inhibitor of bromodomain and extra-terminal (BET) proteins. 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. Optional tumor biopsy will be obtained prior to Day 1 of CPI-0610 administration. Cross-trial comparisons with JAKi monotherapy have limitations due to. Pelabresib - MorphoSys. Description. While CPI-0610, Nil, and the combination significantly reduced spleen size , only the combination significantly reduced donor leukaemic CD45. 3), and the WEE1 inhibitor adavosertib a moderate response (SPM score 84). . . BET proteins regulate key oncogenic pathways, including NFκB and TGFβ signaling which are important drivers of pro-inflammatory cytokine (Ck) expression and. Modify: 2023-11-04. Background: Pelabresib (CPI-0610) is a potent, first-in-class, selective, oral small-molecule inhibitor of bromodomain and extraterminal domain (BET). As previously reported at ASH 2020, 42 of 63 evaluable patients (67%) achieved a ≥35%. Recent. Pelabresib (CPI-0610) Combined with Ruxolitinib for JAK Inhibitor Treatment-Naïve Patients with Myelofibrosis: Durability of Response and Safety Beyond Week 24. 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. Like ruxolitinib failure, there is also no uniformly accepted. 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. Pelabresib is being investigated as a treatment for myelofibrosis and has not yet. 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 through selective gene regulation of key oncogenic, fibrotic, and inflammatory factors with potential to transform the standard of care in myelofibrosis (MF). 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. Here we report the safety, pharmacokinetics, pharmacodynamics, and preliminary clinical activity from the first-in-human phase I study of pelabresib in patients with relapsed. V126. 2f). CPI-0610 inhibits BRD4-BD1 with an IC50 of 39 nM, and with an EC50 value of 0. Abramson JS, Blum KA, Flinn IW, Gutierrez M, Goy A, Maris M, et al. Methods: Phase 2 trial with 3 arms: CPI-0610 monotherapy (Arm 1) or RUX + CPI-0610 “add-on” (Arm 2) in pts who have progressed/ had an inadequate response to RUX, or CPI-0610 + RUX in JAK inhibitor-naïve pts with anemia (Arm 3). 8% median improvement in TSS for transfusion dependent (TD. 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 rapidly suppressed expression of both proinflammatory cytokines. We previously evaluated CPI-0610 in three Phase 1 clinical trials in an aggregate of 138 patients with hematological malignancies. e. - Mechanism of Action & Protocol. CPI-0610, CPI-1205 and CPI-0209 are investigational therapies and have not been approved by the FDA (or any other regulatory authority). Here we present results from MANIFEST. , et al. , Goy A. In one of. . Kremyanskaya, M, Mascarenhas J, Palandri F, et al. We are also exploring other novel cancer epigenetics targets in preclinical testing to fuel a sustainable pipeline of innovative small-molecule product candidates. Upon administration, pelabresib binds to the acetylated lysine recognition motifs on the bromodomain of BET. For a discussion of other risks and uncertainties, any of. Methods: Phase 2 trial with 3 arms: CPI-0610 monotherapy (Arm 1) or RUX + CPI-0610 “add-on” (Arm 2) in pts who have progressed/ had an inadequate response to RUX, or CPI-0610 + RUX in JAK inhibitor-naïve pts with anemia (Arm 3). 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. [Google Scholar]In addition, the Company is amending the design of MANIFEST to include a third cohort designed to evaluate treatment with CPI-0610 in combination with ruxolitinib as a first-line therapy in JAK 1/. Contact Ronald AldridgeJohn O. Alternative Names: CPI-0610. Adis is an information provider. 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. Methods: Phase 2 trial with 3 arms: CPI-0610 monotherapy (Arm 1) or RUX + CPI-0610 “add-on” (Arm 2) in pts who have progressed/ had an inadequate response to RUX, or CPI-0610 + RUX in JAK inhibitor-naïve pts with anemia (Arm 3). placebo and ruxolitinib in JAK. Clear anti-tumor activity was observed in. 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. There is a high unmet need for a treatment that can potentially delay or reverse BM fibrosis in patients (pts) with MF. 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. (Nasdaq: CNST) today announced that two oral. , et al. The 14 days of CPI-0610 dosing and the 7-day break together constitute 1 cycle of treatment. 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. 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. Final gross price and currency may vary according to local VAT and billing address. CPI-0610 has been evaluated in 3 Phase 1 studies in > 140 patients with lymphoma, multiple myeloma and acute leukemias/myelodysplastic syndrome/MF. “Our goal is to drive CPI-0610 to registration and to transform the standard of care in myelofibrosis and potentially other hematologic diseases. 1,2. The. CPI-0610 displays potent cytotoxicity against MM cell lines and patient-derived MM cells through G1 cell cycle arrest and caspase. Pelabresib (CPI-0610) Catalog No. 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. 5% rate of reduction in spleen volume of at least 35%. Importantly, CC-90010 has a longer terminal half-life [∼60 h (±15% CV)] for the RP2D than other BET. CPI-0610 is a potent, selective, and cell-active BET inhibitor. Background: Pelabresib (CPI-0610; PELA) is a bromodomain and extraterminal domain (BET) inhibitor in development for the treatment of myelofibrosis (MF). Arm 3 (1L) – CPI-0610 + ruxolitinib in JAK-inhibitor-naïve patients. Ruxolitinib (marketed as Jakafi) is the standard of care treatment for patients with. The two patients treated with a combination of CPI-0610 and ruxolitinib (i. Here, we review preclinical and clinical data on Pelabresib (CPI-0610), an investigational oral small-molecule potent BET-inhibitor being explored in MF. It is designed to downregulate BET target genes and modify nuclear factor kappa B. Arm 3 (1L) – CPI-0610 + ruxolitinib interim efficacy subgroup analysis in JAK-inhibitor-naïve patients. CPI-0610 is a small molecule inhibitor of bromodomain and extra-terminal (BET) proteins. Study of bb2121 in Multiple Myeloma Rochester, MN Study CRB-401 is a 2-part, non-randomized, open label, multi-site Phase 1 study of bb2121 in adults with relapsed/refractory multiple myeloma (MM). – Amends second-line trial design to stratify for transfusion dependence based on positive preliminary data –– Expands study to include an additio. These findings indicate that BET inhibition not only results in a robust reduction of MYC transcription and activity but also suppresses the expression of. CPI-0610 is a small molecule inhibitor of bromodomain and extra-terminal (BET) proteins. Placebo and Ruxolitinib in JAKi Treatment Naive MF Patients - AdisInsightA 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). 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. 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. MANIFEST-2, A GLOBAL, PHASE 3, RANDOMIZED, DOUBLE-BLIND, ACTIVE-CONTROL STUDY OF CPI 0610 AND RUXOLITINIB VS. 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. Modify: 2023-11-04. As previously reported at ASH 2020, 42 of 63 evaluable patients (67%) achieved a ≥35%. Pelabresib Anhydrous is the anhydrous form of pelabresib, a small molecule inhibitor of the Bromodomain and Extra-Terminal (BET) family of proteins, with potential antineoplastic activity. Participation eligibility. 40) were amide or urea analogs such as RO6870810 (TEN-010), birabresib (OTX015, MK-8628), CPI-0610 137, and BAY-1238097 (Fig. In addition to improvements in spleen volume and constitutional symptoms, the interim data suggest improvements in anemia, transfusion dependence, and bone marrow fibrosis. Scandura, MD, PhD, reflected on its potential role for patients with myelofibrosis and studies evaluating. 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. 17, 2019. 5,6 Analysis of. Abstract. 1491. 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). Our study found IKZF1 and IRF4 to be among the primary targets of CPI-0610, along with MYC . - Mechanism of. Phone Number: 1-877-MDA-6789. The abstracts include. 7%) evaluable patients achieved ≥35% SVR and 11 of 14 (78. Products with only one mechanism of action are approved. Aliquot to avoid multiple freeze/thaw cycles. Interim data from the trial demonstrated reduction in spleen volume, BM fibrosis, anemia and blood transfusions, as well as total. CPI-0610. W. Here we present results from MANIFEST. Certain more-dramatic changes, such as incorporation of an amide isostere ( 11 ) or removal of the acetamide methylene linker ( 12 ), led to a substantial. @article{osti_1855473, title = {Identification of a Benzoisoxazoloazepine Inhibitor (CPI-0610) of the Bromodomain and Extra-Terminal}, author = {Albrecht, Brian K. Ruxolitinib is the only FDA-approved treatment for myelofibrosis. Pts can experience intolerance, inadequate response or loss of response to first-line cytoreductive therapies (hydroxyurea [HU] or interferon alfa-2a). ” Data Highlights . A. Pelabresib is a small molecule inhibitor of bromodomain and extra-terminal (BET) proteins. Study Description. We would like to show you a description here but the site won’t allow us. CPI-0209, a second-generation enhancer of zeste homolog 2 (EZH2) inhibitor, in Phase 2 development for hematological malignancies and solid tumors by Constellation. Table 3 lists three such trials, early results from which have been presented. Here, the safety, efficacy, and pharmacodynamics of ten BET inhibitors currently in clinical trials were evaluated. 8 g/mol. Doses of 170 and 230 mg QD are associated with a 50% average. Although CPI-0610 was tested at doses as high as. CPI-0610 treatment of CD34+ cells from MF patients in MK differentiating conditions in the presence of SCF, IL6, IL9 and TPO resulted in a dose-dependent. 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. Pelabresib (CPI-0610) is an investigational, oral, small-molecule bromodomain and extraterminal (BET) domain inhibitor. Additionally, CPI-0610 decreased BRD4 and c-Myc expressions and affected MAPK, JAK/STAT, and AKT signalling pathways in human DLBCL cells. 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. 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. CPI-0610 is a first-in-class inhibitor of bromodomain and extraterminal domain (BET) proteins, which regulate gene transcription in numerous pro-fibrotic pathways. CPI-0610 is a selective and potent oral BETi, being evaluated in the first study of a BETi in MF. When. . 8. About CPI-0610. Participant eligibility includes age, gender, type and stage of disease, and previous treatments or health concerns. Treatment with JAKi ruxolitinib (rux) or fedratinib in the frontline setting is associated with. Constellation’s epigenetics platform includes a deep understanding of the biological contexts in which BET proteins operate. 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. 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. S. CPI-0610 will be administered 200mg orally once a daily for 14 consecutive days followed by a 7-day break. Ann Oncol. 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. Table 3 lists three such trials, early results from which have been presented. 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. Jennifer A Mertz, PhD 1 *, Patricia J Keller,. CPI 0610 ; View More. Maris 3 , I. 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. Targets. CPI-0610 can become a part of the standard of care and even expand the overall addressable market in myelofibrosis indication. 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. UPDATE: Constar Intl (CNST) Reports Update on MANIFEST Clinical Trial of CPI-0610 in Myelofibrosis Article Related Press Releases ( 1 ) Stock Quotes (1) Comments (0) FREE Breaking News Alerts from. CPI-0610 has been evaluated in 3 Phase 1 studies in > 140 patients with lymphoma, multiple myeloma and acute leukemias/myelodysplastic syndrome/MF. 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. 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) 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. “There is a dose-dependent and concentration-dependent inhibition of IL8 and CCR1, and both are NF-kB dependent genes,” Senderowicz said. Arm 3 is evaluating CPI-0610 in combination with ruxolitinib in JAK-inhibitor-naïve MF patients. As in Arm 2, the TEAEs recorded for Arm 3 were generally mild and showed the combination was well tolerated (Table 3). 6 of 21 (29%) evaluable non-TD patients achieved SVR35 at 24 weeks, the primary endpoint for cohort 2B. We would like to show you a description here but the site won’t allow us. Data from pacritinib in the first line setting, seen here, cannot be compared to any arm of the MANIFEST trial. CPI-0610, CPI-1205 and CPI-0209 are investigational therapies and have not been approved by the FDA (or any other regulatory authority). Keywords: CPI-0610; JAKi treatment-naive; MANIFEST-2; myelofibrosis; pelabresib; ruxolitinib. Keywords: MPN, SVR35, TSS50, ruxolitinib, fedratinib, momelotinib MPN-379 Matching-Adjusted Indirect Comparison (MAIC) of Pelabresib (CPI-0610) in Combination With Ruxolitinib vs. Create: 2012-07-23. 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. Methods: MANIFEST (ClinicalTrails. Here we present results from MANIFEST. Royalty Pharma will purchase the rights to receive 3% of future net sales of CPI-0209. Spleen response rates in first-line patients at 12 weeks and 24 weeks in line with previously reported data and differentiated from standard of careSpleen responses demonstrated. It has potential applications in the treatment of various forms of cancer . 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. Pelabresib (CPI-0610; PELA) is an oral, small-molecule, investigational BET inhibitor that downregulates NF-κB signaling and other relevant genes involved in MF. MANIFEST (ClinicalTrails. Spleen response rates in first-line patients at 12 weeks and 24 weeks in line with previously. . 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. Pelabresib is a small molecule inhibitor of bromodomain and extra-terminal (BET) proteins. doi: 10. 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). 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. Authors Jigar Raythatha 1 , Lauren Arnold 1 Affiliation 1 Constellation Pharmaceuticals. Purpose of Review Myelofibrosis (MF) is a myeloproliferative neoplasm characterized by bone marrow fibrosis, megakaryocyte. For a discussion of other risks and uncertainties, any of. BET proteins regulate key oncogenic pathways, including NFκB and TGFβ signaling which are important drivers of pro-inflammatory cytokine (Ck) expression and. For example, patients experienced immune responses, improvements in quality of life, and an occasional. A phase I study of Cpi-0610, a Bromodomain And Extra Terminal Protein (BET) inhibitor in patients with relapsed or refractory lymphoma. at UCLA. We further show that CPI-0610 inhibits MM cell growth in the presence of cytokines and when co-cultured with bone marrow stromal cells. Pelabresib (CPI-0610) monotherapy in patients with myelofibrosis – update of clinical and translational data from the ongoing manifest trial. W. Arms 1 and 2 are studying CPI-0610 as a monotherapy or in combination with ruxolitinib in. (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. 2015; 126:1491. doi: 10. 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). For a discussion of other risks and uncertainties, any of. In a phase II trial of CPI-0610 added to ruxolitinib, 63% of patients with no prior JAK inhibitor treatment had at least a 35% reduction in spleen volume (SVR35, the primary endpoint) and an. Description. The study evaluated CPI-0610 as a monotherapy in arm 1, as an add-on to ruxolitinib in arm 2, and in combination with ruxolitinib in the arm 3. We are also exploring other novel cancer epigenetics targets in preclinical testing to fuel a sustainable pipeline of innovative small-molecule product candidates. 9 Inhibiting BET may modify critical MF pathways, including. As the most extensively characterized BET protein, BRD4 has. JAK Inhibitor Monotherapy in Patients With Intermediate or High-Risk Myelofibrosis Vikas Gupta PhD1, John Mascarenhas MD2, Marina Kremyanskaya MD,. CPI-0610 will be administered 200mg orally once a daily for 14 consecutive days followed by a 7-day break. PELA combined with ruxolitinib (RUX) has shown a 56% response rate for ≥50% reduction in total symptom score (TSS) at Wk 24 from baseline (BL; TSS50) in Janus kinase inhibitor. 1182/blood. According to Mayo Clinic, “Myelofibrosis is an uncommon type of. and Hewitt, Michael C. The combination was well-tolerated. 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%. Aims: Data (Sep 2021 data cut) on the safety and efficacy of pelabresib in combination with RUX in pts with MF from Arms 2 and 3 of the ongoing, open-label. BET inhibitor CPI-0610 is well tolerated and induces responses in diffuse large B-cell lymphoma and follicular. 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. 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. 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 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; 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. 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. 9 weeks in the combination arm. Single agent CPI-0610 treatment also significantly decreased tumour weight by 42% when compared to vehicle (Fig. 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. 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). Treatment with an investigational small molecule less than 2 weeks before the first dose of CPI-0610. CPI-0610 monotherapy arm (n = 36): patients no longer on rux with resistant/refractory or intolerant MF and Dynamic International Prognostic Scoring System (DIPSS) ≥ intermediate; CPI-0610 starting dose at 125 mg once daily on days 1-14 (21-day dosing cycles). CPI-0610 showed signals of clinical activity, both as a monotherapy and in combination with ruxolitinib, in refractory myelofibrosis (MF) patients. The CPI-0610 starting daily dose was 125 mg, 2 weeks on, 2 weeks off. FRANCESCA PALANDRI via Scopus - Elsevier. CPI-0610 inhibits the expression of Nuclear receptor binding SET domain protein 3 (NSD3) target genes. Pelabresib (CPI-0610) Combined with Ruxolitinib for JAK Inhibitor Treatment-Naïve Patients with Myelofibrosis: Durability of Response and Safety Beyond Week 24. Abstract. The study evaluated CPI-0610 as a monotherapy in arm 1, as an add-on to ruxolitinib in arm 2, and in combination with ruxolitinib in the arm 3. and Gehling, Victor S. 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. (B) Comparison of average IC 50 s of BET inhibitors from patient-derived samples. 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. An additional cohort is recruiting JAKi naïve patients to receive CPI-0610/ruxolitinib combination, and showed encouraging preliminary activity [33]. 9% median reduction in spleen volume at 24 weeks and a 58. 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. 9%. An in vivo experiment exhibited that CPI-0610 decreased the primary tumour growth of the DLBCL xenograft model. 1491. Preclinical studies have shown that CC-90010 has significant. 4. A Phase 3, Randomized, Double-blind, Active-Control Study of CPI-0610 and Ruxolitinib vs. CPI-0610 induces apoptosis and G 1 cell cycle arrest associated with MYC downregulation. CPI-0610 is a selective and potent oral BETi, being evaluated in the first study of a BETi in MF. A. (Nasdaq: CNST), a clinical-stage. Background: Pelabresib (CPI-0610), an investigational product, in combination with ruxolitinib (ruxo) has shown encouraging responses in terms of ≥35% reduction in spleen volume from baseline (SVR35) and ≥50% reduction in total symptoms score (TSS) from baseline (TSS50) in Janus kinase inhibitor (JAKi) treatment-naïve patients with.