Overall, the use of. Resources and Links. Pelabresib (CPI-0610; PELA) is an oral, small-molecule, investigational BET inhibitor that downregulates NF-κB signaling and other relevant genes involved in MF. Treatment with JAKi ruxolitinib (rux) or fedratinib in the frontline setting is associated with. An additional cohort is recruiting JAKi naïve patients to receive CPI-0610/ruxolitinib combination, and showed encouraging preliminary activity [Citation 33]. 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. So, combinations with Navitoclax which is Bcl-xL cell inhibitor, CPI-0610, which is BET inhibitor, Luspatercept which is anemia drug. The combination of rucaparib and CPI-0610 resulted in a significant 58% decrease in tumour weight when compared to vehicle (Fig. We are also exploring other novel cancer epigenetics targets in preclinical testing to fuel a sustainable pipeline of innovative small-molecule product candidates. CPI-0610 inhibits BRD4-BD1 with an IC50 of 39 nM, and with an EC50 value of 0. [1] [2]. BET proteins are known to promote cancer growth. CPI-0610 is a small molecule inhibitor of bromodomain and extra-terminal (BET) proteins. BET proteins regulate key oncogenic pathways, including NFκB and TGFβ signaling which are important drivers of pro-inflammatory cytokine (Ck) expression and bone marrow. CPI-0610 is given orally once daily (QD) on days 1-14 of a 21-day cycle. Optional tumor biopsy will be obtained prior to Day 1 of CPI-0610 administration. However, toxicity studies. CPI-0610 is a selective and potent oral BETi, being evaluated in the first study of a BETi in MF. METHODS MANIFEST (ClinicalTrails. Pelabresib (CPI-0610) monotherapy in patients with myelofibrosis – update of clinical and translational data from the ongoing manifest trial. Jennifer A Mertz, PhD 1 *, Patricia J Keller,. Furthermore, the use of CPI-0610 in combination with suberoylanilide. 8. HemaSphere 2022;6:99-100). Importantly, CC-90010 has a longer terminal half-life [∼60 h (±15% CV)] for the RP2D than other BET. Arm 3 (1L) – CPI-0610 + ruxolitinib in JAK-inhibitor-naïve patients. Participation eligibility. “Preliminary data demonstrate the potential for the combination of CPI-0610 and. 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). CPI-0610 is a small molecule inhibitor of BET proteins with a novel mechanism of action and potential for disease-modifying effects in MF. Tolerability and Efficacy of Navitoclax Alone or in Combination With Ruxolitinib in Participants With Myelofibrosis. Blood. Strategic Funding PartnershipCPI-0610 (Constellation Pharmaceuticals, Cambridge, MA) is a potent, orally bioavailable inhibitor of BET proteins that is being studied in different clinical scenarios (as a single agent after ruxolitinib, as an “add-on” therapy to ruxolitinib and in combination with ruxolitinib in JAK inhibitor naïve patients with MF) in the ongoing. (Nasdaq: CNST) today announced that two oral. Products with only one mechanism of action are approved. JAKi are currently approved for treatment of MF, including ruxolitinib. Pelabresib is being investigated as a treatment for myelofibrosis and has not yet. Arm 3 (1L) – CPI-0610 + ruxolitinib in JAK-inhibitor-naïve patients. 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. chem. 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. Here, the safety, efficacy, and pharmacodynamics of ten BET inhibitors currently in clinical trials were evaluated. Pelabresib is currently being investigated as a treatment for myelofibrosis and. Mascarenhas J, Harrison C, Luptakova K, et al. Multiple studies are evaluating pelabresib (CPI-0610) for the treatment of patients with myeloproliferative neoplasms (MPNs). 4. 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. 21 of 29 evaluable patients (72%) achieved SVR35 at 12 weeksCAMBRIDGE, Mass. Background: Pelabresib (CPI-0610; PELA) is a bromodomain and extraterminal domain (BET) inhibitor in development for the treatment of myelofibrosis. 8 g/mol. Pelabresib in combination with ruxolitinib is in a Phase 3 clinical trial ( NCT04603495 ) for myelofibrosis patients that have not been previously treated with Janus kinase inhibitors. Figure 2. Purpose of Review Myelofibrosis (MF) is a myeloproliferative neoplasm characterized by bone marrow fibrosis, megakaryocyte. Pelabresib (CPI-0610) Combined with Ruxolitinib for JAK Inhibitor Treatment-Naïve Patients with Myelofibrosis: Durability of Response and Safety Beyond Week 24. 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 is a highly promising Phase 3 product candidate with the potential to address unmet medical needs that have been identified by both patients and physicians. Kremyanskaya M, Mascarenhas J, Palandri F, et al. Pelabresib (previously CPI-0610) is a first-in-class, selective, oral small-molecule BET proteins inhibitor. 1,2. 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•]. CPI-0610 inhibits the expression of Nuclear receptor binding SET domain protein 3 (NSD3) target genes. An in vivo experiment exhibited that CPI-0610 decreased the primary tumour growth of the DLBCL xenograft model. We do not sell or distribute actual drugs. 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. 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. 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. 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. CPI-0610. It has potential applications in the treatment of various forms of cancer . 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. 22, 10. 2012-07-23. 2019 Nov;11(14):1553-1555. 2020-04-14. Pelabresib (CPI-0610) Combined with Ruxolitinib for JAK Inhibitor Treatment-Naïve Patients with Myelofibrosis: Durability of Response and Safety Beyond Week 24. In preclinical studies, pelabresib (CPI-0610), an investigational (BET) bromodomain inhibitor, downregulated NF-κB signaling and demonstrated antitumor. Spleen response rates in first-line patients at 12 weeks and 24 weeks in line with previously. This study is sponsored by Constellation Pharmaceuticals a MorphoSys Company. 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. 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. However, only a single failed study has been published in treating Ph(-) myeloproliferative neoplasm (MPN). As the most extensively characterized BET protein, BRD4 has. 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). CPI-0610 discontinuation due to TEAEs occurred in 12% of patients, and six Grade 5 TEAEs were recorded. MANIFEST-2, a global, phase 3, randomized, double-blind, active-control study of CPI-0610 and ruxolitinib vs. 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. Products with only one mechanism of action are approved. Most BET inhibitors in the clinic, including GSK525762, CPI-0610, OTX-015, and MT1, have similar structures as JQ1 and exhibited good preliminary effects on. In preclinical studies, pelabresib downregulated NF-κB signaling and demonstrated antitumor activity in vitro. Arm 1 (2L) – CPI-0610 monotherapy in JAK-inhibitor-experienced or -ineligible patients . The MANIFEST trial investigating this drug had 3 arms; the second arm combined ruxolitinib. 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. , Dec. Severe. 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. The maximum decline in the platelet count occurs around day 14, with recovery over the following 1-2 week break from treatment. CPI-0610 is a selective and potent oral BETi, being evaluated in the first study of a BETi in MF. ” Data Highlights . 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. . 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. - Mechanism of. 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. and Bellon, Steve and Bergeron,. Mascarenhas J, Harrison C, Luptakova K, et al. 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. 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). 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. at UCLA. 2 + cells in the bone marrow (protected by the niche. Taken together, these paired BM biopsy and in vitro myeloid maturation results demonstrated an effect of CPI-0610 in promoting erythroid and MK differentiation. 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. An early signal of clinical activity was seen in the phase 1 portion of the MANIFEST study (NCT02158858) that. 2 of 10 (20%) and 4 of 11 (36%) evaluable non-transfusion-dependent (non-TD) patients achieved SVR35 (the. 1,2 “Preliminary data demonstrate the. Pelabresib is a small molecule inhibitor of bromodomain and extra-terminal (BET) proteins. Ann Oncol. @article{osti_1855473, title = {Identification of a Benzoisoxazoloazepine Inhibitor (CPI-0610) of the Bromodomain and Extra-Terminal}, author = {Albrecht, Brian K. 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. Placebo and Ruxolitinib in JAKi Treatment Naive MF Patients. Pelabresib is a small molecule inhibitor of bromodomain and extra-terminal (BET) proteins. 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. A. CPI-0610, CPI-1205 and CPI-0209 are investigational therapies and have not been approved by the FDA (or any other regulatory authority). Go to. 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). 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. Molecular Weight. 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). (B) Comparison of average IC 50 s of BET inhibitors from patient-derived samples. PLACEBO AND RUXOLITINIB IN JAK INHIBITOR-TREATMENT-NAIVE MYELOFIBROSIS PATIENTS. The combination was well-tolerated. The benzoisoxazoloazepine CPI-0610 decreased MYC transcripts in vivo and reduced leukemia xenograft tumor growth, which was synergistic with doxorubicin treatment [117]. 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. For example, patients experienced immune responses, improvements in quality of life, and an occasional. We would like to show you a description here but the site won’t allow us. Kremyanskaya, M, Mascarenhas J, Palandri F, et al. Abramson J. 1. 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. Alternative Names: CPI-0610. We further show that CPI-0610 inhibits MM cell growth in the presence of cytokines and when co-cultured with bone marrow stromal cells. clinicaltrials. Pelabresib (CPI-0610) monotherapy in patients with myelofibrosis – update of clinical and translational data from the ongoing Manifest trial. Our study found IKZF1 and IRF4 to be among the primary targets of CPI-0610, along with MYC . 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. Abramson JS, Blum KA, Flinn IW, Gutierrez M, Goy A, Maris M, et al. 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). To further dissect the underlying mechanism of these relative improvements in bone marrow composition and histotopography induced by CPI-0610, CD34+ hematopoietic stem cells were isolated from peripheral blood collected from multiple MF patients at baseline to evaluate the impact of CPI-0610 on MK and erythroid differentiation in vitro. Mertz 6 , R. Royalty Pharma will purchase the rights to receive 3% of future net sales of CPI-0209. 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. With more data on the agent expected to be released from trials in this space toward the end of the year, Joseph M. 1 (PubChem release 2021. 1, 2 BET proteins regulate transcription of specific genes integrating an array of oncogenic signals, including NF-κB pathway activation. Contact Ronald Aldridge Pelabresib (CPI-0610) is an investigational, selective oral bromodomain and extraterminal domain inhibitor (BETi). 5% rate of reduction in spleen volume of at least 35%. Collectively, these data indicate that CPI-0610 +/- RUX might. The body weights of the. 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]. There is no guarantee that. Among the most common treatment-emergent adverse events (TEAEs) for CPI-0610 monotherapy in 46 safety-evaluable patients in Arm 1,. 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. 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. 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. 6%) evaluable patients achieved ≥50% TSS reduction at 24 weeks) 92 and a randomized phase 3 trial of. Latest Information Update: 01 Aug 2023. 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. - Mechanism of Action & Protocol. 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. ” Data Highlights . 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. placebo and ruxolitinib in JAK. 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). CPI-0610 is a novel small-molecule bromodomain and extra terminal protein (BET) inhibitor used in patients with relapsed or refractory disease. In addition to improvements in spleen volume and constitutional symptoms, the interim data suggest improvements in anemia, transfusion dependence, and bone marrow fibrosis. The 14 days of CPI-0610 dosing and the 7-day break together constitute 1 cycle of treatment. 2f), supporting the potential for BETi to be used for ovarian cancer. Study Description. MANIFEST TrialMascarenhas 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. CPI-0610 is a first-in-class inhibitor of bromodomain and extraterminal domain (BET) proteins, which regulate gene transcription in numerous pro-fibrotic pathways. Continued high rate of SVR35 in 1L patients: 72% at 12 weeks and 67% at 24 weeksSVR35 responses and transfusion dependence conversion observed in. CPI-0610, CPI-1205 and CPI-0209 are investigational therapies and have not been approved by the FDA (or any other regulatory authority). For a discussion of other risks and uncertainties, any of. CPI-0610 is a small molecule inhibitor of the Bromodomain and Extra-Terminal (BET) family of proteins, with potential antineoplastic activity. METHODS. 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). Single agent CPI-0610 treatment also significantly decreased tumour weight by 42% when compared to vehicle (Fig. Arms 1 and 2 are studying CPI-0610 as a monotherapy or in combination with ruxolitinib in. Pelabresib (CPI-0610) The MANIFEST clinical trial is evaluating the role of Pelabresib (CPI-0610), a BET inhibitor in combination with Jakafi (ruxoltinib) in patients with myelofibrosis (MF). 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. In: Clinical Lymphoma, Myeloma and Leukemia, Vol. ” Data HighlightsCPI-0610, CPI-1205 and CPI-0209 are investigational therapies and have not been approved by the FDA (or any other regulatory authority). 35. Findings from the phase 2 MANIFEST trial showed that at 12 weeks, the BET inhibitor CPI-0610 in combination with ruxolitinib demonstrated a 72. Pts can experience intolerance, inadequate response or loss of response to first-line cytoreductive therapies (hydroxyurea [HU] or interferon alfa-2a). at UCLA. BET inhibitor CPI-0610 is well tolerated and induces responses in diffuse large B-cell lymphoma and follicular lymphoma: preliminary analysis of an ongoing phase 1 study. The two patients treated with a combination of CPI-0610 and ruxolitinib (i. 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. Abstract. Some activity was reported with CPI-0610 as a single agent in the second-line setting. Phase 2 Part: Open-label study of CPI-0610 with and without Ruxolitinib in patients with Myelofibrosis. Description. erated CPI-0610 well; thrombocytopenia was the only overlapping toxicity with ruxolitinib but was non-cumulative and reversible. Taken together, these paired BM biopsy and in vitro myeloid maturation results demonstrated an effect of CPI-0610 in promoting erythroid and MK differentiation. Pacritinib in Patients With Primary Myelofibrosis, Post Polycythemia Vera Myelofibrosis, or Post-Essential Thrombocythemia Myelofibrosis. These results may partially explain CPI-0610's clinical effects in MF patients, including rising hemoglobin, reduced transfusion dependency and reduction in spleen volume and. 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. Royalty Pharma will purchase the rights to receive 3% of future net sales of CPI-0209. 5,6 Analysis of. 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. 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. 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). 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 showed signals of clinical activity, both as a monotherapy and in combination with ruxolitinib, in refractory myelofibrosis (MF) patients. Browse Publications Technical Papers 2020-01-0610. Menu icon A vertical stack of three evenly. 8% median improvement in TSS for transfusion dependent (TD. Methods: Eligible patients were those whose lymphoma had progressed and for whom no effective therapies are available. A. In MF patients, there are multiple studies from a single-agent arm in this phase 2 study in the second-line setting, then adding it to ruxolitinib while patients are on a stable dose of ruxolitinib, and combining it from the very beginning, This study is kind of 3 sets of patients, including. 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. The future of epigenetic therapy: CPI-0610 for the treatment of myeloidfibrosis Epigenomics. 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. Maris 3 , I. , Dec. MANIFEST-2, a global, phase 3, randomized, double-blind, active-control study of CPI-0610 and ruxolitinib vs. A Phase 1 Study Evaluating CPI-0610 in Patients With Previously Treated Multiple Myeloma - Full Text View. 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. The results provide evidence of synergy between CPI-0610 and rux in these myelofibrosis patients, and the spleen and symptom benefits are. Downsized turbocharged gasoline direct injection (TGDI) engines with high specific power and torque can enable reduced fuel. S. 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. Modify: 2023-11-04. Clinical data presented at 2019 American Society of Hematology annual meeting suggested that CPI-0610 could offer meaningful benefits beyond standard of care in myelofibrosis In addition to. CPI-0209, a second-generation enhancer of zeste homolog 2 (EZH2) inhibitor, in Phase 2 development for hematological malignancies and solid tumors by Constellation. Authors Jigar Raythatha 1 , Lauren Arnold 1 Affiliation 1 Constellation Pharmaceuticals. Here, the safety, efficacy, and pharmacodynamics of ten BET inhibitors currently in clinical trials were evaluated. 2f). These are phase three studies that are planned to start soon for possible approval for combinations over JAK inhibitor alone for different problems that people face. Additionally, we have begun planning for a randomized. The dose will not be adjusted for body weight or. 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. Adis is an information provider. Pelabresib (CPI-0610) is a synthetic, small-molecule inhibitor of the tandem amino-terminal bromodomains (BD1 and BD2) of BET proteins currently in clinical. While CPI-0610, Nil, and the combination significantly reduced spleen size , only the combination significantly reduced donor leukaemic CD45. MOR210/TJ210/HIB210 is a human antibody directed against C5aR1, the receptor of the complement factor C5a, currently in Phase 1 clinical development. A minimum 2-week period between the last treatment with a therapeutic antibody and the. Abstract. 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 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. Here we present results from MANIFEST. 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. MANIFEST TrialCPI-0610 (4), 35. Pelabresib (CPI-0610) Catalog No. This Phase 3, randomized, blinded study is comparing CPI-0610 and ruxolitinib with placebo and ruxolitinib in JAKi treatment-naive patients with primary A Phase 3, Randomized, Double-blind, Active-Control Study of Pelabresib (CPI-0610) and Ruxolitinib vs. gov identifier: NCT02158858 ), a global, open. Constellation developed pelabresib (CPI-0610) which inhibits members of the BET family of chromosome-binding. The CPI-0610 starting daily dose was 125 mg, 2 weeks on, 2 weeks off. CPI-0610-mediated BET. METHODS MANIFEST (ClinicalTrails. 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. For a discussion of other risks and uncertainties, any of. [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/. CPI-0610, CPI-1205 and CPI-0209 are investigational therapies and have not been approved by the FDA (or any other regulatory authority). 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. RVX2135, FT-1101, BAY1238097. However, protein levels of BCL2, NF- κ B and MCL1 remain unchanged in MM cells upon BET inhibition. 05, 2020 (GLOBE NEWSWIRE) -- Constellation Pharmaceuticals, Inc. CPI-0610 displays potent cytotoxicity against MM cell lines and patient-derived MM cells through G 1 cell cycle arrest and caspase-dependent apoptosis. 6 of 21 (29%) evaluable non-TD patients achieved SVR35 at 24 weeks, the primary endpoint for cohort 2B. Pelabresib (CPI-0610) in Myelofibrosis: Pelabresib is an oral small-molecule BET inhibitor currently under investigation for the treatment of MF. As the inhibition of individual BET bromodomains will lead to different. 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. their clin ical invest igation s are focused on cancer therapies. For CPI-0610 added on to ongoing treatment with ruxolitinib, there was a 24. Ruxolitinib is the only FDA-approved treatment for myelofibrosis. 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. BET proteins inhibition can potentially modify the pathogenic pathways which contribute to many diseases including malignancies. 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. Patients tolerated CPI-0610 well; thrombocytopenia was the only overlapping toxicity with ruxolitinib but was non-cumulative and reversible. “There is a dose-dependent and concentration-dependent inhibition of IL8 and CCR1, and both are NF-kB dependent genes,” Senderowicz said. Conclusions: CPI-0610 is a well-tolerated, and an effective therapeutic agent for the treatment of MF. Here we report the results from the first-in human Phase 1 study of CPI-0610 in patients with relapsed or refractory lymphomas (NCT01949883). 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. When. We also confirmed the in vivo efficacy of CPI-0610 in a MM xenograft mouse. Arm 2 (2L) – CPI-0610 + ruxolitinib in ruxolitinib-experienced 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). 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. . 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. 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. 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. Flinn 4 , A. The first study (poster #420) enrolled 32 patients with B-cell lymphoma and assigned them to oral CPI-1205 twice daily in 28-day cycles. Abstract. 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. Like ruxolitinib failure, there is also no uniformly accepted. , Goy A. 07) Dates. Treatment with JAK inhibitor (JAKi) ruxolitinib (rux) or fedratinib. 2022, p. 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. 9% median reduction in spleen volume at 24 weeks and a 58. ” The data were gathered from 44 patients. As previously reported at ASH 2020, 42 of 63 evaluable patients (67%) achieved a ≥35%. Pelabresib (CPI-0610) is an investigational, selective oral bromodomain and extraterminal domain inhibitor (BETi). Human Immunology Biosciences (HI-Bio) obtained exclusive worldwide rights to develop and commercialize MOR210 across all indications worldwide, with the exception of Greater China and South. Data published in two abstracts suggest that CPI-0610 may have potential disease-modifying effects in treating myelofibrosis ; All ten evaluable patients experienced spleen volume reductions ; Improvements in symptom scores, bone marrow fibrosis, and hemoglobin levels also seen ; Two transfusion dependent patients became transfusion. CPI-0610 is being studied in multiple different ways. 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. CPI-0610 induces apoptosis and G 1 cell cycle arrest associated with MYC downregulation. Nov 2022;CPI-0610 showed signals of clinical activity, both as a monotherapy and in combination with ruxolitinib, in refractory myelofibrosis (MF) patients Patients treated with CPI-0610 exhibited improvement in spleen volume, constitutional symptoms, anemia, bone marrow fibrosis, and transfusion dependenceA potent, oral small-molecule bromodomain and extraterminal domain (BET) inhibitor—CPI-0610—improves spleen volume and symptoms when added to the Janus kinase (JAK) inhibitor ruxolitinib (Jakafi) in ruxolitinib-naïve patients with myelofibrosis. In preclinical studies, pelabresib downregulated NF-κB signaling and demonstrated antitumor activity in vitro. About CPI-0610. 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. 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. Your purchase entitles you to full access to the information. 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. 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. 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, 2014Constellation Pharmaceuticals Provides Updates of MANIFEST Study for CPI-0610 and EZH2 Franchise. , Gutierrez M. Interim data from the trial demonstrated reduction in spleen volume, BM fibrosis, anemia and blood transfusions, as well as total. Demonstration of efficacy and safety in these 3 arms has led to the continued development of CPI-0610. 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. Pelabresib is a small molecule inhibitor of bromodomain and extra-terminal (BET) proteins. Article. Pelabresib (CPI-0610) is a small molecule inhibitor of bromodomain and extra-terminal (BET) proteins. – Amends second-line trial design to stratify for transfusion dependence based on positive preliminary data –– Expands study to include an additio. Assessing the Impact of Lubricant and Fuel Composition on LSPI and Emissions in a Turbocharged Gasoline Direct Injection Engine 2020-01-0610. 23. Preclinical studies have shown that CC-90010 has significant. Pelabresib (CPI-0610) Monotherapy in Patients With High-Risk Essential Thrombocythemia Refractory or Intolerant to Hydroxyurea: Preliminary Results From MANIFEST Study pdf | 552. Doses (mg) of 6 12, 24, 48, 80, 120, 170, 230, 300 (capsules) and 125 and 225. In solution, store at -20ºC and use within 3 months to prevent loss of potency. CPI-0610 inhibits BRD4-BD1 with an IC50 of 39 nM, and with an EC50 value of 0. e. 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). Create: 2012-07-23. 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. ”Mr. Clear anti-tumor activity was observed in. 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. 2018; 29 (Abstract 41O) Google Scholar; CC-90010 is a novel, oral, reversible, small-molecule inhibitor of BET proteins. I-BET151 showed beneficial effects in the treatment of GBM and leukemia. Download scientific diagram | BET bromodomain inhibitor molecules. / Mascarenhas, John; Kremyanskaya, Marina; Patriarca, Andrea et al. Abramson JS, Blum KA, Flinn IW, et al. Table 3 lists three such trials, early results from which have been presented. S7853. Haematologica. For a discussion of other risks and uncertainties, any of. 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. 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. 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. In the phase II MANIFEST study, Pelabresib is being evaluated as monotherapy and in combination with the JAK inhibitor ruxolitinib. Ruxolitinib (marketed as Jakafi) is the standard of care treatment for patients with. 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) is a synthetic, small-molecule inhibitor of the tandem amino-terminal bromodomains (BD1 and BD2) of BET proteins currently in clinical development. 41O A phase I study of CPI-0610, a bromodomain and extra terminal protein (BET) inhibitor in patients with relapsed or refractory lymphoma K. 18 μM for MYC.