However, toxicity studies. 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. Multiple studies are evaluating pelabresib (CPI-0610) for the treatment of patients with myeloproliferative neoplasms (MPNs). The Phase 3 MANIFEST-2 study is evaluating pelabresib combined with ruxoliti. The 14 days of CPI-0610 dosing and the 7-day break together constitute 1 cycle of treatment. 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). CPI-0610 (pelabresib) is an oral pan BET inhibitor in clinical development []. The future of epigenetic therapy: CPI-0610 for the treatment of myeloidfibrosis Epigenomics. Arms 1 and 2 are studying CPI-0610 as a monotherapy or in combination with ruxolitinib in. 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. Treatment with a therapeutic antibody less than 4 weeks before the first. Royalty Pharma will purchase the rights to receive 3% of future net sales of CPI-0209. Clear anti-tumor activity was observed in. 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. Phase 2 Part: Open-label study of CPI-0610 with and without Ruxolitinib in patients with Myelofibrosis. 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. 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. I-BET151 showed beneficial effects in the treatment of GBM and leukemia. The Phase 1 portion of the CPI-0209 Phase1/2 clinical trial is an open label, dose escalation study in patients with advanced tumors. , Flinn I. . Pelabresib (CPI-0610) is a potent and selective benzoisoxazoloazepine BET bromodomain inhibitor. Pelabresib (CPI-0610) monotherapy in patients with myelofibrosis – update of clinical and translational data from the ongoing Manifest trial. Here we present results from MANIFEST. Alternative Names: CPI-0610. Modify: 2023-11-04. There is no guarantee that. 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. Severe. 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. BET protein inhibition is. Pelabresib (CPI-0610) is an investigational, selective oral bromodomain and extraterminal domain inhibitor (BETi). Figure 2. We further show that CPI-0610 inhibits MM cell growth in the presence of cytokines and when co-cultured with bone marrow stromal cells. Constellation Pharmaceuticals Provides Updates of MANIFEST Study for CPI-0610 and EZH2 Franchise. In preclinical studies, pelabresib downregulated NF-κB signaling and demonstrated antitumor activity in vitro. . Myelofibrosis is characterized by the presence of bone marrow fibrosis, increased cytokine production and inflammation, over activation of the JAK-STAT. gov NCT No: NCT02158858 Opens a new window. S. 7%) evaluable patients achieved ≥35% SVR and 11 of 14 (78. Delaney has a track. CPI-0610 inhibits BRD4-BD1 with an IC50 of 39 nM, and with an EC50 value of 0. Background: Pelabresib (CPI-0610; PELA) is a bromodomain and extraterminal domain (BET) inhibitor in development for the treatment of myelofibrosis (MF). Pelabresib (CPI-0610) is an investigational, selective oral bromodomain and extraterminal domain inhibitor (BETi). 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. CPI-0610 is thought to reduce and suppress the differentiation of myeloid cells into megakaryocytes in the bone marrow, potentially leading to disease modification. 6 of 21 (29%) evaluable non-TD patients achieved SVR35 at 24 weeks, the primary endpoint for cohort 2B. 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 . Mascarenhas, MD. Arm 3 is evaluating CPI-0610 in combination with ruxolitinib in JAK-inhibitor-naïve MF patients. [1] [2]. 2019 Nov;11(14):1553-1555. MANIFEST-2, a global, phase 3, randomized, double-blind, active-control study of CPI-0610 and ruxolitinib vs. The combination of rucaparib and CPI-0610 resulted in a significant 58% decrease in tumour weight when compared to vehicle (Fig. 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. The dose will not be adjusted for body weight or. 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. Menu icon A vertical stack of three evenly. Ann Oncol. For a discussion of other risks and uncertainties, any of. 18 μM for MYC. CPI-0610. , Goy A. CPI-0610-mediated BET inhibition overcomes the protective effects conferred by cytokines and bone marrow stromal cells. Constellation Pharmaceuticals was a clinical-stage biopharmaceutical company developing novel therapeutics that selectively modulate gene expression to address serious unmet medical needs in patients with cancer. Patients tolerated CPI-0610 well; thrombocytopenia was the only overlapping toxicity with ruxolitinib but was non-cumulative and reversible. This CPI-0610-induced dose-dependent maturation of aberrant immature MK cells may play a role in reducing MF disease manifestations. 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 data were gathered from 44 patients. CPI-0610 is a small molecule inhibitor of the Bromodomain and Extra-Terminal (BET) family of proteins, with potential antineoplastic activity. Spleen response rates in first-line patients at 12 weeks and 24 weeks in line with previously. 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. A minimum 2-week period between the last treatment with a therapeutic antibody and the. The dose will not be adjusted for body weight or. Pts can experience intolerance, inadequate response or loss of response to first-line cytoreductive therapies (hydroxyurea [HU] or interferon alfa-2a). Mascarenhas J, Kremyanskaya M, Patriarca A, Harrison C, Bose P, Rampal RK, et al. We further show that CPI-0610 inhibits MM cell growth in the presence of cytokines and when co-cultured with bone marrow stromal cells. Methods: Phase 2 trial with 3 arms: CPI-0610 monotherapy (Arm 1) or RUX + CPI-0610 “add-on. According to Mayo Clinic, “Myelofibrosis is an uncommon type of. and Cote, Alexandre and Leblanc, Yves and Nasveschuk, Christopher G. RVX2135, FT-1101, BAY1238097. Pelabresib (CPI-0610) is an investigational, selective oral bromodomain and extraterminal domain inhibitor (BETi). FRANCESCA PALANDRI via Scopus - Elsevier. Overall, the use of. 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. There is a high unmet need for a treatment that can potentially delay or reverse BM fibrosis in patients (pts) with MF. 37 of 51 evaluable patients (73%) achieved a 35% reduction in spleen volume (SVR35) at 12 weeks and had a median spleen. It is designed to downregulate BET target genes and modify nuclear factor kappa B. In preclinical studies, pelabresib downregulated NF-κB signaling and demonstrated antitumor activity in vitro. , Flinn I. CPI-0610 is a selective and potent oral BETi, being evaluated in the first study of a BETi in MF. 8 of 21 (38%. We also confirmed the in vivo efficacy of CPI-0610 in a MM xenograft mouse. Mascarenhas J, Harrison C, Luptakova K, 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). CPI-0209, a second-generation enhancer of zeste homolog 2 (EZH2) inhibitor, in Phase 2 development for hematological malignancies and solid tumors by Constellation. 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. 8% median improvement in TSS for transfusion dependent (TD. Like ruxolitinib failure, there is also no uniformly accepted. ” Data HighlightsCPI-0610, CPI-1205 and CPI-0209 are investigational therapies and have not been approved by the FDA (or any other regulatory authority). 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. Pelabresib is a small molecule inhibitor of bromodomain and extra-terminal (BET) proteins. Arm 3 (1L) – CPI-0610 + ruxolitinib interim efficacy subgroup analysis in JAK-inhibitor-naïve patients. 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. In the phase II MANIFEST study, Pelabresib is being evaluated as monotherapy and in combination with the JAK inhibitor ruxolitinib. 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. 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. 1491. The benzoisoxazoloazepine CPI-0610 decreased MYC transcripts in vivo and reduced leukemia xenograft tumor growth, which was synergistic with doxorubicin treatment [117]. 41O A phase I study of CPI-0610, a bromodomain and extra terminal protein (BET) inhibitor in patients with relapsed or refractory lymphoma K. 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. Spleen response rates in first-line patients at 12 weeks and 24 weeks in line with previously. Store lyophilized at -20ºC, keep desiccated. 2015; 126:1491. However, only a single failed study has been published in treating Ph(-) myeloproliferative neoplasm (MPN). 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. 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. BET inhibitor CPI-0610 is well tolerated and induces responses in diffuse large B-cell lymphoma and follicular. 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 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. 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. Pelabresib is a small molecule inhibitor of bromodomain and extra-terminal (BET) proteins. 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. S7853. 2217/epi-2019-0274. For example, patients experienced immune responses, improvements in quality of life, and an occasional. Tolerability and Efficacy of Navitoclax Alone or in Combination With Ruxolitinib in Participants With Myelofibrosis. Collectively, these data indicate that CPI-0610 +/- RUX might. Here, the safety, efficacy, and pharmacodynamics of ten BET inhibitors currently in clinical trials were evaluated. Mertz 6 , R. Adis is an information provider. Pelabresib has the potential to be a first. - Mechanism of Action & Protocol. Here, we review preclinical and clinical data on Pelabresib (CPI-0610), an investigational oral small-molecule potent BET-inhibitor being explored in MF. Doses of 170 and 230 mg QD are associated with a 50% average. V126. 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. 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). MANIFEST-2, a global, phase 3, randomized, double-blind, active-control study of CPI-0610 and ruxolitinib vs. Blum 1 , J. 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. 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. 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. The company is currently. CPI-0610 will be administered 200mg orally once a daily for 14 consecutive days followed by a 7-day break. 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). 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. 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. 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. Price : $50 *. , Aug. CPI-0610 has been evaluated in 3 Phase 1 studies in > 140 patients with lymphoma, multiple myeloma and acute leukemias/myelodysplastic syndrome/MF. 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. We previously evaluated CPI-0610 in three Phase 1 clinical trials in an aggregate of 138 patients with hematological malignancies. e. CPI-0610 is a selective and potent oral BETi, being evaluated in the first study of a BETi in MF. 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. , CPI-0610 added onto existing treatment with ruxolitinib) have been treated for over 16 months. 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. 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)7019 Background: High-risk essential thrombocythemia (HR ET) is characterized by thrombocytosis, thrombohemorrhagic events and systemic symptoms. CPI-0610. (Nasdaq: CNST), a clinical-stage. , Maris M. In preclinical studies, pelabresib (CPI-0610), an investigational (BET) bromodomain inhibitor, downregulated NF-κB signaling and demonstrated antitumor activity in vitro. Preclinical studies have shown that CC-90010 has significant. 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. 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. 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). at UCLA. 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. Article. 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. Blood. About CPI-0610. Cross-trial comparisons with JAKi monotherapy have limitations due to. METHODS MANIFEST (ClinicalTrails. Clear anti-tumor activity was observed in. 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. CPI-0610 is a selective and potent oral small molecule BETi with effects on megakaryocyte differentiation and Ck production in preclinical studies (unpublished data) and has shown antitumor activity and a wide therapeutic window in a Phase 1 lymphoma study (Blum KA, 2018). 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). chem. 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. 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. Molecular Weight. BET inhibitors combined with other drugs may have better prospects. 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. Storage. A Phase 1 Study Evaluating CPI-0610 in Patients With Previously Treated Multiple Myeloma - Full Text View. As previously reported at ASH 2020, 42 of 63 evaluable patients (67%) achieved a ≥35%. Furthermore, in a Phase 1 clinical trial of CPI-0610, the Company also showed that the dose-limiting toxicity of thrombocytopenia was reversible and non-cumulative. This study is exploring either CPI-0610 alone or in combination with ruxolitinib (Janus kinase 1/2 inhibitor). We would like to show you a description here but the site won’t allow us. 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). 6%) evaluable patients achieved ≥50% TSS reduction at 24 weeks) 92 and a randomized phase 3 trial of. A Phase 3, Randomized, Double-blind, Active-Control Study of CPI-0610 and Ruxolitinib vs. As the most extensively characterized BET protein, BRD4 has. Pacritinib in Patients With Primary Myelofibrosis, Post Polycythemia Vera Myelofibrosis, or Post-Essential Thrombocythemia Myelofibrosis. 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. Abstract. TEN-010 (5), 36. Pelabresib (CPI-0610) Catalog No. BET proteins regulate key oncogenic pathways, including NFκB and TGFβ signaling which are important drivers of pro-inflammatory cytokine (Ck) expression and. 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. CPI-0610 is a first-in-class inhibitor of bromodomain and extraterminal domain (BET) proteins, which regulate gene transcription in numerous pro-fibrotic pathways. (C)-JQ1, I-BET762, OTX015, I-BET151, CPI203, PFI-1, MS436, CPI-0610 chemical structures are shown. CPI-0610 has been well tolerated, with the principal toxicity being dose-dependent thrombocytopenia that is reversible and non-cumulative. Between September 2013 and March 2015 44 patients had been enrolled and treated at doses of 6, 12, 24, 48, 80, 120, 170. Pelabresib (CPI-0610) in Myelofibrosis: Pelabresib is an oral small-molecule BET inhibitor currently under investigation for the treatment of MF. CPI-0610 inhibits BRD4-BD1 with an IC50 of 39 nM, and with an EC50 value of 0. Data from pacritinib in the first line setting, seen here, cannot be compared to any arm of the MANIFEST trial. Kremyanskaya, M, Mascarenhas J, Palandri F, et al. The abstracts include. 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. 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]. MANIFEST-2: CPI-0610 Shows Benefit in Myelofibrosis. 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. Conclusions: CPI-0610 is a well-tolerated, and an effective therapeutic agent for the treatment of MF. , Gutierrez M. 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. HemaSphere 2022;6:99-100). 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). “We are excited about the emerging profile of CPI-0610,” said Jigar Raythatha, Chief Executive Officer of Constellation Pharmaceuticals. 39), all of which have undergone phase I. Resources and Links. Here we report the results from the first-in human Phase 1 study of CPI-0610 in patients with relapsed or refractory lymphomas (NCT01949883). 1, 2 BET proteins regulate transcription of specific genes integrating an array of oncogenic signals, including NF-κB pathway activation. 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. Treatment with JAKi ruxolitinib (rux) or fedratinib in the frontline setting is associated with. Treatment with an investigational small molecule less than 2 weeks before the first dose of CPI-0610. 05, 2020 (GLOBE NEWSWIRE) -- Constellation Pharmaceuticals, Inc. The. Pelabresib is being investigated as a treatment for myelofibrosis and has not. The BET Inhibitor, CPI-0610, Promotes Myeloid Differentiation in Myelofibrosis Patient Bone Marrow and Peripheral CD34+ Hematopoietic Stem Cells. 2217/epi-2019. Abramson JS, Blum KA, Flinn IW, Gutierrez M, Goy A, Maris M, et al. The CPI-0610 starting daily dose was 125 mg, 2 weeks on, 2 weeks off. 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. doi: 10. Table 3 lists three such trials, early results from which have been presented. CPI-0610 is a selective and potent oral BETi, being evaluated in the first study of a BETi in MF. CPI-0610 treatment resulted in MM cytotoxicity in vitro by inducing G 1 cell cycle arrest and caspase-dependent apoptosis. Go to. To make progress in CPI studies on this disease, herein, we review and summarize the mechanisms of activation of the PD-L1. Findings from the phase 2 MANIFEST trial showed that at 12 weeks, the BET inhibitor CPI-0610 in combination with ruxolitinib demonstrated a 72. 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). 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. 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. CPI-0610 discontinuation due to TEAEs occurred in 12% of patients, and six Grade 5 TEAEs were recorded. 2018; 29 (Abstract 41O) Google Scholar; CC-90010 is a novel, oral, reversible, small-molecule inhibitor of BET proteins. MANIFEST Trial of CPI-0610. CPI-0610 is a potent, selective, and cell-active BET inhibitor. We are also exploring other novel cancer epigenetics targets in preclinical testing to fuel a sustainable pipeline of innovative small-molecule product candidates. com) was kept as a stock solution (10mg/ml) in DMSO (Sigma-Aldrich) and prepared and stored in. Downsized turbocharged gasoline direct injection (TGDI) engines with high specific power and torque can enable reduced fuel. 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. PMID: 31729905 DOI: 10. BET Inhibitor CPI-0610 is well tolerated and induces responses in diffuse large B-cell lymphoma and follicular lymphoma: preliminary analysis of an ongoing. The bromodomain and extraterminal (BET) proteins recognize acetylated lysine residues on. These findings indicate that BET inhibition not only results in a robust reduction of MYC transcription and activity but also suppresses the expression of. 07) Dates. Treatment with JAK inhibitor (JAKi) ruxolitinib (rux) or fedratinib. 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). CPI-0209, a second-generation enhancer of zeste homolog 2 (EZH2) inhibitor, in Phase 2 development for hematological malignancies and solid tumors by Constellation. 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. 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. Authors Jigar Raythatha 1 , Lauren Arnold 1 Affiliation 1 Constellation Pharmaceuticals. 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. placebo and ruxolitinib in JAK. Flinn 4 , A. CPI-0610 is being studied in multiple different ways. For a discussion of other risks and uncertainties, any of. 18 μM for MYC [1] . Placebo and Ruxolitinib in JAKi Treatment Naive MF Patients. 2 of 10 (20%) and 4 of 11 (36%) evaluable non-transfusion-dependent (non-TD) patients achieved SVR35 (the. 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 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. Our study found IKZF1 and IRF4 to be among the primary targets of CPI-0610, along with MYC . Contact Ronald Aldridge Pelabresib (CPI-0610) is an investigational, selective oral bromodomain and extraterminal domain inhibitor (BETi). 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 showed signals of clinical activity, both as a monotherapy and in combination with ruxolitinib, in refractory myelofibrosis (MF) patients. 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. Pelabresib is being investigated as a treatment for myelofibrosis and has not. A. Abstract. Abramson J. 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. We further show that CPI-0610 inhibits MM cell growth in the presence of cytokines and when co-cultured with bone marrow stromal cells. CPI-0610-mediated BET. Treatment with a therapeutic antibody less than 4 weeks before the first dose 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). In patients with MF, the bone marrow becomes overactive, leading to scarring and. 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. It has potential applications in the treatment of various forms of cancer . Ruxolitinib is the only FDA-approved treatment for myelofibrosis. The Phase 3 MANIFEST-2 study is evaluating pelabresib combined with ruxoliti. 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 the monotherapy group, TD patients had a spleen volume response (SVR) of 25%, while in the non-TD group, SVR was 0%. 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. Pelabresib (CPI-0610) is an investigational, oral, small-molecule bromodomain and extraterminal (BET) domain inhibitor. Products with only one mechanism of action are approved. Garner ,Optional tumor biopsy will be obtained prior to Day 1 of CPI-0610 administration. Pelabresib is a small molecule inhibitor of bromodomain and extra-terminal (BET) proteins. 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. Methods: Eligible patients were those whose lymphoma had progressed and for whom no effective therapies are available. (B) Comparison of average IC 50 s of BET inhibitors from patient-derived samples. Open in a separate window. their clin ical invest igation s are focused on cancer therapies. 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. Contact Ronald AldridgeJohn O. About CPI-0610. We are also exploring other novel cancer epigenetics targets in preclinical testing to fuel a sustainable pipeline of innovative small-molecule product candidates. Abramson 2 , M. The oral bromodomain and extra-terminal domain (BET) inhibitor, CPI-0610, demonstrated spleen volume reduction (SVR), symptom improvement, and reduction in bone marrow fibrosis as monotherapy or in combination with the JAK inhibitor ruxolitinib (Jakafi) in patients with myelofibrosis (MF), according to. 34 of 60 evaluable patients (57%) achieved a ≥50% reduction in Total. 1,2. In preclinical studies, pelabresib (CPI-0610), an investigational (BET) bromodomain inhibitor, downregulated NF-κB signaling and demonstrated antitumor. 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. 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. Pelabresib (CPI-0610) Combined with Ruxolitinib for JAK Inhibitor Treatment-Naïve Patients with Myelofibrosis: Durability of Response and Safety Beyond Week 24. (Nasdaq: CNST) today announced that two oral. ABBV-075 and JQ1 were tested. 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). Pelabresib (CPI-0610) Monotherapy in Patients With High-Risk Essential Thrombocythemia Refractory or Intolerant to Hydroxyurea: Preliminary Results From MANIFEST Study pdf | 552. , Dec. 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. Abramson J. The combination was well-tolerated. Study Description. 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. and Gehling, Victor S. CPI-0610 displays potent cytotoxicity against MM cell lines and patient-derived MM cells through G1 cell cycle arrest and caspase. Taken together, these paired BM biopsy and in vitro myeloid maturation results demonstrated an effect of CPI-0610 in promoting erythroid and MK differentiation. We do not sell or distribute actual drugs. 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. 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. 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. JAKi are currently approved for treatment of MF, including ruxolitinib. In lyophilized form, the chemical is stable for 36 months. (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. Phone Number: 1-877-MDA-6789. The two patients treated with a combination of CPI-0610 and ruxolitinib (i. BET proteins regulate key oncogenic pathways, including NFκB and TGFβ signaling which are important drivers of pro-inflammatory cytokine (Ck) expression and. Recent. MANIFEST (ClinicalTrails. As the inhibition of individual BET bromodomains will lead to different. CPI-0610 is a potent, selective, and cell-active BET inhibitor. 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. Upon administration, pelabresib binds to the acetylated lysine recognition motifs on the bromodomain of BET. Targets. 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. 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. 8. About CPI-0610. We would like to show you a description here but the site won’t allow us. Pelabresib is a small molecule inhibitor of bromodomain and extra-terminal (BET) proteins. 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). 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.