About CPI-0610. 34 of 60 evaluable patients (57%) achieved a ≥50% reduction in Total. We further show that CPI-0610 inhibits MM cell growth in the presence of cytokines and when co-cultured with bone marrow stromal cells. 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. Abstract. CPI-0610 (pelabresib) is an oral pan BET inhibitor in clinical development []. CPI-0610 is a small molecule inhibitor of bromodomain and extra-terminal (BET) proteins. 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-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. HemaSphere 2022;6:99-100). 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. Here we present results from MANIFEST. The. Das (Selleck. , Dec. CPI-0610 data was 29% and 38%, which also compares favorably with the above data. 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. Pelabresib (CPI-0610), a potent and selective small molecule BET proteins inhibitor, has a MTD of 225 mg once daily for 14 days with a 7-day break, clear pharmacokinetic/p. We are also exploring other novel cancer epigenetics targets in preclinical testing to fuel a sustainable pipeline of innovative small-molecule product candidates. In preclinical studies, pelabresib (CPI-0610), an investigational (BET) bromodomain inhibitor, downregulated NF-κB signaling and demonstrated antitumor. 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. CPI-0610 is given orally once daily (QD) on days 1-14 of a 21-day cycle. Treatment with an investigational small molecule less than 2 weeks before the first dose of CPI-0610. 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. 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. 8% median improvement in TSS for transfusion dependent (TD. CPI-0610 (0-1500 nM; 72 hours; Multiple myeloma cell lines and primary MM cells) treatment reduces the viability of MM cells in a dose-dependent manner [2]. 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). The CPI-0610 starting daily dose was 125 mg, 2 weeks on, 2 weeks off. Pelabresib (CPI-0610) is an oral small-molecule investigational inhibitor of BET protein bromodomains currently being developed for the treatment of patients with MF. 1491. 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. 1491. In preclinical studies, pelabresib downregulated NF-κB signaling and demonstrated antitumor activity in vitro. 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. CPI-0610 will be administered 200mg orally once a daily for 14 consecutive days followed by a 7-day break. 2012-07-23. Pelabresib (CPI-0610; PELA) is an oral, small-molecule, investigational BET inhibitor that downregulates NF-κB signaling and other relevant genes involved in MF. Constellation Pharmaceuticals Provides Updates of MANIFEST Study for CPI-0610 and EZH2 Franchise. 2f). In ruxolitinib treatment-naïve and previously treated patients with myelofibrosis, pelabresib combined with ruxolitinib resulted in splenic and symptom responses and BM fibrosis improvement and was generally well tolerated. CPI-0610 is a potent, selective, and cell-active BET inhibitor. While CPI-0610, Nil, and the combination significantly reduced spleen size , only the combination significantly reduced donor leukaemic CD45. A 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. About CPI-0610. 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 . Phone Number: 1-877-MDA-6789. There is no guarantee that. 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. CPI-203 and CPI-0610 were obtained from Constellation Pharmaceuticals and kept as a solid powder at room temperature (RT). 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. 2217/epi-2019. 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. Abstract. 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. ” The data were gathered from 44 patients. Multiple studies are evaluating pelabresib (CPI-0610) for the treatment of patients with myeloproliferative neoplasms (MPNs). Constellation developed pelabresib (CPI-0610) which inhibits members of the BET family of chromosome-binding. ” Data HighlightsCPI-0610, CPI-1205 and CPI-0209 are investigational therapies and have not been approved by the FDA (or any other regulatory authority). Upon administration, pelabresib binds to the acetylated lysine recognition motifs on the bromodomain of BET. Additionally, we have begun planning for a randomized. 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. Adis is an information provider. CPI-0209, a second-generation enhancer of zeste homolog 2 (EZH2) inhibitor, in Phase 2 development for hematological malignancies and solid tumors by Constellation. CPI-0610 has been evaluated in 3 Phase 1 studies in > 140 patients with lymphoma, multiple myeloma and acute leukemias/myelodysplastic syndrome/MF. Products with only one mechanism of action are approved. 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 being studied in multiple different ways. CPI-0610 is a selective and potent oral BETi, being evaluated in the first study of a BETi in MF. 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. 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. 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; The effect of CPI-0610 on the viability of MM cell lines and primary MM cells was determined by measuring MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; Chemicon International. The two patients. Most of. Mascarenhas, MD. CPI-0610-mediated BET inhibition overcomes the protective effects conferred by cytokines and bone marrow stromal cells. 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. Pelabresib (CPI-0610) is an investigational, selective oral bromodomain and extraterminal domain inhibitor (BETi). Background: Pelabresib (CPI-0610; PELA) is a bromodomain and extraterminal domain (BET) inhibitor in development for the treatment of myelofibrosis. 6%) evaluable patients achieved ≥50% TSS reduction at 24 weeks) 92 and a randomized phase 3 trial of. 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. 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. 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. 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. RVX2135, FT-1101, BAY1238097. and Hewitt, Michael C. 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. Store lyophilized at -20ºC, keep desiccated. 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 7. Methods: Eligible patients were those whose lymphoma had progressed and for whom no effective therapies are available. 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. 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). Between September 2013 and March 2015 44 patients had been enrolled and treated at doses of 6, 12, 24, 48, 80, 120, 170. Masarova says that CPI-0610, a bromodomain, and extra-terminal (BET) inhibitor holds promise in patients with myelofibrosis since it could alter the transcription factors and potentially overcome the patient’s resistance to ruxolitinib (Jakafi). Constellation’s epigenetics platform includes a deep understanding of the biological contexts in which BET proteins operate. Brief Summary: A Phase 3, randomized, blinded study comparing pelabresib (CPI-0610) and ruxolitinib with placebo and ruxolitinib in. Taken together, these paired BM biopsy and in vitro myeloid maturation results demonstrated an effect. However, protein levels of BCL2, NF- κ B and MCL1 remain unchanged. A Phase 1 Study Evaluating CPI-0610 in Patients With Previously Treated Multiple Myeloma - Full Text View. Background: Pelabresib (CPI-0610) is a potent, first-in-class, selective, oral small-molecule inhibitor of bromodomain and extraterminal domain (BET) proteins which is able to modify the expression of genes involved in nuclear factor kappa B (NFκB) signaling in patients with myelofibrosis (MF). CPI-0610 is a first-in-class inhibitor of bromodomain and extraterminal domain (BET) proteins, which regulate gene transcription in numerous pro-fibrotic pathways. 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. 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. As the inhibition of individual BET bromodomains will lead to different. 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. 37 of 51 evaluable patients (73%) achieved a 35% reduction in spleen volume (SVR35) at 12 weeks and had a median spleen. Pelabresib is a small molecule inhibitor of bromodomain and extra-terminal (BET) proteins. In preclinical studies, pelabresib (CPI-0610), an investigational (BET) bromodomain inhibitor, downregulated NF-κB signaling and demonstrated antitumor. placebo and ruxolitinib in JAK. placebo and ruxolitinib in JAK. Royalty Pharma will purchase the rights to receive 3% of future net sales of CPI-0209. Phase 2 Part: Open-label study of CPI-0610 with and without Ruxolitinib in patients with Myelofibrosis. Clear anti-tumor activity was observed in. CPI-0610 induces apoptosis and G 1 cell cycle arrest associated with MYC downregulation. For CPI-0610 added on to ongoing treatment with ruxolitinib, there was a 24. CPI-0610 is a small molecule inhibitor of BET proteins with a novel mechanism of action and potential for disease-modifying effects in MF. CPI-0610 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). We would like to show you a description here but the site won’t allow us. , Blum K. 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. 2f), supporting the potential for BETi to be used for ovarian cancer. The 14 days of CPI-0610 dosing and the 7-day break together constitute 1 cycle of treatment. CPI-0610 showed signals of clinical activity, both as a monotherapy and in combination with ruxolitinib, in refractory myelofibrosis (MF) patients. Patients in the two second-line arms are being stratified based on transfusion dependent status. METHODS. Our study found IKZF1 and IRF4 to be among the primary targets of CPI-0610, along with MYC . 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. 1. – Amends second-line trial design to stratify for transfusion dependence based on positive preliminary data –– Expands study to include an additio. The Phase 1 portion of the CPI-0209 Phase1/2 clinical trial is an open label, dose escalation study in patients with advanced tumors. CPI-0610 is a potent, selective, and cell-active BET inhibitor. Arms 1 and 2 are studying CPI-0610 as a monotherapy or in combination with ruxolitinib in. 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). Mascarenhas J, Harrison C, Luptakova K, et al. 2 of 10 (20%) and 4 of 11 (36%) evaluable non-transfusion-dependent (non-TD) patients achieved SVR35 (the. Phase 2 Part: Open-label study of CPI-0610 with and without Ruxolitinib in patients with Myelofibrosis. 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. 05. Ruxolitinib is the only FDA-approved treatment for myelofibrosis. Confirmation of the preliminary results in a. CPI-0610 inhibits BRD4-BD1 with an IC50 of 39 nM, and with an EC50 value of 0. Like ruxolitinib failure, there is also no uniformly accepted. 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. , Maris M. Pelabresib is a small molecule inhibitor of bromodomain and extra-terminal (BET) proteins. and Vaswani, Rishi G. doi: 10. Mertz 6 , R. CPI-0610 is a small molecule inhibitor of bromodomain and extra-terminal (BET) proteins. The results provide evidence of synergy between CPI-0610 and rux in these myelofibrosis patients, and the spleen and symptom benefits are. 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 a unique, first-in-class, oral, small-molecule inhibitor of bromodomain and extraterminal domain (BET) proteins, designed to promote disease-modifying activity. MANIFEST-2, A GLOBAL, PHASE 3, RANDOMIZED, DOUBLE-BLIND, ACTIVE-CONTROL STUDY OF CPI 0610 AND RUXOLITINIB VS. , et al. The bromodomain and extraterminal (BET) proteins recognize acetylated lysine residues on. 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. Background: Pelabresib (CPI-0610) is a potent, first-in-class, selective, oral small-molecule inhibitor of bromodomain and extraterminal domain (BET). Taken together, these paired BM biopsy and in vitro myeloid maturation results demonstrated an effect of CPI-0610 in promoting erythroid and MK differentiation. 365. BET proteins inhibition can potentially modify the pathogenic pathways which contribute to many diseases including malignancies. 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 a potent, first-in-class, selective, oral small-molecule BET inhibitor, which is able to modify the expression of genes involved in nuclear factor kappa B (NFκB) signaling in pts with MF. The 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). Pelabresib is being investigated as a treatment for myelofibrosis and has not. 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. 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). Article. 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. Interim data from this study have shown promising results,. and Cote, Alexandre and Leblanc, Yves and Nasveschuk, Christopher G. 18 μM for MYC. Open in a separate window. However, toxicity studies. In the monotherapy group, TD patients had a spleen volume response (SVR) of 25%, while in the non-TD group, SVR was 0%. Purpose of Review Myelofibrosis (MF) is a myeloproliferative neoplasm characterized by bone marrow fibrosis, megakaryocyte. Context: Pelabresib (CPI-0610) combined with ruxolitinib showed encouraging spleen and symptom responses in Janus kinase inhibitor (JAKi)-naïve patients with intermediate or high-risk. However, protein levels of BCL2, NF- κ B and MCL1 remain unchanged in MM cells upon BET inhibition. CPI-0610 is a potent, selective and unique BET inhibitor under investigation in MF patients as monotherapy or in combination with ruxolitinib in the MANIFEST trial (NCT02158858). 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. 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. 2022, p. Menu icon A vertical stack of three evenly. Conclusions: CPI-0610 is a well-tolerated, and an effective therapeutic agent for the treatment of MF. BET protein inhibition is. When. Sims 6 , F. Pelabresib is a small molecule inhibitor of bromodomain and extra-terminal (BET) proteins. To make progress in CPI studies on this disease, herein, we review and summarize the mechanisms of activation of the PD-L1. 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. These findings indicate that BET inhibition not only results in a robust reduction of MYC transcription and activity but also suppresses the expression of. Abstract. 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. Pelabresib is a small molecule inhibitor of bromodomain and extra-terminal (BET) proteins. MANIFEST (ClinicalTrails. For a discussion of other risks and uncertainties, any of. A. Pelabresib (CPI-0610) is an oral, small-molecule, investigational BET inhibitor that downregulates NF-κB gene expression and other relevant genes involved in MF disease pathways. 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. For a discussion of other risks and uncertainties, any of. CPI 0610 ; View More. CPI-0610 is a selective and potent oral BETi, being evaluated in the first study of a BETi in MF. 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. For a discussion of other risks and uncertainties, any of. CPI-0610-mediated BET. MANIFEST-2, a global, phase 3, randomized, double-blind, active-control study of CPI-0610 and ruxolitinib vs. Go to. 1,2 “Preliminary data demonstrate the. CPI-0610 significantly delayed tumor growth and increased theCPI-0610 is an effective BET inhibitor in multiple myeloma (MM) and is currently being tested in phase I clinical trial [84]. Contact Ronald Aldridge Pelabresib (CPI-0610) is an investigational, selective oral bromodomain and extraterminal domain inhibitor (BETi). Patients tolerated CPI-0610 well; thrombocytopenia was the only overlapping toxicity with ruxolitinib but was non-cumulative and reversible. Treatment with a therapeutic antibody less than 4 weeks before the first dose of CPI-0610. , CPI-0610 added onto existing treatment with ruxolitinib) have been treated for over 16 months. Pelabresib (CPI-0610; PELA) is an oral, small-molecule, investigational BET inhibitor that downregulates NF-κB signaling and other relevant genes involved in MF. A Phase 3, Randomized, Double-blind, Active-Control Study of CPI-0610 and Ruxolitinib vs. , Gutierrez M. 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. The Grade 3 and 4 TEAEs were mostly hematological with anemia being the most commonly recorded Grade 3 TEAE. Pelabresib is being investigated as a treatment for myelofibrosis and has not yet been. 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. 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. An early signal of clinical activity was seen in the phase 1 portion of the MANIFEST study (NCT02158858) that. Contact Ronald AldridgeJohn O. CPI-0610 discontinuation due to TEAEs occurred in 12% of patients, and six Grade 5 TEAEs were recorded. 40) were amide or urea analogs such as RO6870810 (TEN-010), birabresib (OTX015, MK-8628), CPI-0610 137, and BAY-1238097 (Fig. 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. Delaney has a track. V126. There is a high unmet need for a treatment that can potentially delay or reverse BM fibrosis in patients (pts) with 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. Maris 3 , I. CPI-0610, CPI-1205 and CPI-0209 are investigational therapies and have not been approved by the FDA (or any other regulatory authority). Authors Jigar Raythatha 1 , Lauren Arnold 1 Affiliation 1 Constellation Pharmaceuticals. Pelabresib is being investigated as a treatment for myelofibrosis and has not. 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. The future of epigenetic therapy: CPI-0610 for the treatment of myeloidfibrosis Epigenomics. Full Title of Study: “A Phase 1/2 Study of CPI-0610, a Small Molecule Inhibitor of BET Proteins: Phase 1 (Dose Escalation of CPI-0610 in Patients. 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. . 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). 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. 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). Pelabresib - MorphoSys. Furthermore, the use of CPI-0610 in combination with suberoylanilide. CPI-0610 is still valuable to pursue with a larger group of patients who are more diverse in baseline characteristics to get a better idea of the response to this agent. Products with only one mechanism of action are approved. Kremyanskaya M, Mascarenhas J, Palandri F, et al. Findings from the phase 2 MANIFEST trial showed that at 12 weeks, the BET inhibitor CPI-0610 in combination with ruxolitinib demonstrated a 72. 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. 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. and ABBV-07 5 (6). 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). Like ruxolitinib failure, there is also no uniformly accepted. Arm 1 (2L) – CPI-0610 monotherapy in JAK-inhibitor-experienced or -ineligible patients . at UCLA. / Mascarenhas, John; Kremyanskaya, Marina; Patriarca, Andrea et al. 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. Arm 3 is evaluating CPI-0610 in combination with ruxolitinib in JAK-inhibitor-naïve MF patients. 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. An additional cohort is recruiting JAKi naïve patients to receive CPI-0610/ruxolitinib combination, and showed encouraging preliminary activity [33]. MANIFEST-2, a global, phase 3, randomized, double-blind, active-control study of CPI-0610 and ruxolitinib vs. Cross-trial comparisons with JAKi monotherapy have limitations due to. Abramson J. 7%) evaluable patients achieved ≥35% SVR and 11 of 14 (78. 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). 1 (PubChem release 2021. - Mechanism of. In lyophilized form, the chemical is stable for 36 months. 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. However, protein levels of BCL2, NF- κ B and MCL1 remain unchanged in MM cells upon BET inhibition. , Aug. 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. 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). com) was kept as a stock solution (10mg/ml) in DMSO (Sigma-Aldrich) and prepared and stored in. In solution, store at -20ºC and use within 3 months to prevent loss of potency. Aliquot to avoid multiple freeze/thaw cycles. 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. 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. Pelabresib is being investigated as a treatment for myelofibrosis and has not yet. 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. 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. , Flinn I. An in vivo experiment exhibited that CPI-0610 decreased the primary tumour growth of the DLBCL xenograft model. Pelabresib has the potential to be a first. ” Data Highlights . CPI0610, CPI-0610. JAKi are currently approved for treatment of MF, including ruxolitinib. “We are excited about the emerging profile of CPI-0610,” said Jigar Raythatha, Chief Executive Officer of Constellation Pharmaceuticals. Molecular studies to further our understanding of the underlying mechanisms of CPI-0610 treatment are ongoing. 35. 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). 18 μM for MYC [1] . 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. , Dec. Jennifer A Mertz, PhD 1 *, Patricia J Keller,. CPI-0610 is a small molecule inhibitor of bromodomain and extra-terminal (BET) proteins. 2018; 29 (Abstract 41O) Google Scholar; CC-90010 is a novel, oral, reversible, small-molecule inhibitor of BET proteins. 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 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. 35, 40, 41 In addition, CPI-0610, PLX51107, and INCB0543294 belong to isoxazole-based BRD4 inhibitors. 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. gov NCT No: NCT02158858 Opens a new window. 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. As in Arm 2, the TEAEs recorded for Arm 3 were generally mild and showed the combination was well tolerated (Table 3). 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. Clear anti-tumor activity was observed in. 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. CPI-0610 is a potent, selective, and cell-active BET inhibitor. CPI-0610 is a drug which acts as a BET inhibitor, mainly acting at the BRD2 and BRD4 subtypes. For a discussion of other risks and uncertainties, any of. 06, 2020 (GLOBE NEWSWIRE) -- Constellation Pharmaceuticals, Inc. Pelabresib (CPI-0610) is a synthetic, small-molecule inhibitor of the tandem amino-terminal bromodomains (BD1 and BD2) of BET proteins currently in clinical. Pelabresib is a small molecule inhibitor of bromodomain and extra-terminal (BET) proteins. We would like to show you a description here but the site won’t allow us. , Maris M. This study is exploring either CPI-0610 alone or in combination with ruxolitinib (Janus kinase 1/2 inhibitor). I-BET151 showed beneficial effects in the treatment of GBM and leukemia. Spleen response rates in first-line patients at 12 weeks and 24 weeks in line with previously. Treatment with a therapeutic antibody less than 4 weeks before the first. TEN-010 (5), 36. Garner ,Optional tumor biopsy will be obtained prior to Day 1 of CPI-0610 administration. 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. 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 symptoms. A total of 41 patients were enrolled, of which 40 patients. 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. Pelabresib is currently being investigated as a treatment for myelofibrosis and. S. BET inhibitor CPI-0610 is well tolerated and induces responses in diffuse large B-cell lymphoma and follicular. 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. 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. 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). 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. BET proteins regulate key oncogenic pathways, including NFκB and TGFβ signaling which are important drivers of pro-inflammatory cytokine (Ck) expression and. 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. [1] [2] [3] [4] Abstract. CPI-0610 induces apoptosis and G 1 cell cycle arrest associated with MYC downregulation. Royalty Pharma will purchase the rights to receive 3% of future net sales of CPI-0209. 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 has been evaluated in 3 Phase 1 studies in > 140 patients with lymphoma, multiple myeloma and acute leukemias/myelodysplastic syndrome/MF. , Blum K. In Arm 2, which examined CPI-0610 in combination with ruxolitinib in ruxolitinib-experienced patients, 29% of evaluable non-TD subjects achieved SVR35 at 24 weeks. 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. Although CPI-0610 was tested at doses as high as. Pelabresib is a small molecule inhibitor of bromodomain and extra-terminal (BET) proteins. Final gross price and currency may vary according to local VAT and billing address. Modify: 2023-11-04. 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). gov identifier: NCT02158858 ), a global, open. ” Data Highlights . So, combinations with Navitoclax which is Bcl-xL cell inhibitor, CPI-0610, which is BET inhibitor, Luspatercept which is anemia drug. A phase I study of CPI-0610, a bromodomain and extra terminal protein (BET) inhibitor in patients with relapsed or refractory lymphoma. The body weights of the. With more data on the agent expected to be released from trials in this space toward the end of the year, Joseph M. 3), and the WEE1 inhibitor adavosertib a moderate response (SPM score 84). 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. 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. Kremyanskaya, M, Mascarenhas J, Palandri F, et al. About CPI-0610.