Spleen response rates in first-line patients at 12 weeks and 24 weeks in line with previously reported data and differentiated from standard of ca. However, protein levels of BCL2, NF- κ B and MCL1 remain unchanged in MM cells upon BET inhibition. 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. 17, 2019. 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). 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. 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. METHODS MANIFEST (ClinicalTrails. CPI-0610 will be administered 200mg orally once a daily for 14 consecutive days followed by a 7-day break. Treatment with a therapeutic antibody less than 4 weeks before the first dose of CPI-0610. Confirmation of the preliminary results in a. , et al. CPI-0610 data was 29% and 38%, which also compares favorably with the above data. Upon administration, pelabresib binds to the acetylated lysine recognition motifs on the bromodomain of BET. BET proteins inhibition can potentially modify the pathogenic pathways which contribute to many diseases including malignancies. We would like to show you a description here but the site won’t allow us. Pelabresib (CPI-0610) Selective benzoisoxaoloazepine BET bromodomain inhibitor for BRD4-BD1 : NSD3 NSD3: AZD 5153 6-hydroxy 2-naphthoic acid ZEN-3694: Orally available BET-BRD4 bromodomain inhibitor Orally available pan-BET bromodomain inhibitor Context: Pelabresib (CPI-0610), a first-in-class, oral, small-molecule inhibitor of BET proteins (BETi), has potential to promote disease-modifying activity through altered gene regulation of key oncogenic, fibrotic, and inflammatory factors in MF. 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-0610 has been evaluated in 3 Phase 1 studies in > 140 patients with lymphoma, multiple myeloma and acute leukemias/myelodysplastic syndrome/MF. Sims 6 , F. 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. 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 (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]. Interim data from this study have shown promising results,. 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 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). 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. Phone Number: 1-877-MDA-6789. 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 can become a part of the standard of care and even expand the overall addressable market in myelofibrosis indication. MANIFEST is an open-label Phase 2 clinical trial of CPI-0610 in patients with myelofibrosis (MF), a rare cancer of the bone marrow that disrupts the body’s normal production of blood cells. Your purchase entitles you to full access to the information. Single agent CPI-0610 treatment also significantly decreased tumour weight by 42% when compared to vehicle (Fig. Initial studies indicated that CPI-0610 offers some improvement in terms of selectivity for (i) BRD4 (2-fold over other BET family members), and (ii) between BRD4. CPI-0610 induces apoptosis and G 1 cell cycle arrest associated with MYC downregulation. 2022, p. Garner ,Optional tumor biopsy will be obtained prior to Day 1 of CPI-0610 administration. Maximal effects were observed 2 hours after treatment. 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. clinicaltrials. Pelabresib (CPI-0610) is an investigational, selective oral bromodomain and extraterminal domain inhibitor (BETi). CPI-0610 is a small molecule inhibitor of bromodomain and extra-terminal (BET) proteins. (C)-JQ1, I-BET762, OTX015, I-BET151, CPI203, PFI-1, MS436, CPI-0610 chemical structures are shown. 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. There is a high unmet need for a treatment that can potentially delay or reverse BM fibrosis in patients (pts) with MF. doi: 10. and Cote, Alexandre and Leblanc, Yves and Nasveschuk, Christopher G. Here we present results from MANIFEST. CPI-0610 has been well tolerated, with the principal toxicity being dose-dependent thrombocytopenia that is reversible and non-cumulative. 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. 1491. 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. 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. Modify: 2023-11-04. 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. 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 minimum 2-week period between the last treatment with a therapeutic antibody and the. 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. @article{osti_1855473, title = {Identification of a Benzoisoxazoloazepine Inhibitor (CPI-0610) of the Bromodomain and Extra-Terminal}, author = {Albrecht, Brian K. Pelabresib (CPI-0610) Combined with Ruxolitinib for JAK Inhibitor Treatment-Naïve Patients with Myelofibrosis: Durability of Response and Safety Beyond Week 24. 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. Pelabresib is being investigated as a treatment for myelofibrosis and has not. The utilization of pelabresib (CPI-0610) monotherapy demonstrated signals of clinical activity in the form of spleen volume reduction, symptom reduction, and hemoglobin benefit in patients with. Nov 2022;Constellation is driving development of the BET inhibitor CPI-0610 for the treatment of myelofibrosis as well as the EZH2 inhibitors CPI-1205 and CPI-0209 for the treatment of metastatic. So, combinations with Navitoclax which is Bcl-xL cell inhibitor, CPI-0610, which is BET inhibitor, Luspatercept which is anemia drug. 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. 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 (CPI-0610; PELA) is an oral, small-molecule, investigational BET inhibitor that downregulates NF-κB signaling and other relevant genes involved in MF. ” Data HighlightsCPI-0610, CPI-1205 and CPI-0209 are investigational therapies and have not been approved by the FDA (or any other regulatory authority). Arm 1 (2L) – CPI-0610 monotherapy in JAK-inhibitor-experienced or -ineligible patients . For a discussion of other risks and uncertainties, any of. 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. Modify: 2023-11-04. For a discussion of other risks and uncertainties, any of. W. The BET Inhibitor, CPI-0610, Promotes Myeloid Differentiation in Myelofibrosis Patient Bone Marrow and Peripheral CD34+ Hematopoietic Stem Cells. Drug selectivity of BRD4 small-molecule inhibitors. 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. Aliquot to avoid multiple freeze/thaw cycles. 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. 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. The Grade 3 and 4 TEAEs were mostly hematological with anemia being the most commonly recorded Grade 3 TEAE. " Constellation. Buy Profile. HemaSphere 2022;6:99-100). CPI-0610 (pelabresib) is an oral pan BET inhibitor in clinical development []. A. CPI-0610 demonstrated activity, both as a monotherapy and as add on to ruxolitinib, in second-line or later settings; Translational data supports potential disease-modifying effects of CPI-0610; 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. FRANCESCA PALANDRI via Scopus - Elsevier. 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. MANIFEST (ClinicalTrails. 1182/blood. 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). 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. 2217/epi-2019-0274. 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. MANIFEST Trial of 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. 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. [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/. BET protein inhibition is. 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. The rate of 63% was still a good response for this therapy since, in similar patient populations, the response rate is usually about 50% to 60%. Pelabresib is being investigated as a treatment for myelofibrosis and has not yet. BET proteins inhibition can potentially modify the pathogenic pathways which contribute to many diseases including malignancies. In preclinical studies, pelabresib (CPI-0610), an investigational (BET) bromodomain inhibitor, downregulated NF-κB signaling and demonstrated antitumor. , Blum K. For research use only. 31 Pharmacokinetic parameters were dose-proportional for the evaluated doses. Pelabresib (CPI-0610) Catalog No. This study is sponsored by Constellation Pharmaceuticals a MorphoSys Company. The median duration of treatment was 11. (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. It has potential applications in the treatment of various forms of cancer . Ann Oncol. Context CPI-0610 is a unique, first-in-class, oral, small-molecule inhibitor of BET proteins, designed to promote disease-modifying activity through selective gene regulation of key oncogenic. CPI-0610, CPI-1205 and CPI-0209 are investigational therapies and have not been approved by the FDA (or any other regulatory authority). MANIFEST TrialCPI-0610 (4), 35. Methods: MANIFEST (ClinicalTrails. Kremyanskaya M, Mascarenhas J, Palandri F, et al. , Goy A. With more data on the agent expected to be released from trials in this space toward the end of the year, Joseph M. Of the 54 patients treated with CPI-0610 and ruxolitinib, 41 were still receiving the combination at that time. We would like to show you a description here but the site won’t allow us. Pelabresib (CPI-0610) Combined with Ruxolitinib for JAK Inhibitor Treatment-Naïve Patients with Myelofibrosis: Durability of Response and Safety Beyond Week 24. Description. . Doses of 170 and 230 mg QD are associated with a 50% average. 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. While CPI-0610, Nil, and the combination significantly reduced spleen size , only the combination significantly reduced donor leukaemic CD45. The maximum decline in the platelet count occurs around day 14, with recovery over the following 1-2 week break from treatment. MANIFEST is an open-label Phase 2 clinical trial of CPI-0610 in patients with myelofibrosis (MF), a rare cancer of the bone marrow that disrupts the body’s normal production of blood cells. 6%) evaluable patients achieved ≥50% TSS reduction at 24 weeks) 92 and a randomized phase 3 trial of. CPI-0610 is a small molecule inhibitor of bromodomain and extra-terminal (BET) proteins. 18 μM for MYC [1] . Spleen response rates in first-line patients at 12 weeks and 24 weeks in line with previously. To make progress in CPI studies on this disease, herein, we review and summarize the mechanisms of activation of the PD-L1. CPI-0610 has been evaluated in 3 Phase 1 studies in > 140 patients with lymphoma, multiple myeloma and acute leukemias/myelodysplastic syndrome/MF. CPI-0610 is thought to reduce and suppress the differentiation of myeloid cells into megakaryocytes in the bone marrow, potentially leading to disease modification. 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. Flinn 4 , A. A phase I study of CPI-0610, a bromodomain and extra terminal protein (BET) inhibitor in patients with relapsed or refractory lymphoma. It has potential applications in the treatment of various forms of cancer . CPI-0610 is a small molecule inhibitor of bromodomain and extra-terminal (BET) proteins. Placebo and Ruxolitinib in JAKi Treatment Naive MF Patients Studio di fase 3, randomizzato, in doppio cieco, con controllo attivo di CPI-0610 e Ruxolitinib rispetto a placebo e Ruxolitinib nei pazienti con MF naïve al trattamento con JAKiPhase 2 Part: Open-label study of CPI-0610 with and without Ruxolitinib in patients with Myelofibrosis. Molecular studies to further our understanding of the underlying mechanisms of CPI-0610 treatment are ongoing. Spleen response rates in first-line patients at 12 weeks and 24 weeks in line with previously. V126. , Dec. 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. 2015; 126:1491. , May 14, 2020 (GLOBE NEWSWIRE) -- Constellation Pharmaceuticals, Inc. 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. CPI-0610 is a selective and potent oral BETi, being evaluated in the first study of a BETi in MF. 9 Inhibiting BET may modify critical MF pathways, including. 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]. Among the most common treatment-emergent adverse events (TEAEs) for CPI-0610 monotherapy in 46 safety-evaluable patients in Arm 1,. Overall, the use of CPI-0610 induced a significant reduction in spleen volume of at least 35% and total symptom score reduction of at least 50%. 6 of 21 (29%) evaluable non-TD patients achieved SVR35 at 24 weeks, the primary endpoint for cohort 2B. 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. Some activity was reported with CPI-0610 as a single agent in the second-line setting. Resources and Links. Jennifer A Mertz, PhD 1 *, Patricia J Keller,. S. Alternative Names: CPI-0610. 8. 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. In one of. CPI-0610, CPI-1205 and CPI-0209 are investigational therapies and have not been approved by the FDA (or any other regulatory authority). 1 (PubChem release 2021. Substitution on the amide nitrogen was not required for potency, as illustrated by 10 (CPI-0610), which also demonstrated greater in vitro metabolic stability than the secondary amides. cpi 0610 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). gov identifier: NCT02158858 ), a global, open. 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. Pelabresib is being investigated as a treatment for myelofibrosis and has not. 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. Mascarenhas J, Kremyanskaya M, Patriarca A, Harrison C, Bose P, Rampal RK, et al. 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. 9% median reduction in spleen volume at 24 weeks and a 58. 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. Here we describe the rationale and design for the phase III MANIFEST-2 (ClinicalTrials. 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 myelofibrosis in Arm 3 of the Phase 2 MANIFEST study (NCT02158858). 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. 3), and the WEE1 inhibitor adavosertib a moderate response (SPM score 84). placebo and ruxolitinib in JAK. CPI-0610 displays potent cytotoxicity against MM cell lines and patient-derived MM cells through G 1 cell cycle arrest and caspase-dependent apoptosis. 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. Here we report the results from the first-in human Phase 1 study of CPI-0610 in patients with relapsed or refractory lymphomas (NCT01949883). MANIFEST-2, a global, phase 3, randomized, double-blind, active-control study of CPI-0610 and ruxolitinib vs. Storage. at UCLA. I-BET151 showed beneficial effects in the treatment of GBM and leukemia. their clin ical invest igation s are focused on cancer therapies. 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. 8% median improvement in TSS for transfusion dependent (TD. CPI-0610 will be administered 200mg orally once a daily for 14 consecutive days followed by a 7-day break. 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. 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. Download scientific diagram | BET bromodomain inhibitor molecules. , Goy A. In the phase II MANIFEST study, Pelabresib is being evaluated as monotherapy and in combination with the JAK inhibitor ruxolitinib. CPI-0610-mediated BET. Data from pacritinib in the first line setting, seen here, cannot be compared to any arm of the MANIFEST trial. and ABBV-07 5 (6). 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. erated CPI-0610 well; thrombocytopenia was the only overlapping toxicity with ruxolitinib but was non-cumulative and reversible. Pelabresib (CPI-0610) is an investigational, oral, small-molecule bromodomain and extraterminal (BET) domain inhibitor. 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. Additionally, we have begun planning for a randomized. Guidelines differ from study to study, and identify who can or cannot participate. MANIFEST-2: CPI-0610 Shows Benefit in Myelofibrosis. 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. - Mechanism of. However, protein levels of BCL2, NF- κ B and MCL1 remain unchanged. 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) 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). CPI-0610 has been evaluated in 3 Phase 1 studies in > 140 patients with lymphoma, multiple myeloma and acute leukemias/myelodysplastic syndrome/MF. . Study Description. 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, CPI-1205 and CPI-0209 are investigational therapies and have not been approved by the FDA (or any other regulatory authority). Here we present results from MANIFEST. In patients with MF, the bone marrow becomes overactive, leading to scarring and. The two patients treated with a combination of CPI-0610 and ruxolitinib (i. Mertz 6 , R. Pelabresib (CPI-0610) is a potent and selective benzoisoxazoloazepine BET bromodomain inhibitor with an IC50 of 39 nM for BRD4-BD1 in TR-FRET assay and currently undergoing human clinical trials for hematological malignancies. CPI-0610 is a 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). 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). . 2020-04-14. We are enrolling MF patients who are Janus-kinase-1/2, or JAK1/JAK2-, inhibitor-naïve, a first. 18 μM for MYC. The future of epigenetic therapy: CPI-0610 for the treatment of myeloidfibrosis Epigenomics. An additional cohort is recruiting JAKi naïve patients to receive CPI-0610/ruxolitinib combination, and showed encouraging preliminary activity [Citation 33]. , Aug. 63 KB ; Poster Updated Durability of Response and Safety in MANIFEST Arm 3: Pelabresib (CPI-0610) Combined With Ruxolitinib for JAK Inhibitor Treatment-Naïve. 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. , Blum K. This CPI-0610-induced dose-dependent maturation of aberrant immature MK cells may play a role in reducing MF disease manifestations. 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). 2018; 29 (Abstract 41O) Google Scholar; CC-90010 is a novel, oral, reversible, small-molecule inhibitor of BET proteins. CPI-0610 has been evaluated in 3 Phase 1 studies in > 140 patients with lymphoma, multiple myeloma and acute leukemias/myelodysplastic syndrome/MF. METHODS MANIFEST (ClinicalTrails. 2018; 29:Pelabresib (CPI-0610) is an investigational, orally administered, small molecule BET inhibitor that reduces expression of BET target genes and modulates NF-κB signaling. The dose will not be adjusted for body weight or. Pelabresib (CPI-0610) monotherapy in patients with myelofibrosis – update of clinical and translational data from the ongoing Manifest trial. According to Mayo Clinic, “Myelofibrosis is an uncommon type of. 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. , Flinn I. Royalty Pharma will purchase the rights to receive 3% of future net sales of CPI-0209. We are currently conducting MANIFEST, a Phase 2 clinical trial of CPI-0610 as a monotherapy and in combination with ruxolitinib (marketed as Jakafi ® /Jakavi ®) in patients with myelofibrosis, or MF, a progressive hematological cancer. TEN-010 (5), 36. Multiple studies are evaluating pelabresib (CPI-0610) for the treatment of patients with myeloproliferative neoplasms (MPNs). Collectively, these data indicate that CPI-0610 +/- RUX might. 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. 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). 2f). Pelabresib (CPI-0610) is an investigational, selective oral bromodomain and extraterminal domain inhibitor (BETi). METHODS MANIFEST (ClinicalTrails. CPI-0610 induces apoptosis and G 1 cell cycle arrest associated with MYC downregulation. 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. Importantly, CC-90010 has a longer terminal half-life [∼60 h (±15% CV)] for the RP2D than other BET. 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. 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. 9%. Table 3 lists three such trials, early results from which have been presented. Kremyanskaya, M, Mascarenhas J, Palandri F, et al. 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. Pelabresib (CPI-0610) is a synthetic, small-molecule inhibitor of the tandem amino-terminal bromodomains (BD1 and BD2) of BET proteins currently in clinical. 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 a small molecule inhibitor of bromodomain and extra-terminal (BET) proteins. 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 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. Menu icon A vertical stack of three evenly. Blood. , CPI-0610 added onto existing treatment with ruxolitinib) have been treated for over 16 months. 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. 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. Here, the safety, efficacy, and pharmacodynamics of ten BET inhibitors currently in clinical trials were evaluated. . A Phase 3, Randomized, Double-blind, Active-Control Study of CPI-0610 and Ruxolitinib vs. Blum 1 , J. 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 being studied in multiple different ways. This study is exploring either CPI-0610 alone or in combination with ruxolitinib (Janus kinase 1/2 inhibitor). 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. Pelabresib (CPI-0610) is a potent and selective benzoisoxazoloazepine BET bromodomain inhibitor. Patients tolerated CPI-0610 well; thrombocytopenia was the only overlapping toxicity with ruxolitinib but was non-cumulative and reversible. 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. In addition, the experimental BET inhibitor CPI-0610 demonstrated an exceptional response (SPM score 97. 07) Dates. 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-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. 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. Ruxolitinib is the only FDA-approved treatment for myelofibrosis. CPI-0610 is a novel small-molecule bromodomain and extra terminal protein (BET) inhibitor used in patients with relapsed or refractory disease. Abramson J. Pelabresib is currently being investigated as a monotherapy and in combination with the JAK inhibitor (JAKi) ruxolitinib (RUX), in. 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. The bromodomain and extraterminal (BET) proteins recognize acetylated lysine residues on. In preclinical studies, pelabresib (CPI-0610), an investigational (BET) bromodomain inhibitor, downregulated NF-κB signaling and demonstrated antitumor. MANIFEST-2, A GLOBAL, PHASE 3, RANDOMIZED, DOUBLE-BLIND, ACTIVE-CONTROL STUDY OF CPI 0610 AND RUXOLITINIB VS. The novel targeted agent CPI-0610 enhanced responses to ruxolitinib in patients with myelofibrosis enrolled in the global phase II MANIFEST-2 trial, investigators reported at the 2020 American Society of Hematology (ASH) Annual Meeting & Exposition. Background: 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. JAKi are currently approved for treatment of MF, including ruxolitinib. 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. Das (Selleck. Constellation has aligned with the FDA on the design of MANIFEST-2, the pivotal Phase 3 clinical trial for CPI-0610 expected to begin in 2H20; Constellation plans to explore additional indications for CPI-0610; CAMBRIDGE, Mass. The company is currently. 21 of 29 evaluable patients (72%) achieved SVR35 at 12 weeksCAMBRIDGE, Mass. Abstract. The combination was well-tolerated. 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. 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, 2014Constellation Pharmaceuticals Provides Updates of MANIFEST Study for CPI-0610 and EZH2 Franchise. Table 3 lists three such trials, early results from which have been presented. 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. Conclusions: CPI-0610 is a well-tolerated, and an effective therapeutic agent for the treatment of MF. CPI-0610-mediated BET inhibition overcomes the protective effects conferred by cytokines and bone marrow stromal cells. Myelofibrosis is characterized by the presence of bone marrow fibrosis, increased cytokine production and inflammation, over activation of the JAK-STAT. 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. In addition to improvements in spleen volume and constitutional symptoms, the interim data suggest improvements in anemia, transfusion dependence, and bone marrow fibrosis. 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. Description. 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 small molecule inhibitor of the Bromodomain and Extra-Terminal (BET) family of proteins, with potential antineoplastic activity. 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. Most of. 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. 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. 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. The CPI-0610 starting daily dose was 125 mg, 2 weeks on, 2 weeks off. CPI-0610 discontinuation due to TEAEs occurred in 12% of patients, and six Grade 5 TEAEs were recorded. 5,6 Analysis of. For a discussion of other risks and uncertainties, any of. Go to. Targets. 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. CPI-0610 is a first-in-class inhibitor of bromodomain and extraterminal domain (BET) proteins, which regulate gene transcription in numerous pro-fibrotic pathways. Arm 3 is evaluating CPI-0610 in combination with ruxolitinib in JAK-inhibitor-naïve MF patients. 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. Create: 2012-07-23. Mascarenhas, MD. 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. Abstract. Of the 36 patients who received CPI-0610 monotherapy, 34 were still receiving the treatment as of Oct. ConclusionsPelabresib (CPI-0610), a first-in-class, oral, small-molecule inhibitor of BET proteins (BETi), has potential to promote disease-modifying activity through altered gene regulation of key oncogenic, fibrotic, and inflammatory factors in MF. JAKi are currently approved for treatment of MF, including ruxolitinib. 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. However, protein levels of BCL2, NF- κ B and MCL1 remain unchanged in MM cells upon BET inhibition. gov NCT No: NCT02158858 Opens a new window. Contact Ronald Aldridge Pelabresib (CPI-0610) is an investigational, selective oral bromodomain and extraterminal domain inhibitor (BETi). Pelabresib is a small molecule inhibitor of bromodomain and extra-terminal (BET) proteins. For a discussion of other risks and uncertainties, any of. Substitution on the amide nitrogen was not required for potency, as illustrated by 10 (CPI-0610), which also demonstrated greater in vitro metabolic stability than the secondary amides. A phase I study of Cpi-0610, a Bromodomain And Extra Terminal Protein (BET) inhibitor in patients with relapsed or refractory lymphoma. 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. CPI-0610 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. The primary endpoint of each trial was to establish the safety of CPI-0610 as a single agent by evaluating the frequency of dose-limiting toxicities associated with treatment with CPI-0610 for 21 days. Treatment with JAKi ruxolitinib (rux) or fedratinib in the frontline setting is associated with. BET inhibitors combined with other drugs may have better prospects. 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. 8 of 21 (38%. Abramson J. CPI-203 and CPI-0610 were obtained from Constellation Pharmaceuticals and kept as a solid powder at room temperature (RT). at UCLA. com) was kept as a stock solution (10mg/ml) in DMSO (Sigma-Aldrich) and prepared and stored in. Methods: Phase 2 trial with 3 arms: CPI-0610 monotherapy (Arm 1) or RUX + CPI-0610 “add-on. CPI-0610 demonstrated activity, both as a monotherapy and as add on to ruxolitinib, in second-line or later settings; Translational data supports potential disease-modifying effects of CPI-0610; CAMBRIDGE, Mass. Interim data from the trial demonstrated reduction in spleen volume, BM fibrosis, anemia and blood transfusions, as well as total. Pelabresib (CPI-0610) in Myelofibrosis: Pelabresib is an oral small-molecule BET inhibitor currently under investigation for the treatment of MF. (B) Comparison of average IC 50 s of BET inhibitors from patient-derived samples. Overall, the use of. 22, 10. 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. 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-1101, CC-90010, and ODM-207 for patients with hematological malignancies and solid tumors and summarized their. 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. BET proteins regulate key oncogenic pathways, including NFκB and TGFβ signaling which are important drivers of pro-inflammatory cytokine (Ck) expression and bone marrow. In: Clinical Lymphoma, Myeloma and Leukemia, Vol. 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). About CPI-0610. 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. CPI-0610 is a selective and potent oral BETi, being evaluated in the first study of a BETi in MF. Optional tumor biopsy will be obtained prior to Day 1 of CPI-0610 administration. 1, 2 BET proteins regulate transcription of specific genes integrating an array of oncogenic signals, including NF-κB pathway activation. 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. ” The data were gathered from 44 patients. As the most extensively characterized BET protein, BRD4 has. Brief Summary: A Phase 3, randomized, blinded study comparing pelabresib (CPI-0610) and ruxolitinib with placebo and ruxolitinib in. Phase 2 Part: Open-label study of CPI-0610 with and without Ruxolitinib in patients with Myelofibrosis. 1. 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. 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). 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). BET proteins regulate key oncogenic pathways, including NFκB and TGFβ signaling which are important drivers of pro-inflammatory cytokine (Ck) expression and.