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. However, the thrombocytopenia was reversible and not cumulative. CPI-0610 induces apoptosis and G 1 cell cycle arrest associated with MYC downregulation. (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. Doses of 170 and 230 mg QD are associated with a 50% average. 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. We further show that CPI-0610 inhibits MM cell growth in the presence of cytokines and when co-cultured with bone marrow stromal cells. In addition, the experimental BET inhibitor CPI-0610 demonstrated an exceptional response (SPM score 97. About CPI-0610. 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). 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. 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. Pelabresib is a small molecule inhibitor of bromodomain and extra-terminal (BET) proteins. Description. , Aug. 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. We also confirmed the in vivo efficacy of CPI-0610 in a MM xenograft mouse. 31 Pharmacokinetic parameters were dose-proportional for the evaluated doses. W. 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. While CPI-0610, Nil, and the combination significantly reduced spleen size , only the combination significantly reduced donor leukaemic CD45. 2 + cells in the bone marrow (protected by the niche. We would like to show you a description here but the site won’t allow us. 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. 3), and the WEE1 inhibitor adavosertib a moderate response (SPM score 84). 1182/blood. It has potential applications in the treatment of various forms of cancer . Collectively, these data indicate that CPI-0610 +/- RUX might. 18 μM for MYC. 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. Here, the safety, efficacy, and pharmacodynamics of ten BET inhibitors currently in clinical trials were evaluated. CPI-0610 is thought to reduce and suppress the differentiation of myeloid cells into megakaryocytes in the bone marrow, potentially leading to disease modification. BET protein inhibition is. 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. A phase I study of CPI-0610, a bromodomain and extra terminal protein (BET) inhibitor in patients with relapsed or refractory lymphoma. Phone Number: 1-877-MDA-6789. 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 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. , Gutierrez M. The future of epigenetic therapy: CPI-0610 for the treatment of myeloidfibrosis Epigenomics. A total of 41 patients were enrolled, of which 40 patients. 40) were amide or urea analogs such as RO6870810 (TEN-010), birabresib (OTX015, MK-8628), CPI-0610 137, and BAY-1238097 (Fig. 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. 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. Jennifer A Mertz, PhD 1 *, Patricia J Keller,. 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. 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. and Vaswani, Rishi G. For a discussion of other risks and uncertainties, any of. MANIFEST-2, A GLOBAL, PHASE 3, RANDOMIZED, DOUBLE-BLIND, ACTIVE-CONTROL STUDY OF CPI 0610 AND RUXOLITINIB VS. 39), all of which have undergone phase I. 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). BET proteins inhibition can potentially modify the pathogenic pathways which contribute to many diseases including malignancies. Store lyophilized at -20ºC, keep desiccated. Patients tolerated CPI-0610 well; thrombocytopenia was the only overlapping toxicity with ruxolitinib but was non-cumulative and reversible. CPI-0610 has been evaluated in 3 Phase 1 studies in > 140 patients with lymphoma, multiple myeloma and acute leukemias/myelodysplastic syndrome/MF. Maximal effects were observed 2 hours after 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). 18 μM for MYC [1] . 1491. 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). at UCLA. 9 weeks in the combination arm. 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. 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 drug which acts as a BET inhibitor, mainly acting at the BRD2 and BRD4 subtypes. at UCLA. The CPI-0610 starting daily dose was 125 mg, 2 weeks on, 2 weeks off. PLACEBO AND RUXOLITINIB IN JAK INHIBITOR-TREATMENT-NAIVE MYELOFIBROSIS PATIENTS. CPI-0610 is a small molecule inhibitor of the Bromodomain and Extra-Terminal (BET) family of proteins, with potential antineoplastic activity. 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 given orally once daily (QD) on days 1-14 of a 21-day cycle. However, protein levels of BCL2, NF- κ B and MCL1 remain unchanged in MM cells upon BET inhibition. 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. 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 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. CPI-0610 will be administered 200mg orally once a daily for 14 consecutive days followed by a 7-day break. 06, 2020 (GLOBE NEWSWIRE) -- Constellation Pharmaceuticals, Inc. Sims 6 , F. Findings from the phase 2 MANIFEST trial showed that at 12 weeks, the BET inhibitor CPI-0610 in combination with ruxolitinib demonstrated a 72. Molecular Weight. Products with only one mechanism of action are approved. Ruxolitinib (marketed as Jakafi) is the standard of care treatment for patients with. 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. Menu icon A vertical stack of three evenly. , Blum K. 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. 6%) evaluable patients achieved ≥50% TSS reduction at 24 weeks) 92 and a randomized phase 3 trial of. e. [1] [2] [3] [4] Abstract. Article. UPDATE: Constar Intl (CNST) Reports Update on MANIFEST Clinical Trial of CPI-0610 in Myelofibrosis Article Related Press Releases ( 1 ) Stock Quotes (1) Comments (0) FREE Breaking News Alerts from. 21 of 29 evaluable patients (72%) achieved SVR35 at 12 weeksCPI-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. Data from pacritinib in the first line setting, seen here, cannot be compared to any arm of the MANIFEST trial. The first study (poster #420) enrolled 32 patients with B-cell lymphoma and assigned them to oral CPI-1205 twice daily in 28-day cycles. CPI-0610 is a potent, selective, and cell-active BET inhibitor. BET proteins inhibition can potentially modify the pathogenic pathways which contribute to many diseases including malignancies. - Mechanism of. METHODS MANIFEST (ClinicalTrails. In one of. 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). In lyophilized form, the chemical is stable for 36 months. 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. CPI-0610 is a unique, first-in-class, oral, small-molecule inhibitor of BET proteins, designed to promote disease-modifying activity through selective gene regulation of key oncogenic, fibrotic, and inflammatory factors with potential to transform the standard of care in MF. Pelabresib (CPI-0610; PELA) is an oral, small-molecule, investigational BET inhibitor that downregulates NF-κB signaling and other relevant genes involved in MF. CPI-203 and CPI-0610 were obtained from Constellation Pharmaceuticals and kept as a solid powder at room temperature (RT). [1] [2]. 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. chem. – Amends second-line trial design to stratify for transfusion dependence based on positive preliminary data –– Expands study to include an additio. Pelabresib is currently being investigated as a treatment for myelofibrosis and. As the most extensively characterized BET protein, BRD4 has. 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. We do not sell or distribute actual drugs. 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. 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. CPI-0610 is a small molecule inhibitor of bromodomain and extra-terminal (BET) proteins. 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. 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. 1 (PubChem release 2021. placebo and ruxolitinib in JAK. 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. The two patients treated with a combination of CPI-0610 and ruxolitinib (i. 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. Spleen response rates in first-line patients at 12 weeks and 24 weeks in line with previously. 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]. 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. , Maris M. 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. The combination of rucaparib and CPI-0610 resulted in a significant 58% decrease in tumour weight when compared to vehicle (Fig. , CPI-0610 added onto existing treatment with ruxolitinib) have been treated for over 16 months. CPI-0610 is a small molecule inhibitor of bromodomain and extra-terminal (BET) proteins. 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. 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. Strategic Funding PartnershipCPI-0610 (Constellation Pharmaceuticals, Cambridge, MA) is a potent, orally bioavailable inhibitor of BET proteins that is being studied in different clinical scenarios (as a single agent after ruxolitinib, as an “add-on” therapy to ruxolitinib and in combination with ruxolitinib in JAK inhibitor naïve patients with MF) in the ongoing. 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. 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 an oral inhibitor of bromodomain and extraterminal domain (BET) proteins that inhibits cytokine production and promotes megakaryocytic and erythroid differentiation. 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, CPI-1205 and CPI-0209 are investigational therapies and have not been approved by the FDA (or any other regulatory authority). 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. 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. 2217/epi-2019-0274. 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%. Keywords: MPN, SVR35, TSS50, ruxolitinib, fedratinib, momelotinib MPN-379 Matching-Adjusted Indirect Comparison (MAIC) of Pelabresib (CPI-0610) in Combination With Ruxolitinib vs. Pelabresib (CPI-0610) Monotherapy in Patients With High-Risk Essential Thrombocythemia Refractory or Intolerant to Hydroxyurea: Preliminary Results From MANIFEST Study pdf | 552. Guidelines differ from study to study, and identify who can or cannot participate. and Hewitt, Michael C. 37 of 51 evaluable patients (73%) achieved a 35% reduction in spleen volume (SVR35) at 12 weeks and had a median spleen. As in Arm 2, the TEAEs recorded for Arm 3 were generally mild and showed the combination was well tolerated (Table 3). CPI-0610, CPI-1205 and CPI-0209 are investigational therapies and have not been approved by the FDA (or any other regulatory authority). Treatment with JAKi ruxolitinib (rux) or fedratinib in the frontline setting is associated with. BET inhibitors combined with other drugs may have better prospects. 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. ”Mr. 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. . Pelabresib has the potential to be a first. 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. 2 of 10 (20%) and 4 of 11 (36%) evaluable non-transfusion-dependent (non-TD) patients achieved SVR35 (the. 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. 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. MANIFEST-2, a global, phase 3, randomized, double-blind, active-control study of CPI-0610 and ruxolitinib vs. Myelofibrosis is characterized by the presence of bone marrow fibrosis, increased cytokine production and inflammation, over activation of the JAK-STAT. 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. For a discussion of other risks and uncertainties, any of. CPI-0610 rapidly suppressed expression of both proinflammatory cytokines. We further show that CPI-0610 inhibits MM cell growth in the presence of cytokines and when co-cultured with bone marrow stromal cells. 此外，在黑色素瘤中，PLX51107可降低PD-L1的表达水平，同时调节免疫细胞和肿瘤微环境[52]。CPI-0610在骨髓纤维化患者中，通过抑制Brd4降低Nf-κb的表达水平，从而抑制IL-8等促炎细胞因子的产生。Another BET inhibitor, CPI-0610, demonstrated ≥50% suppression of CCR1 at 6 h post-dose, which correlated with the clinical response in patients with R/R lymphoma. The benzoisoxazoloazepine CPI-0610 decreased MYC transcripts in vivo and reduced leukemia xenograft tumor growth, which was synergistic with doxorubicin treatment [117]. HemaSphere 2022;6:99-100). 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. 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. CPI-0610 is a unique, first-in-class, oral, small-molecule inhibitor of BET (BETi) proteins, designed to promote disease-modifying activity through selective gene regulation of key oncogenic, fibrotic, and inflammatory factors with potential to transform the standard of care in MF. The company is currently. BET Inhibitor CPI-0610 is well tolerated and induces responses in diffuse large B-cell lymphoma and follicular lymphoma: preliminary analysis of an ongoing. Most of. Doses (mg) of 6 12, 24, 48, 80, 120, 170, 230, 300 (capsules) and 125 and 225. 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. Arm 2 (2L) – CPI-0610 + ruxolitinib in ruxolitinib-experienced patients. In patients with MF, the bone marrow becomes overactive, leading to scarring and. 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. Ann Oncol. 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. 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. 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). In the MANIFEST-2 phase 3 study, CPI-0610 plus ruxolitinib will be compared to placebo plus ruxolitinib in JAK inhibitor–naïve MF patients with at least DIPSS intermediate-1 disease, splenomegaly by imaging, and symptomatic MF. 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. 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. CPI-0610 will be administered 200mg orally once a daily for 14 consecutive days followed by a 7-day break. 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. There is a high unmet need for a treatment that can potentially delay or reverse BM fibrosis in patients (pts) with MF. 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. Between September 2013 and March 2015 44 patients had been enrolled and treated at doses of 6, 12, 24, 48, 80, 120, 170. and ABBV-07 5 (6). CPI-0610-mediated BET inhibition overcomes the protective effects conferred by cytokines and bone marrow stromal cells. CPI-0610-mediated BET. In the monotherapy group, TD patients had a spleen volume response (SVR) of 25%, while in the non-TD group, SVR was 0%. Ruxolitinib is the only FDA-approved treatment for myelofibrosis. CPI-0610 displays potent cytotoxicity against MM cell lines and patient-derived MM cells through G1 cell cycle arrest and caspase. 4. , et al. With more data on the agent expected to be released from trials in this space toward the end of the year, Joseph M. Your purchase entitles you to full access to the information. Treatment with JAKi ruxolitinib (rux) or fedratinib in the frontline setting is associated with. , Flinn I. Arm 3 (1L) – CPI-0610 + ruxolitinib interim efficacy subgroup analysis in JAK-inhibitor-naïve patients. Purpose of Review Myelofibrosis (MF) is a myeloproliferative neoplasm characterized by bone marrow fibrosis, megakaryocyte. So, combinations with Navitoclax which is Bcl-xL cell inhibitor, CPI-0610, which is BET inhibitor, Luspatercept which is anemia drug. Data published in two abstracts suggest that CPI-0610 may have potential disease-modifying effects in treating myelofibrosis ; All ten evaluable patients experienced spleen volume reductions ; Improvements in symptom scores, bone marrow fibrosis, and hemoglobin levels also seen ; Two transfusion dependent patients became transfusion. . CPI-0610 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. Mascarenhas, MD. According to Mayo Clinic, “Myelofibrosis is an uncommon type of. Arms 1 and 2 are studying CPI-0610 as a monotherapy or in combination with ruxolitinib in. Over the past decade, numerous pan-BET inhibitors have been generated, and some of them are currently in clinical trials, such as OTX-015, CPI-0610, and I-BET762. 1,2. Haematologica. 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 Phase 3 MANIFEST-2 study is evaluating pelabresib combined with ruxoliti. 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. CPI-0610 has been well tolerated, with the principal toxicity being dose-dependent thrombocytopenia that is reversible and non-cumulative. 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. Continued high rate of SVR35 in 1L patients: 72% at 12 weeks and 67% at 24 weeksSVR35 responses and transfusion dependence conversion observed in. CPI-0610 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. Abramson 2 , 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. 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. 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 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. 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). Methods: Eligible patients were those whose lymphoma had progressed and for whom no effective therapies are available. 2f), supporting the potential for BETi to be used for ovarian cancer. The median duration of treatment was 11. CPI-0610 treatment resulted in MM cytotoxicity in vitro by inducing G 1 cell cycle arrest and caspase-dependent apoptosis. Interim data from the trial demonstrated reduction in spleen volume, BM fibrosis, anemia and blood transfusions, as well as total. For a discussion of other risks and uncertainties, any of. Figure 2. In preclinical studies, pelabresib (CPI-0610), an investigational (BET) bromodomain inhibitor, downregulated NF-κB signaling and demonstrated antitumor. Arm 1 (2L) – CPI-0610 monotherapy in JAK-inhibitor-experienced or -ineligible patients . We further show that CPI-0610 inhibits MM cell growth in the presence of cytokines and when co-cultured with bone marrow stromal cells. 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%. 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. 05. Phase 2 Part: Open-label study of CPI-0610 with and without Ruxolitinib in patients with Myelofibrosis. Conclusions: CPI-0610 is a well-tolerated, and an effective therapeutic agent for the treatment of MF. 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. , Goy A. CPI-0610. Pacritinib in Patients With Primary Myelofibrosis, Post Polycythemia Vera Myelofibrosis, or Post-Essential Thrombocythemia Myelofibrosis. Abramson JS, Blum KA, Flinn IW, Gutierrez M, Goy A, Maris M, et al. . placebo and ruxolitinib in JAK. For a discussion of other risks and uncertainties, any of. their clin ical invest igation s are focused on cancer therapies. 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 ; View More. Pts can experience intolerance, inadequate response or loss of response to first-line cytoreductive therapies (hydroxyurea [HU] or interferon alfa-2a). 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 is a first-in-class inhibitor of bromodomain and extraterminal domain (BET) proteins, which regulate gene transcription in numerous pro-fibrotic pathways. Pelabresib is being investigated as a treatment for myelofibrosis and has not yet. There has been significant progress in immune checkpoint inhibitor (CPI) therapy in many solid tumor types. Interim data from this study have shown promising results,. MOR210/TJ210/HIB210 is a human antibody directed against C5aR1, the receptor of the complement factor C5a, currently in Phase 1 clinical development. Pelabresib is a small molecule inhibitor of bromodomain and extra-terminal (BET) proteins. , CPI-0610 added onto existing treatment with ruxolitinib) have been treated for over 16 months. CPI-0610 induces apoptosis and G 1 cell cycle arrest associated with MYC downregulation. CPI-0610 demonstrated activity, both as a monotherapy and as add on to ruxolitinib, in second-line or later settings; Translational data supports potential disease-modifying effects of CPI-0610; Arm 3 (1L) – CPI-0610 + ruxolitinib interim efficacy subgroup analysis in JAK-inhibitor-naïve patients As previously reported at ASH 2020, 42 of 63 evaluable patients (67%) achieved a ≥35% reduction in spleen volume (SVR35) at 24 weeks (the primary endpoint for Arm 3). CPI-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. For example, patients experienced immune responses, improvements in quality of life, and an occasional. MANIFEST TrialMascarenhas served as lead author of a study presented at the 2022 European Hematology Association (EHA) Congress, titled, “BET inhibitor pelabresib (CPI-0610) combined with ruxolitinib in. 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. 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. TEN-010 (5), 36. 2018; 29 (Abstract 41O) Google Scholar; CC-90010 is a novel, oral, reversible, small-molecule inhibitor of BET proteins. Importantly, CC-90010 has a longer terminal half-life [∼60 h (±15% CV)] for the RP2D than other BET. In preclinical studies, pelabresib downregulated NF-κB signaling and demonstrated antitumor activity in vitro. MANIFEST-2, a global, phase 3, randomized, double-blind, active-control study of CPI-0610 and ruxolitinib vs. Treatment with an investigational small molecule less than 2 weeks before the first dose of CPI-0610. Flinn 4 , A. 8 g/mol. 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. The results provide evidence of synergy between CPI-0610 and rux in these myelofibrosis patients, and the spleen and symptom benefits are. 2f). Pelabresib is a small molecule inhibitor of bromodomain and extra-terminal (BET) proteins. CPI-0610 displays potent cytotoxicity against MM cell lines and patient-derived MM cells through G 1 cell cycle arrest and caspase-dependent apoptosis. Pelabresib (CPI-0610) is an investigational, selective oral bromodomain and extraterminal domain inhibitor (BETi). Severe. . 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. Pelabresib (CPI-0610) is a small molecule inhibitor of bromodomain and extra-terminal (BET) proteins. CPI-0610 inhibits BRD4-BD1 with an IC50 of 39 nM, and with an EC50 value of 0. Downsized turbocharged gasoline direct injection (TGDI) engines with high specific power and torque can enable reduced fuel. Contact Ronald AldridgePelabresib (CPI-0610) is an investigational, selective oral bromodomain and extraterminal domain inhibitor (BETi). An early signal of clinical activity was seen in the phase 1 portion of the MANIFEST study (NCT02158858) that. CPI-0610 is a selective and potent oral BETi, being evaluated in the first study of a BETi in MF. 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. Arm 3 is evaluating CPI-0610 in combination with ruxolitinib in JAK-inhibitor-naïve MF patients. CPI-0610 discontinuation due to TEAEs occurred in 12% of patients, and six Grade 5 TEAEs were recorded. Blum 1 , J. ” Data Highlights . 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). 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 . 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 Data presented at ASCO and EHA from the MANIFEST study suggest that CPI-0610 may have disease-modifying effects. 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). Background: Pelabresib (CPI-0610) is a potent, first-in-class, selective, oral small-molecule inhibitor of bromodomain and extraterminal domain (BET). , Blum K. 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. Participant eligibility includes age, gender, type and stage of disease, and previous treatments or health concerns. 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). Treatment with JAK inhibitor (JAKi) ruxolitinib (rux) or fedratinib. 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. Computed by PubChem 2. 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. A phase I study of Cpi-0610, a Bromodomain And Extra Terminal Protein (BET) inhibitor in patients with relapsed or refractory lymphoma. 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. 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. Modify: 2023-11-04. Article. ” The data were gathered from 44 patients. Abramson J. CPI-0610 is a selective and potent oral BETi, being evaluated in the first study of a BETi in MF. Pelabresib (CPI-0610) is an investigational, selective oral bromodomain and extraterminal domain inhibitor (BETi). Blood. Goy 5 , J. BET proteins are known to promote cancer growth. CPI-0610 is a potent, selective, and cell-active BET inhibitor. [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/. 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. Pelabresib is currently being investigated as a monotherapy and in combination with the JAK inhibitor (JAKi) ruxolitinib (RUX), in. Create: 2012-07-23. Contact Ronald AldridgeJohn O. 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. ” The data were gathered from 44 patients. CPI-0610 is a small molecule inhibitor of bromodomain and extra-terminal (BET) proteins. For CPI-0610 added on to ongoing treatment with ruxolitinib, there was a 24. METHODS MANIFEST (ClinicalTrails. CPI-0610 is a small molecule inhibitor of bromodomain and extra-terminal (BET) proteins. However, only a single failed study has been published in treating Ph(-) myeloproliferative neoplasm (MPN). 06, 2020 (GLOBE NEWSWIRE) -- Constellation Pharmaceuticals, Inc. 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 bromodomain and extraterminal (BET) proteins recognize acetylated lysine residues on. As previously reported at ASH 2020, 42 of 63 evaluable patients (67%) achieved a ≥35%. 41O A phase I study of CPI-0610, a bromodomain and extra terminal protein (BET) inhibitor in patients with relapsed or refractory lymphoma K. I-BET151 showed beneficial effects in the treatment of GBM and leukemia. 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. Demonstration of efficacy and safety in these 3 arms has led to the continued development of CPI-0610. 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. Products with only one mechanism of action are approved. 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). Pelabresib is a small molecule inhibitor of bromodomain and extra-terminal (BET) proteins. JAK Inhibitor Monotherapy in Patients With Intermediate or High-Risk Myelofibrosis Vikas Gupta PhD1, John Mascarenhas MD2, Marina Kremyanskaya MD,. Recent. 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. 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. 1. However, protein levels of BCL2, NF- κ B and MCL1 remain unchanged. 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. Constellation Pharmaceuticals Provides Updates of MANIFEST Study for CPI-0610 and EZH2 Franchise. 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. Additionally, CPI-0610 decreased BRD4 and c-Myc expressions and affected MAPK, JAK/STAT, and AKT signalling pathways in human DLBCL cells. In addition to improvements in spleen volume and constitutional symptoms, the interim data suggest improvements in anemia, transfusion dependence, and bone marrow fibrosis. S. 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. 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. 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. Phase 2 Part: Open-label study of CPI-0610 with and without Ruxolitinib in patients with Myelofibrosis. A Phase 3, Randomized, Double-blind, Active-Control Study of CPI-0610 and Ruxolitinib vs. Constellation developed pelabresib (CPI-0610) which inhibits members of the BET family of chromosome-binding. 1,2 “Preliminary data demonstrate the. CPI-0610 data was 29% and 38%, which also compares favorably with the above data. 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. 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. Arm 3 (1L) – CPI-0610 + ruxolitinib interim efficacy subgroup analysis in JAK-inhibitor-naïve patients. 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. 2217/epi-2019. CPI-0610 is a selective and potent oral BETi, being evaluated in the first study of a BETi in MF. Of the 36 patients who received CPI-0610 monotherapy, 34 were still receiving the treatment as of Oct. The dose will not be adjusted for body weight or. Here we describe the rationale and design for the phase III MANIFEST-2 (ClinicalTrials. However, toxicity studies.