CPI-0610 will be administered 200mg orally once a daily for 14 consecutive days followed by a 7-day break. In the monotherapy group, TD patients had a spleen volume response (SVR) of 25%, while in the non-TD group, SVR was 0%. As previously reported at ASH 2020, 42 of 63 evaluable patients (67%) achieved a ≥35%. 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). 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. Pelabresib (CPI-0610) is an investigational, selective oral bromodomain and extraterminal domain inhibitor (BETi). Arm 1 (2L) – CPI-0610 monotherapy in JAK-inhibitor-experienced or -ineligible patients . 34 of 60 evaluable patients (57%) achieved a ≥50% reduction in Total. Garner ,Optional tumor biopsy will be obtained prior to Day 1 of CPI-0610 administration. Store lyophilized at -20ºC, keep desiccated. 11 is a potent selective inhibitor of BET proteins, which inhibits BRD4 BD1 with IC 50 of 39 nM in TR-FRET (time-resolved fluorescence energy transfer) assay, and exhibits anti-tumor. 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-mediated BET inhibition overcomes the protective effects conferred by cytokines and bone marrow stromal cells. 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. 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. Overall, the use of. Constellation is evaluating CPI-0610 in combination with ruxolitinib in JAK-inhibitor-naïve MF patients (Arm 3), with a primary endpoint of the proportion of patients with a ≥35% spleen volume. CPI-0610 is a unique, first-in-class, oral, small-molecule inhibitor of 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. S. 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. doi: 10. Ruxolitinib (marketed as Jakafi) is the standard of care treatment for patients with. MANIFEST is an open-label Phase 2 clinical trial of CPI-0610 in patients with myelofibrosis (MF), a rare cancer of the bone marrow that disrupts the body’s normal production of blood cells. Methods: MANIFEST (ClinicalTrails. Background: Pelabresib (CPI-0610) is a potent, first-in-class, selective, oral small-molecule inhibitor of bromodomain and extraterminal domain (BET). 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). Open in a separate window. @article{osti_1855473, title = {Identification of a Benzoisoxazoloazepine Inhibitor (CPI-0610) of the Bromodomain and Extra-Terminal}, author = {Albrecht, Brian K. Keywords: MPN, SVR35, TSS50, ruxolitinib, fedratinib, momelotinib MPN-379 Matching-Adjusted Indirect Comparison (MAIC) of Pelabresib (CPI-0610) in Combination With Ruxolitinib vs. 7%) evaluable patients achieved ≥35% SVR and 11 of 14 (78. 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). , 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, 2014Constellation Pharmaceuticals Provides Updates of MANIFEST Study for CPI-0610 and EZH2 Franchise. Findings from the phase 2 MANIFEST trial showed that at 12 weeks, the BET inhibitor CPI-0610 in combination with ruxolitinib demonstrated a 72. Collectively, these data indicate that CPI-0610 +/- RUX might. CPI-0610 has been evaluated in 3 Phase 1 studies in > 140 patients with lymphoma, multiple myeloma and acute leukemias/myelodysplastic syndrome/MF. 2022, p. Ruxolitinib is the only FDA-approved treatment for myelofibrosis. 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. (Nasdaq: CNST) today announced that two oral. 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. An additional cohort is recruiting JAKi naïve patients to receive CPI-0610/ruxolitinib combination, and showed encouraging preliminary activity [33]. MANIFEST is an open-label Phase 2 clinical trial of CPI-0610 in patients with myelofibrosis (MF), a rare cancer of the bone marrow that disrupts the body’s normal production of blood cells. Context: Pelabresib (CPI-0610) combined with ruxolitinib showed encouraging spleen and symptom responses in Janus kinase inhibitor (JAKi)-naïve patients with intermediate or high-risk. However, toxicity studies. CPI-0610 is a selective and potent oral BETi, being evaluated in the first study of a BETi in MF. Keywords: CPI-0610; JAKi treatment-naive; MANIFEST-2; myelofibrosis; pelabresib; ruxolitinib. Price : $50 *. CPI-0610 is a potent and selective small molecule designed to promote anti-tumor activity by selectively inhibiting the function of BET proteins to decrease the expression of. CPI-0610 is a small molecule inhibitor of bromodomain and extra-terminal (BET) proteins. Our study found IKZF1 and IRF4 to be among the primary targets of CPI-0610, along with MYC . , Goy A. Treatment with a therapeutic antibody less than 4 weeks before the first dose of CPI-0610. . An additional cohort is recruiting JAKi naïve patients to receive CPI-0610/ruxolitinib combination, and showed encouraging preliminary activity [Citation 33]. Pelabresib is currently being investigated as a monotherapy and in combination with the JAK inhibitor (JAKi) ruxolitinib (RUX), in. Pelabresib (CPI-0610) is an investigational, selective oral bromodomain and extraterminal domain inhibitor (BETi). Of the 36 patients who received CPI-0610 monotherapy, 34 were still receiving the treatment as of Oct. A. CPI-0610 is a potent, selective, and cell-active BET inhibitor. However, only a single failed study has been published in treating Ph(-) myeloproliferative neoplasm (MPN). 6%) evaluable patients achieved ≥50% TSS reduction at 24 weeks) 92 and a randomized phase 3 trial of. 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. CPI-0610 treatment resulted in MM cytotoxicity in vitro by inducing G 1 cell cycle arrest and caspase-dependent apoptosis. 21 of 29 evaluable patients (72%) achieved SVR35 at 12 weeksCAMBRIDGE, Mass. , Maris M. Taken together, these paired BM biopsy and in vitro myeloid maturation results demonstrated an effect. BET proteins regulate key oncogenic pathways, including NFκB and TGFβ signaling which are important drivers of pro-inflammatory cytokine (Ck) expression and. CPI-0610 treatment of CD34+ cells from MF patients in MK differentiating conditions in the presence of SCF, IL6, IL9 and TPO resulted in a dose-dependent. Spleen response rates in first-line patients at 12 weeks and 24 weeks in line with previously. 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. JAKi are currently approved for treatment of MF, including ruxolitinib. JAK Inhibitor Monotherapy in Patients With Intermediate or High-Risk Myelofibrosis Vikas Gupta PhD1, John Mascarenhas MD2, Marina Kremyanskaya MD,. Treatment with JAK inhibitor (JAKi) ruxolitinib (rux) or fedratinib. 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. To make progress in CPI studies on this disease, herein, we review and summarize the mechanisms of activation of the PD-L1. Pelabresib is being investigated as a treatment for myelofibrosis and has not yet. Authors Jigar Raythatha 1 , Lauren Arnold 1 Affiliation 1 Constellation Pharmaceuticals. Pelabresib is a small molecule inhibitor of bromodomain and extra-terminal (BET) proteins. 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). BET proteins inhibition can potentially modify the pathogenic pathways which contribute to many diseases including malignancies. 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. Blood. Adis is an information provider. Flinn 4 , A. Haematologica. 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. CPI-0610, CPI-1205 and CPI-0209 are investigational therapies and have not been approved by the FDA (or any other regulatory authority). 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). " Constellation. A Phase 3, randomized, blinded study comparing pelabresib (CPI-0610) and ruxolitinib with placebo and ruxolitinib in myelofibrosis (MF) patients that have not been previously treated with Janus kinase inhibitors (JAKi). CPI-0610 is a small molecule inhibitor of bromodomain and extra-terminal (BET) proteins. 23. 1, 2 BET proteins regulate transcription of specific genes integrating an array of oncogenic signals, including NF-κB pathway activation. 2f), supporting the potential for BETi to be used for ovarian cancer. To further dissect the underlying mechanism of these relative improvements in bone marrow composition and histotopography induced by CPI-0610, CD34+ hematopoietic stem cells were isolated from peripheral blood collected from multiple MF patients at baseline to evaluate the impact of CPI-0610 on MK and erythroid differentiation in vitro. BET inhibitors combined with other drugs may have better prospects. 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. Contact Ronald AldridgePelabresib (CPI-0610) is an investigational, selective oral bromodomain and extraterminal domain inhibitor (BETi). Aims: Data (Sep 2021 data cut) on the safety and efficacy of pelabresib in combination with RUX in pts with MF from Arms 2 and 3 of the ongoing, open-label. Contact Ronald Aldridge Pelabresib (CPI-0610) is an investigational, selective oral bromodomain and extraterminal domain inhibitor (BETi). CPI-0610 discontinuation due to TEAEs occurred in 12% of patients, and six Grade 5 TEAEs were recorded. placebo and ruxolitinib in JAK. Here we present results from MANIFEST. 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. Demonstration of efficacy and safety in these 3 arms has led to the continued development of CPI-0610. CPI-0610, CPI-1205 and CPI-0209 are investigational therapies and have not been approved by the FDA (or any other regulatory authority). In the phase II MANIFEST study, Pelabresib is being evaluated as monotherapy and in combination with the JAK inhibitor ruxolitinib. 9%. The company is currently. Taken together, these paired BM biopsy and in vitro myeloid maturation results demonstrated an effect of CPI-0610 in promoting erythroid and MK differentiation. Mascarenhas J, Harrison C, Luptakova K, et al. In ruxolitinib treatment-naïve and previously treated patients with myelofibrosis, pelabresib combined with ruxolitinib resulted in splenic and symptom responses and BM fibrosis improvement and was generally well tolerated. CPI-0610 is a potent, selective, and cell-active BET inhibitor. METHODS MANIFEST (ClinicalTrails. Patients in the two second-line arms are being stratified based on transfusion dependent status. Products with only one mechanism of action are approved. 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 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. Create: 2012-07-23. 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. 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. Goy 5 , J. [1] [2] [3] [4] Abstract. Pelabresib (CPI-0610) is an investigational, oral, small-molecule bromodomain and extraterminal (BET) domain inhibitor. CPI-0610 is a small molecule inhibitor of bromodomain and extra-terminal (BET) proteins. The Phase 3 MANIFEST-2 study is evaluating pelabresib combined with ruxoliti. Table 3 lists three such trials, early results from which have been presented. These findings indicate that BET inhibition not only results in a robust reduction of MYC transcription and activity but also suppresses the expression of. Treatment with JAKi ruxolitinib (rux) or fedratinib in the frontline setting is associated with. Abstract. CPI-0610 showed encouraging action in JAK inhibitor-naive anemic MF patients, a population with a poor prognosis, as well as ruxolitinib-refractory MF patients. The novel 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. Arm 3 (1L) – CPI-0610 + ruxolitinib in JAK-inhibitor-naïve patients. However, the thrombocytopenia was reversible and not cumulative. 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. 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. A Phase 3, randomized, blinded study comparing pelabresib (CPI-0610) and ruxolitinib with placebo and ruxolitinib in myelofibrosis (MF) patients that have not been previously treated with Janus kinase inhibitors (JAKi). CPI-0610 is a 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. , Dec. 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. Tolerability and Efficacy of Navitoclax Alone or in Combination With Ruxolitinib in Participants With Myelofibrosis. Purpose of Review Myelofibrosis (MF) is a myeloproliferative neoplasm characterized by bone marrow fibrosis, megakaryocyte. 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. When. 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. Royalty Pharma will purchase the rights to receive 3% of future net sales of CPI-0209. ” The data were gathered from 44 patients. 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 the clonal disease cells of origin in MF. Recent. 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. Conclusions: CPI-0610 is a well-tolerated, and an effective therapeutic agent for the treatment of MF. However, protein levels of BCL2, NF- κ B and MCL1 remain unchanged in MM cells upon BET inhibition. Pelabresib (CPI-0610) is an investigational selective small molecule designed to promote anti-tumor activity by inhibiting the function of bromodomain and extra-terminal domain (BET) proteins to decrease the expression of abnormally expressed genes in cancer. CPI-0610 is 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. CPI 0610 ; View More. 1,2. 2217/epi-2019. , Goy A. Most BET inhibitors in the clinic, including GSK525762, CPI-0610, OTX-015, and MT1, have similar structures as JQ1 and exhibited good preliminary effects on. cpi 0610 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). 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. The. 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 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. Molecular Weight. [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/. 07) Dates. BET proteins are known to promote cancer growth. gov NCT No: NCT02158858 Opens a new window. CPI-0610 inhibits BRD4-BD1 with an IC50 of 39 nM, and with an EC50 value of 0. ” Data HighlightsCPI-0610, CPI-1205 and CPI-0209 are investigational therapies and have not been approved by the FDA (or any other regulatory authority). With 63 myelofibrosis patients now treated and evaluable in the company’s mid-stage study, the 24-week spleen response rate to its oral drug, CPI-0610 — when used on top of Jakafi, Incyte’s. We plan to provide a further update on CPI-0610 in oral and poster presentations and at an investor event at the ASH meeting on December 9. Here we describe the rationale and design for the phase III MANIFEST-2 (ClinicalTrials. Arm 3 (1L) – CPI-0610 + ruxolitinib in JAK-inhibitor-naïve patients. CPI-0610 is a novel small-molecule bromodomain and extra terminal protein (BET) inhibitor used in patients with relapsed or refractory disease. , Maris M. 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). Finally, in Arm 3, which looked at CPI-0610 in combination with ruxolitinib in JAK-inhibitor-naïve patients, 67% of subjects achieved a ≥35% reduction in SVR35 at the 24. So, combinations with Navitoclax which is Bcl-xL cell inhibitor, CPI-0610, which is BET inhibitor, Luspatercept which is anemia drug. 8. About CPI-0610. 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. Blum 1 , J. About CPI-0610. Single agent CPI-0610 treatment also significantly decreased tumour weight by 42% when compared to vehicle (Fig. 1. . 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. 2019 Nov;11(14):1553-1555. 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. We are also exploring other novel cancer epigenetics targets in preclinical testing to fuel a sustainable pipeline of innovative small-molecule product candidates. The 14 days of CPI-0610 dosing and the 7-day break together constitute 1 cycle of treatment. 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) is an oral small-molecule investigational inhibitor of BET protein bromodomains currently being developed for the treatment of patients with MF. 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. Figure 2. Molecular studies to further our understanding of the underlying mechanisms of CPI-0610 treatment are ongoing. Arm 3 (1L) – CPI-0610 + ruxolitinib interim efficacy subgroup analysis in JAK-inhibitor-naïve patients. - Mechanism of. Pelabresib (CPI-0610) Monotherapy in Patients With High-Risk Essential Thrombocythemia Refractory or Intolerant to Hydroxyurea: Preliminary Results From MANIFEST Study pdf | 552. at UCLA. 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 added onto existing treatment with ruxolitinib) have been treated for over 16 months. 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. 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. 8% median improvement in TSS for transfusion dependent (TD. 2217/epi-2019-0274. Interim data from the trial demonstrated reduction in spleen volume, BM fibrosis, anemia and blood transfusions, as well as total. 45 Although small-molecule pan-BET inhibitors show promising effects in clinical evaluation, there are still problems and challenges to overcome, such as the moderate clinical. Pelabresib (CPI-0610) Combined with Ruxolitinib for JAK Inhibitor Treatment-Naïve Patients with Myelofibrosis: Durability of Response and Safety Beyond Week 24. Maximal effects were observed 2 hours after treatment. 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. In MF patients, there are multiple studies from a single-agent arm in this phase 2 study in the second-line setting, then adding it to ruxolitinib while patients are on a stable dose of ruxolitinib, and combining it from the very beginning, This study is kind of 3 sets of patients, including. Myelofibrosis is characterized by the presence of bone marrow fibrosis, increased cytokine production and inflammation, over activation of the JAK-STAT. Pelabresib (CPI-0610; PELA) is an oral, small-molecule, investigational BET inhibitor that downregulates NF-κB signaling and other relevant genes involved in MF. 9 Inhibiting BET may modify critical MF pathways, including. However, protein levels of BCL2, NF- κ B and MCL1 remain unchanged in MM cells upon BET inhibition. These are phase three studies that are planned to start soon for possible approval for combinations over JAK inhibitor alone for different problems that people face. Pelabresib (CPI-0610) monotherapy in patients with myelofibrosis – update of clinical and translational data from the ongoing manifest trial. Pelabresib (CPI-0610) monotherapy in patients with myelofibrosis – update of clinical and translational data from the ongoing Manifest trial. This study is sponsored by Constellation Pharmaceuticals a MorphoSys Company. 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. 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. 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. 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. 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 published target genes. Delaney has a track. “We are excited about the emerging profile of CPI-0610,” said Jigar Raythatha, Chief Executive Officer of Constellation Pharmaceuticals. CPI-0610 inhibits the expression of Nuclear receptor binding SET domain protein 3 (NSD3) target genes. Like ruxolitinib failure, there is also no uniformly accepted. Ann Oncol. Preclinical and clinical data on Pelabresib (CPI-0610), an investigational oral small-molecule potent BET-inhibitor being explored in MF, suggest it offers a much-needed innovative treatment approach for patients with MF. CPI-0610 significantly delayed tumor growth and increased theCPI-0610 is an effective BET inhibitor in multiple myeloma (MM) and is currently being tested in phase I clinical trial [84]. Arm 2 (2L) – CPI-0610 + ruxolitinib in ruxolitinib-experienced patients. 3 weeks in the monotherapy arm and 25. 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. 37 of 51 evaluable patients (73%) achieved a 35% reduction in spleen volume (SVR35) at 12 weeks and had a median spleen. Guidelines differ from study to study, and identify who can or cannot participate. MANIFEST-2: CPI-0610 Shows Benefit in Myelofibrosis. 4. BET protein inhibition is. ABBV-075 and JQ1 were tested. Maris 3 , I. Here we report the safety, pharmacokinetics, pharmacodynamics, and preliminary clinical activity from the first-in-human phase I study of pelabresib in patients with relapsed. 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. For research use only. Pelabresib (CPI-0610) is a potent and selective benzoisoxazoloazepine BET bromodomain inhibitor. 1491. Data from pacritinib in the first line setting, seen here, cannot be compared to any arm of the MANIFEST trial. Computed by PubChem 2. 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. 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). The bromodomain and extraterminal (BET) proteins recognize acetylated lysine residues on. Contact Ronald AldridgeJohn O. 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. It has potential applications in the treatment of various forms of cancer . 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 . 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. The median duration of treatment was 11. 6 of 21 (29%) evaluable non-TD patients achieved SVR35 at 24 weeks, the primary endpoint for cohort 2B. CPI-0610 rapidly suppressed expression of both proinflammatory cytokines. 3), and the WEE1 inhibitor adavosertib a moderate response (SPM score 84). MANIFEST TrialCPI-0610 (4), 35. CPI-0610 inhibits BRD4-BD1 with an IC50 of 39 nM, and with an EC50 value of 0. The combination was well-tolerated. Pelabresib (CPI-0610) is an investigational, selective oral bromodomain and extraterminal domain inhibitor (BETi). Pelabresib is being investigated as a treatment for myelofibrosis and has not. Here, the safety, efficacy, and pharmacodynamics of ten BET inhibitors currently in clinical trials were evaluated. 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. their clin ical invest igation s are focused on cancer therapies. 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. ” Data Highlights . 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. Mascarenhas J, Kremyanskaya M, Patriarca A, Harrison C, Bose P, Rampal RK, et al. Participation eligibility. gov identifier: NCT02158858 ), a global, open. The body weights of the. 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. 5% rate of reduction in spleen volume of at least 35%. , et al. 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. Phase 1 Part (Complete): Open-label, sequential dose escalation study of pelabresib in patients with previously treated Acute Leukemia, Myelodysplastic. Pelabresib is currently being investigated as a treatment for myelofibrosis and. , Blum K. Treatment with JAKi ruxolitinib (rux) or fedratinib in the frontline setting is associated with. 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. The abstracts include. A. 18 μM for MYC. About CPI-0610. HemaSphere 2022;6:99-100). 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). For example, patients experienced immune responses, improvements in quality of life, and an occasional. There is a high unmet need for a treatment that can potentially delay or reverse BM fibrosis in patients (pts) with 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. and Cote, Alexandre and Leblanc, Yves and Nasveschuk, Christopher G. Placebo and Ruxolitinib in JAKi Treatment Naive MF Patients. and ABBV-07 5 (6). placebo and ruxolitinib in JAK. Pts can experience intolerance, inadequate response or loss of response to first-line cytoreductive therapies (hydroxyurea [HU] or interferon alfa-2a). We also confirmed the in vivo efficacy of CPI-0610 in a MM xenograft mouse. We previously evaluated CPI-0610 in three Phase 1 clinical trials in an aggregate of 138 patients with hematological malignancies. 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. Kremyanskaya, M, Mascarenhas J, Palandri F, et al. Abramson JS, Blum KA, Flinn IW, et al. The results provide evidence of synergy between CPI-0610 and rux in these myelofibrosis patients, and the spleen and symptom benefits are. We further show that CPI-0610 inhibits MM cell growth in the presence of cytokines and when co-cultured with bone marrow stromal cells. The two patients treated with a combination of CPI-0610 and ruxolitinib (i. Drug selectivity of BRD4 small-molecule inhibitors. 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. Abramson J. Jennifer A Mertz, PhD 1 *, Patricia J Keller,. Browse Publications Technical Papers 2020-01-0610. and Vaswani, Rishi G. 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. For a discussion of other risks and uncertainties, any of. A phase I study of Cpi-0610, a Bromodomain And Extra Terminal Protein (BET) inhibitor in patients with relapsed or refractory lymphoma. In July 2012, LLS began its partnership with Constellation to support three first-in-human Phase 1 clinical trials for blood cancer patients and is currently supporting "A Phase 3, Randomized, Double-blind, Active-Control Study of CPI-0610 and Ruxolitinib vs. Treatment with a therapeutic antibody less than 4 weeks before the first. 31 Pharmacokinetic parameters were dose-proportional for the evaluated doses. Treatment with an investigational small molecule less than 2 weeks before the first dose of CPI-0610. For a discussion of other risks and uncertainties, any of. CPI-203 and CPI-0610 were obtained from Constellation Pharmaceuticals and kept as a solid powder at room temperature (RT). CPI-0610-mediated BET. 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]. Ruxolitinib is the only FDA-approved treatment for myelofibrosis. 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. CPI-0610 is a drug which acts as a BET inhibitor, mainly acting at the BRD2 and BRD4 subtypes. 18 μM for MYC. CPI-0610 induces apoptosis and G 1 cell cycle arrest associated with MYC downregulation. MANIFEST-2, A GLOBAL, PHASE 3, RANDOMIZED, DOUBLE-BLIND, ACTIVE-CONTROL STUDY OF CPI 0610 AND RUXOLITINIB VS. 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. [1] [2]. In: Clinical Lymphoma, Myeloma and Leukemia, Vol. The maximum decline in the platelet count occurs around day 14, with recovery over the following 1-2 week break from treatment. 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). 365. Constellation is driving development of the BET inhibitor CPI-0610 for the treatment of myelofibrosis as well as the EZH2 inhibitors CPI-1205 and CPI0209 for the treatment of metastatic castration. As previously reported at ASH 2020, 42 of 63 evaluable patients (67%) achieved a ≥35%. V126. MANIFEST Trial of CPI-0610. CPI-0610 is a small molecule inhibitor of bromodomain and extra-terminal (BET) proteins. 39), all of which have undergone phase I. 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. 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. com) was kept as a stock solution (10mg/ml) in DMSO (Sigma-Aldrich) and prepared and stored in. 35. 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. 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. Products with only one mechanism of action are approved. Pacritinib in Patients With Primary Myelofibrosis, Post Polycythemia Vera Myelofibrosis, or Post-Essential Thrombocythemia Myelofibrosis. Methods: MANIFEST (ClinicalTrails. We further show that CPI-0610 inhibits MM cell growth in the presence of cytokines and when co-cultured with bone marrow stromal cells. 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. 37. METHODS MANIFEST (ClinicalTrails. Between September 2013 and March 2015 44 patients had been enrolled and treated at doses of 6, 12, 24, 48, 80, 120, 170. 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. 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. Clear anti-tumor activity was observed in. BET Inhibitor CPI-0610 is well tolerated and induces responses in diffuse large B-cell lymphoma and follicular lymphoma: preliminary analysis of an ongoing. Go to. 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. CPI-0209, a second-generation enhancer of zeste homolog 2 (EZH2) inhibitor, in Phase 2 development for hematological malignancies and solid tumors by Constellation. Additionally, CPI-0610 decreased BRD4 and c-Myc expressions and affected MAPK, JAK/STAT, and AKT signalling pathways in human DLBCL cells. Like ruxolitinib failure, there is also no uniformly accepted. CPI-0610. 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. 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.