- |||||||||| ASXL1 Mutations in AML Are Associated with a Distinct Epigenetic State Which Highlights Vulnerabilities to Specific Epigenetic-Targeted Agents (Halls G-H (San Diego Convention Center)) - Nov 6, 2024 - Abstract #ASH2024ASH_5817;
Notably, compared to parental cells, OCIAML3 ASXL1 Y591* cells exhibited reduced sensitivity to standard anti-AML chemotherapeutic agents, including cytarabine, etoposide and daunorubicin...Our findings also demonstrate and confirm that mtASXL1-expressing AML cells exhibited increased sensitivity to BETi (pelabresib or birabresib)...Importantly, in the NSG mice engrafted with luciferized OCIAML3 ASXL1 Y591*, monotherapy with NEO2734 (5 mg/kg QD), pelabresib (30 mg/kg QD) or SEL120-34A (40 mg/kg QD), compared to vehicle control, significantly reduced AML burden. Collectively these findings highlight previously uncharacterized biologic effects of the presence of mtASXL1 and support the rationale for further evaluating AML therapies incorporating BETi, HAT-BETi or inhibitor of mediator kinase.
- |||||||||| pelabresib (DAK539) / Novartis
Enrollment open, Trial completion date, Trial primary completion date: An Extension Study for Patients Previously Enrolled in Studies with Pelabresib (clinicaltrials.gov) - Oct 30, 2024
P3, N=50, Recruiting,
Collectively these findings highlight previously uncharacterized biologic effects of the presence of mtASXL1 and support the rationale for further evaluating AML therapies incorporating BETi, HAT-BETi or inhibitor of mediator kinase. Not yet recruiting --> Recruiting | Trial completion date: Jun 2024 --> Jun 2029 | Trial primary completion date: Jun 2024 --> Jun 2029
- |||||||||| MODULE 4: Future Directions in the Management of MF (Manchester Grand Hyatt San Diego, Seaport Ballroom EFGH; In-Person; Virtual) - Oct 5, 2024 - Abstract #ASH2024ASH_130;
PELA+RUX significantly reduced splenomegaly, with a trend toward reduced TSS at W24, and improved anemia at W24 and W48 compared with PBO+RUX in JAKi-na This program is supported by educational grants from CTI BioPharma, a Sobi Company, Geron Corporation, GSK, Incyte Corporation and Karyopharm Therapeutics.Mechanism of antitumor activity of navitoclax and biological rationale for its evaluation for MF Available efficacy and safety findings from the Phase III TRANSFORM-1 study of navitoclax in combination with ruxolitinib versus ruxolitinib alone for patients with previously untreated MF Potential role of navitoclax in the up-front setting and ongoing evaluation for relapsed/refractory (R/R) disease in the Phase III TRANSFORM-2 study Rationale for the evaluation of BET inhibitors for MF; updated findings from the Phase III MANIFEST-2 study combining pelabresib to ruxolitinib for JAK inhibitor-na
- |||||||||| Jakafi (ruxolitinib) / Incyte, pelabresib (CPI-0610) / Novartis
Pelabresib Plus Ruxolitinib Combination Therapy in JAK Inhibitor-Na (LEVEL 3, HALL B3) - Aug 30, 2024 - Abstract #SOHO2024SOHO_630;
P3
This program is supported by educational grants from CTI BioPharma, a Sobi Company, Geron Corporation, GSK, Incyte Corporation and Karyopharm Therapeutics.Mechanism of antitumor activity of navitoclax and biological rationale for its evaluation for MF Available efficacy and safety findings from the Phase III TRANSFORM-1 study of navitoclax in combination with ruxolitinib versus ruxolitinib alone for patients with previously untreated MF Potential role of navitoclax in the up-front setting and ongoing evaluation for relapsed/refractory (R/R) disease in the Phase III TRANSFORM-2 study Rationale for the evaluation of BET inhibitors for MF; updated findings from the Phase III MANIFEST-2 study combining pelabresib to ruxolitinib for JAK inhibitor-na Pelabresib may enhance clinical responses to ruxolitinib by further reducing JAK2 VAF levels and decreasing NF-?B
- |||||||||| Jakafi (ruxolitinib) / Incyte, pelabresib (CPI-0610) / Novartis
Safety and Efficacy of Pelabresib in Combination With Ruxolitinib for JAK Inhibitor-Na (LEVEL 3, HALL B3) - Aug 30, 2024 - Abstract #SOHO2024SOHO_629;
P3
Pelabresib may enhance clinical responses to ruxolitinib by further reducing JAK2 VAF levels and decreasing NF-?B Pelabresib+ruxolitinib significantly reduced splenomegaly, with numerically smaller TSS at W24, and improved anemia at W24 and W48 compared with placebo+ruxolitinib in JAKi-na
- |||||||||| Review, Journal: Advances in pharmacotherapy for myelofibrosis: what is the current state of play? (Pubmed Central) - Jun 7, 2024
Pelabresib+ruxolitinib significantly reduced splenomegaly, with numerically smaller TSS at W24, and improved anemia at W24 and W48 compared with placebo+ruxolitinib in JAKi-na Nowadays three more JAKi, fedratinib, pacritinib, and momelotinib, are available for both ruxolitinib-resistant and na
- |||||||||| Jakafi (ruxolitinib) / Incyte, pelabresib (DAK539) / Novartis
Trial completion date: Phase 3 Study of Pelabresib (CPI-0610) in Myelofibrosis (MF) (MANIFEST-2) (clinicaltrials.gov) - Mar 15, 2024
P3, N=430, Active, not recruiting,
PELA+RUX significantly and durably reduced splenomegaly, with a trend toward reduced TSS, and improved anemia and BMF at Wk 24 compared with PBO+RUX in JAKi treatment-na Trial completion date: Dec 2026 --> Dec 2027
- |||||||||| Jakafi (ruxolitinib) / Novartis, Incyte, pelabresib (CPI-0610) / MorphoSys, navitoclax (ABT 263) / AbbVie
Journal, Monotherapy: New drugs in myelofibrosis: Critical assessment of additional value to monotherapy with JAK inhibitors. (Pubmed Central) - Feb 9, 2024
The favorable safety profile supports the ongoing pivotal study of pelabresib in patients with myelofibrosis using the recommended phase 2 dose of 125?mg tablet QD.CLINICAL TRIAL REGISTRATION: NCT02158858. Ruxolitinib in combination with navitoclax or pelabresib in myelofibrosis: activity in JAKi-na
- |||||||||| Jakafi (ruxolitinib) / Novartis, Incyte, pelabresib (CPI-0610) / MorphoSys
Pelabresib in Combination with Ruxolitinib for Janus Kinase Inhibitor Treatment-Na (Marriott Marquis - Pacific Ballroom) - Nov 3, 2023 - Abstract #ASH2023ASH_3312;
P1/2, P3
As DIPSS Int-1 pts have been excluded or underrepresented in prior randomized trials in MF, MANIFEST-2 will also provide important insights in assessing the benefits of starting treatment at an earlier stage of the disease. Primary results from the pivotal Phase 3 MANIFEST-2 trial of pela and rux versus placebo and rux in JAKi treatment-na
- |||||||||| Pre-Clinical Efficacy of CDK7 Inhibitor-Based Combinations in Cellular Models of Advanced Myeloproliferative Neoplasms (MPN) Transformed to AML (SDCC - Halls G-H) - Nov 3, 2023 - Abstract #ASH2023ASH_2205;
Treatment with JAK inhibitor (JAKi), e.g., ruxolitinib, venetoclax or hypomethylating agents alone or in combination are ineffective in improving the poor survival in MPN-sAML...Present studies demonstrate that treatment with ATP-competitive, covalent CDK7 inhibitors (CDK7i) SY-1365, and clinical grade SY-5609, dose-dependently (20 to 250 nM) increased % G1 while reducing the % of cell-cycle S phase SET2 and HEL cells...SY-5609 treatment also exerted synergistic lethality with the BETi pelabresib or BD2-selective BETi ABBV-744 or the CBP/p300 inhibitor GNE-049 in MPN-sAML cells...Additionally, compared to each drug or vehicle control, co-treatment with SY-5609 and OTX015 (30 mg/kg/day by oral gavage) reduced more MPN-sAML burden and significantly improved survival in a HEL-Luc/GFP xenograft model without inducing toxicity. These findings demonstrate promising preclinical activity of CDK7 inhibition against the cellular models of MPN-sAML, supporting the rationale to further evaluate in vivo efficacy of CDK7i-based combinations against advanced MPN with excess blasts or MPN-sAML.
- |||||||||| Jakafi (ruxolitinib) / Incyte, pelabresib (DAK539) / Novartis
Trial primary completion date: Phase 3 Study of Pelabresib (CPI-0610) in Myelofibrosis (MF) (MANIFEST-2) (clinicaltrials.gov) - Sep 25, 2023
P3, N=431, Active, not recruiting,
These findings demonstrate promising preclinical activity of CDK7 inhibition against the cellular models of MPN-sAML, supporting the rationale to further evaluate in vivo efficacy of CDK7i-based combinations against advanced MPN with excess blasts or MPN-sAML. Trial primary completion date: Mar 2024 --> Aug 2023
- |||||||||| Jakafi (ruxolitinib) / Novartis, Incyte, pelabresib (CPI-0610) / MorphoSys
Journal, Monotherapy: Matching-adjusted indirect comparison of pelabresib/ruxolitinib combination vs JAKi monotherapy in myelofibrosis. (Pubmed Central) - Sep 18, 2023
P1/2
Janus kinase inhibitors (JAKis) ruxolitinib, fedratinib, and pacritinib are the current standard of care in symptomatic myelofibrosis (MF)...Given the absence of a head-to-head clinical comparison between JAKi monotherapy and JAKi with BETi combination therapy, we performed an unanchored matching-adjusted indirect comparison analysis to adjust for differences between studies and allow for the comparison of SVR35, TSS50, and TSS measured at several timepoints in arm 3 of MANIFEST (pelabresib with ruxolitinib in JAKi treatment-naive patients with MF), with data from the following JAKi monotherapy studies in JAKi treatment-naive patients: COMFORT-I and COMFORT-II (ruxolitinib), SIMPLIFY-1 (ruxolitinib and momelotinib), and JAKARTA (fedratinib)...Improvements in TSS were observed as early as Week 12 and were durable. These results indicate that pelabresib with ruxolitinib may have a potentially higher efficacy than JAKi monotherapy in JAKi treatment-na
- |||||||||| MODULE 3: Future Directions in the Management of MF (LEVEL 3, MEAL THEATER 1; Virtual) - Aug 11, 2023 - Abstract #SOHO2023SOHO_338;
This activity is supported through independent medical education grants from Bristol Myers Squibb, CTI Biopharma Corp, and GlaxoSmithKline. Mechanism of antitumor activity of navitoclax and biological rationale for its evaluation in patients with MF, Published research with navitoclax alone and in combination with ruxolitinib for MF; ongoing Phase III studies, Rationale for the inhibition of BET proteins in patients with MF; mechanisms of action of pelabresib and BMS-986158, Early clinical trial findings and ongoing research with BET inhibitors as monotherapy and in combination with JAK2 inhibitors for MF, Mechanism of action of, available data with and ongoing evaluation of luspatercept as monotherapy or combined with a JAK2 inhibitor for patients with MF and anemia; current role, if any, Published activity and safety data with and ongoing investigation of other novel agents and strategies (eg, bomedemstat, zilurgisertib, selinexor, navtemadlin) in MF,
- |||||||||| Current and Emergent Therapies for ET (Level 3, Room 332C) - Jun 21, 2023 - Abstract #SOHO2023SOHO_23;
P1, P1/2,
Mechanism of antitumor activity of navitoclax and biological rationale for its evaluation in patients with MF, Published research with navitoclax alone and in combination with ruxolitinib for MF; ongoing Phase III studies, Rationale for the inhibition of BET proteins in patients with MF; mechanisms of action of pelabresib and BMS-986158, Early clinical trial findings and ongoing research with BET inhibitors as monotherapy and in combination with JAK2 inhibitors for MF, Mechanism of action of, available data with and ongoing evaluation of luspatercept as monotherapy or combined with a JAK2 inhibitor for patients with MF and anemia; current role, if any, Published activity and safety data with and ongoing investigation of other novel agents and strategies (eg, bomedemstat, zilurgisertib, selinexor, navtemadlin) in MF, HU and Peg-IFN were compared in a phase 3 study (MPD-RC 112) in patients with ET and polycythemia vera (PV), which resulted in similar rates of complete response and thrombotic events at 12 months.7 With longer treatment, Peg-IFN has demonstrated improved molecular responses in both ET and PV, though the clinical implications of molecular response in these settings are not yet clear.7
- |||||||||| pelabresib (CPI-0610) / MorphoSys
Review, Journal: Pelabresib (CPI-0610): An Exciting Novel Drug for the Treatment of Myelofibrosis. (Pubmed Central) - May 17, 2023
Based on these encouraging results, the Phase III MANIFEST-2 study was initiated. Pelabresib offers a much-needed innovative treatment approach for patients with MF, either as monotherapy or in combination with the current standard of care.
- |||||||||| JQ-1 / Roche, pelabresib (CPI-0610) / MorphoSys
Role of BRD4 signaling in the pathogenesis of hidradenitis suppurativa (HS) () - Mar 4, 2023 - Abstract #ISID2023ISID_1742;
Similarly, HS epithelial cells in culture treated with BRD4 inhibitor, JQ1, show attenuated transcription of these genes. In summary, our data show a role of BRD4 signaling in HS pathogenesis and BRD4 inhibitors could provide a novel therapeutic strategy for the management of this debilitating disease.
- |||||||||| pelabresib (DAK539) / Novartis
Trial completion date, Trial primary completion date, Metastases: Study Evaluating Food Effect and QTc in Patients With Advanced Malignancies (clinicaltrials.gov) - Jan 31, 2023
P1, N=32, Recruiting,
In summary, our data show a role of BRD4 signaling in HS pathogenesis and BRD4 inhibitors could provide a novel therapeutic strategy for the management of this debilitating disease. Trial completion date: Mar 2023 --> Nov 2023 | Trial primary completion date: Dec 2022 --> Mar 2023
- |||||||||| Jakafi (ruxolitinib) / Incyte, pelabresib (DAK539) / Novartis
Enrollment closed, Trial completion date, Trial primary completion date: MANIFEST: A Phase 2 Study of CPI-0610 With and Without Ruxolitinib in Patients With Myelofibrosis (clinicaltrials.gov) - Dec 7, 2022
P1/2, N=341, Active, not recruiting,
Trial completion date: Mar 2023 --> Nov 2023 | Trial primary completion date: Dec 2022 --> Mar 2023 Recruiting --> Active, not recruiting | Trial completion date: Dec 2022 --> Dec 2024 | Trial primary completion date: Dec 2022 --> Dec 2023
- |||||||||| Review, Journal: Anemia in myelofibrosis: current and emerging treatment options. (Pubmed Central) - Nov 5, 2022
This review summarizes current and emerging treatments for anemia in MF, including luspatercept and KER-050 (transforming growth factor-β ligand traps), momelotinib and pacritinib (JAK inhibitors), pelabresib (a bromodomain extra-terminal domain inhibitor), PRM-151 (an antifibrotic agent), imetelstat (a telomerase inhibitor), and navitoclax (a BCL-2/BCL-xL inhibitor). Therapeutic combinations with ruxolitinib may offer another treatment approach.
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