A Randomized Phase II Trial of Oral Decitabine and Cedazuridine and Venetoclax Compared With Oral Decitabine and Cedazuridine, Venetoclax, and Enasidenib for Newly Diagnosed Older Adults With IDH2 Mutant Acute Myeloid Leukemia: A MyeloMATCH Treatment Trial

This phase II MyeloMATCH treatment trial studies how well ASTX727 and venetoclax plus enasidenib works compared to ASTX727 and venetoclax alone for the treatment of older patients with newly diagnosed acute myeloid leukemia (AML) or younger patients who are considered unfit for standard treatment, and who have an abnormal change (mutation) in the IDH2 gene. This gene mutation can cause AML to grow and spread. This trial is being done to see if adding enasidenib to the usual treatment can help more patients with the IDH2 gene get rid of AML. Cedazuridine is in a class of medications called cytidine deaminase inhibitors. It prevents the breakdown of decitabine, making it more available in the body so that decitabine will have a greater effect. Decitabine is in a class of medications called hypomethylation agents. It works by helping the bone marrow produce normal blood cells and by killing abnormal cells in the bone marrow. Venetoclax is in a class of medications called B-cell lymphoma-2 (BCL-2) inhibitors. It may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. Enasidenib works by stopping the growth and spread of tumor cells that have the IDH2 mutation. Giving ASTX727 and venetoclax plus enasidenib may work better in treating AML patients with the IDH2 mutation.

Start Date03 Feb 2025

Sponsor / Collaborator

National Cancer Institute

NCT06661915 / Not yet recruitingPhase 2IIT

A Randomized Phase 2 Trial of ASTX727 +/- Iadademstat in Accelerated/Blast-Phase Philadelphia Chromosome-Negative Myeloproliferative Neoplasms (MPNs)

This phase II trial compares the effect of ASTX727 in combination with iadademstat to ASTX727 alone in treating patients with accelerated or blast phase Philadelphia chromosome negative myeloproliferative neoplasms (MPNs). ASTX727 is a combination of two drugs, cedazuridine and decitabine. Cedazuridine is in a class of medications called cytidine deaminase inhibitors. It prevents the breakdown of decitabine, making it more available in the body so that decitabine will have a greater effect. Decitabine is in a class of medications called hypomethylation agents. It works by helping the bone marrow produce normal blood cells and by killing abnormal cells in the bone marrow. Iadademstat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving ASTX727 in combination with iadademstat may be more effective than ASTX727 alone in treating patients with accelerated or blast phase Philadelphia chromosome negative MPNs.

Start Date31 Jan 2025

Sponsor / Collaborator

National Cancer Institute

NCT06284460 / WithdrawnPhase 1/2IIT

Phase I/II Study of a Combination of Decitabine and Cedazuridine (ASTX727) and ASTX029, an ERK Inhibitor, for Patients With RAS Pathway Mutant Myelodysplastic Syndromes and Myelodysplastic/Myeloproliferative Neoplasms

The goal of Part 1 of this clinical research study is to find the highest tolerable dose of ASTX029 that can be given in combination with ASTX727 to participants who have RAS-mutant MDS or MDS/MPN. The goal of Part 2 of this clinical research study is to learn if the dose of ASTX029 found in Part 1 can help to control the disease when used in combination with ASTX727.

Start Date31 Jan 2025

Sponsor / Collaborator

The University of Texas MD Anderson Cancer Center

100 Clinical Results associated with Decitabine/Cedazuridine

100 Translational Medicine associated with Decitabine/Cedazuridine

100 Patents (Medical) associated with Decitabine/Cedazuridine

Literatures (Medical) associated with Decitabine/Cedazuridine

01 Nov 2024·British Journal of Haematology

Oral decitabine/cedazuridine versus intravenous decitabine for acute myeloid leukaemia: A randomised, crossover, registration, pharmacokinetics study

Article

Author: Keer, Harold ; Platzbecker, Uwe ; Arnan, Montserrat ; Lunghi, Monia ; Krauter, Jürgen ; Geissler, Klaus ; Sano, Yuri ; Metzelder, Stephan K. ; Fracchiolla, Nicola Stefano ; Novák, Jan ; Lübbert, Michael ; Koristek, Zdenek ; Illes, Arpad ; Rodríguez‐Macías, Gabriela ; Oganesian, Aram ; Mayer, Jiří ; del Castillo, Teresa Bernal ; Santini, Valeria ; Keating, Mary‐Margaret

SummaryThis study compared decitabine exposure when administered IV (DEC‐IV) at a dose of 20 mg/m2 for 5‐days with orally administered decitabine with cedazuridine (DEC‐C), as well as the clinical efficacy and safety of DEC‐C in patients with acute myeloid leukaemia (AML) who were ineligible for intensive induction chemotherapy. In all, 89 patients were randomised 1:1 to DEC‐IV or oral DEC‐C (days 1–5 in a 28‐day treatment cycle), followed by 5 days of the other formulation in the next treatment cycle. All patients received oral DEC‐C for subsequent treatment cycles until treatment discontinuation. Equivalent systemic decitabine exposures were demonstrated (5‐day area under the curve ratio between the two decitabine formulations of 99.64 [90% confidence interval 91.23%, 108.80%]). Demethylation rates also were similar (≤1.1% difference). Median overall survival (OS), clinical response and safety profile with oral DEC‐C were consistent with those previously observed with DEC‐IV. Next‐generation sequencing was performed to identify molecular abnormalities that impact OS and TP53 mutations were associated with a poor outcome. These findings support the use of oral DEC‐C in patients with AML.

01 Sep 2024·Clinical Lymphoma Myeloma and Leukemia

Oral Decitabine/Cedazuridine Is an Effective Ambulatory Therapy for Patients With Myelofibrosis Refractory to JAK2 Inhibitor Therapy

Article

Author: Sivakumar, Ganesh ; Handa, Shivani ; Srisuwananukorn, Andrew ; Tremblay, Douglas ; Dueck, Amylou ; Kremyanskaya, Marina ; Mascarenhas, John O ; Ginzburg, Yelena ; Hoffman, Ronald

BACKGROUNDOutcomes are dismal for patients with myelofibrosis (MF) who are no longer responsive to JAK2 inhibitors (JAKi) and/or have increasing blast cell numbers. Although prior reports have suggested the benefits of intravenous decitabine (DAC) combined with ruxolitinib for patients with Myeloproliferative Neoplasm (MPN) accelerated/blast phase (AP/BP), decitabine-cedazuridine (DEC-C), an oral fixed-dose combination providing equivalent pharmacokinetic exposure, has not been evaluated in MF.METHODSWe conducted a retrospective analysis of 14 patients with high-risk MF refractory to ruxolitinib or MPN-AP (10-19% blasts) treated with DEC-C +/- JAKi at Mount Sinai Hospital from 2021 to 2024.RESULTSThe cohort was elderly (median age,76 years) and almost uniformly possessed high risk mutations with 13 of the 14 patients progressing on JAKi therapy. With a median follow-up of 9.4 months, the median overall survival (OS) was 29 months for the entire cohort. Median OS was 10.8 months for MPN-AP and was not reached for ruxolitinib refractory MF patients. All patients (n = 9) receiving > 4 cycles of DEC-C had clinical benefit exemplified by a reduction in blast cell numbers, spleen size, and lack of progression to MPN-BP (78%). Furthermore, 3/14 patients proceeded to allogeneic stem cell transplant. Myelosuppression was a common adverse event which was managed by reducing the number of days of administration of DEC-C from 5 to 3 per cycle.CONCLUSIONSThis report demonstrates the feasibility, tolerability, and clinical benefit of an exclusively ambulatory regimen for high-risk, elderly patients with advanced MF which warrants further evaluation in a prospective clinical trial.

01 Apr 2024·The Lancet Haematology

Oral decitabine and cedazuridine plus venetoclax for older or unfit patients with acute myeloid leukaemia: a phase 2 study

Article

Author: Konopleva, Marina ; Ravandi, Farhad ; Kadia, Tapan ; Montalban-Bravo, Guillermo ; Kornblau, Steven ; Rausch, Caitlin R ; Issa, Ghayas ; Huang, Xuelin ; Pierce, Sherry ; DiNardo, Courtney D ; Kantarjian, Hagop ; Short, Nicholas ; Garcia-Manero, Guillermo ; Jain, Nitin ; Islam, Rabiul ; Daver, Naval ; Montalbano, Kathryn ; Alvarado, Yesid ; Abuasab, Tareq ; Yilmaz, Musa ; Jabbour, Elias ; Maiti, Abhishek ; Masarova, Lucia ; Bataller, Alex ; Bazinet, Alexandre

BACKGROUNDHypomethylating agents combined with venetoclax are effective regimens in patients with acute myeloid leukaemia who are ineligible for intensive chemotherapy. Decitabine and cedazuridine (ASTX727) is an oral formulation of decitabine that achieves equivalent area-under-curve exposure to intravenous decitabine. We performed a single centre phase 2 study to evaluate the efficacy and safety of ASTX727 plus venetoclax.METHODSThis study enrolled patients with newly diagnosed (frontline treatment group) acute myeloid leukaemia who were ineligible for intensive chemotherapy (aged ≥75 years, an Eastern Cooperative Oncology Group [ECOG] performance status of 2-3, or major comorbidities) or relapsed or refractory acute myeloid leukaemia. Being aged 18 years or older and having an ECOG performance status of 2 or less were requirements for the relapsed or refractory disease treatment cohort, without any limits in the number of previous lines of therapy. Treatment consisted of ASTX727 (cedazuridine 100 mg and decitabine 35 mg) orally for 5 days and venetoclax 400 mg orally for 21-28 days in 28-day cycles. The primary outcome was overall response rate of ASTX727 plus venetoclax. Living patients who have not completed cycle one were not evaluable for response. Safety was analysed in all patients who started treatment. This study was registered on ClinicalTrials.gov (NCT04746235) and is ongoing. The data cutoff date for this analysis was Sept 22, 2023.FINDINGSBetween March 16, 2021, and Sept 18, 2023, 62 patients were enrolled (49 frontline and 13 relapsed or refractory) with a median age of 78 years (IQR 73-82). 36 (58%) were male; 53 (85%) were White, 4 (6%) Black, 2 (3%) Asian and 3 (5%) other or did not answer. 48 (77%) of 62 patients were European LeukemiaNet 2022 adverse risk, 24 (39%) had antecedent myelodysplastic syndromes, 12 (19%) had previously failed a hypomethylating agent, ten (16%) had therapy-related acute myeloid leukaemia, and 11 (18%) had TP53 mutations. The median follow-up time was 18·3 months (IQR 8·8-23·3). The overall response rate was 30 (64%) of 47 patients (95% CI 49-77) in frontline cohort and six (46%) of 13 patients (19-75) in relapsed or refractory cohort. The most common grade 3 or worse treatment-emergent adverse events were febrile neutropenia in 11 (18%) of 62 patients, pneumonia in eight (13%), respiratory failure in five (8%), bacteraemia in four (6%), and sepsis in four (6%). Three deaths occurred in patients in remission (one sepsis, one gastrointestinal haemorrhage, and one respiratory failure) and were potentially treatment related.INTERPRETATIONASTX727 plus venetoclax is an active fully oral regimen and safe in most older or unfit patients with acute myeloid leukaemia. Our findings should be confirmed in larger multicentric studies.FUNDINGMD Anderson Cancer Center Support Grant, Myelodysplastic Syndrome/Acute Myeloid Leukaemia Moon Shot, Leukemia SPORE, Taiho Oncology, and Astex Pharmaceuticals.

News (Medical) associated with Decitabine/Cedazuridine

05 Nov 2024

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Syndax Announces Revumenib Abstracts to Be Presented at the 66th ASH Annual Meeting

– New monotherapy and combination data in acute leukemia further highlight revumenib's compelling clinical profile – – 64% ORR (62/97) in expanded dataset of patients with R/R KMT2Ar acute leukemia in Ph 2 AUGMENT-101 pivotal cohort – – 88% ORR (23/26) in SAVE trial testing revumenib, venetoclax and decitabine/cedazuridine combination in R/R AML – WALTHAM, Mass., Nov. 5, 2024 /PRNewswire/ -- Syndax Pharmaceuticals (Nasdaq:SNDX) today announced that multiple abstracts evaluating revumenib, an oral small molecule menin inhibitor, have been accepted for oral presentation at the 66th American Society of Hematology (ASH) Annual Meeting being held in San Diego, California, December 7-10, 2024. The oral presentations will highlight data evaluating the safety and efficacy of revumenib as monotherapy or in combination for the treatment of patients with acute leukemias. Copies of the abstracts are now available online on the ASH website. "The data being presented this year at ASH demonstrate Syndax's commitment to develop revumenib as a practice-changing therapy for adult and pediatric patients with acute leukemias," said Neil Gallagher, M.D., Ph.D., President, Head of Research and Development at Syndax. "We look forward to presenting these data and continuing to rapidly advance the development of revumenib for adult and pediatric acute leukemia patients who may respond to menin inhibition, such as patients with KMT2Ar or mNPM1 alterations." The FDA has granted Priority Review for the New Drug Application (NDA) for revumenib for the treatment of adult and pediatric patients with relapsed or refractory (R/R) KMT2A-rearranged (KMT2Ar) acute leukemia. The NDA is being reviewed under the FDA's Real-Time Oncology Review Program (RTOR) and has a Prescription Drug User Fee Act (PDUFA) target action date of December 26, 2024. In March 2024, the Company announced the completion of enrollment in the final AUGMENT-101 pivotal trial cohort in patients with R/R mutant nucleophosmin (mNPM1) acute myeloid leukemia (AML). Topline data is expected in the fourth quarter of 2024 and could support a supplemental NDA filing for revumenib in R/R mNPM1 AML in the first half of 2025. The Company will host an in-person investor event, along with a live webcast, to discuss the latest data supporting the Company's pipeline on Monday, December 9, 2024 at 7:00 a.m. PT/ 10:00 a.m. ET during the ASH Annual Meeting. The live webcast will be available on the Investor section of the Company's website at , where a replay of the event will also be available for a limited time. Overview of Abstracts Accepted for Presentation at 66th ASH Annual Meeting New Data from Phase 2 Portion of the AUGMENT-101 Trial of Revumenib in R/R KMT2Ar Acute Leukemia Syndax previously presented positive data from the protocol-defined interim analysis of the pivotal Phase 2 portion of the AUGMENT-101 trial of revumenib in adult and pediatric patients with R/R KMT2Ar AML and acute lymphoid leukemia (ALL). The trial met its primary endpoint at the protocol-defined interim analysis with a complete remission (CR) or a CR with partial hematological recovery (CRh) rate of 23% (13/57; 95% CI: 12.7-35.8; one-sided p-value = 0.0036) among the 57 efficacy evaluable patients in the KMT2Ar cohort as of the July 2023 data cutoff (DCO) date. This updated analysis (DCO: February 2024) includes 116 patients in the Phase 2 safety population (an increase of 22 patients who were enrolled and treated with revumenib after the previous July 2023 DCO), and 97 patients in the Phase 2 efficacy population (an increase of 40 patients who were newly enrolled or who reached sufficient follow-up after the previous July 2023 DCO). Within this larger efficacy population of patients with R/R KTM2Ar acute leukemia from the Phase 2 portion of the AUGMENT-101 trial (n=97), 23% (22/97) of patients achieved CR/CRh (95% CI: 15%-32%). The CRc rate was 42% (95% CI: 32%-53%) and the ORR was 64% (95% CI: 54%-73%). Among patients with measurable residual disease (MRD) results available, 61% (11/18) of CR/CRh responders and 58% (21/36) of CRc responders achieved MRD negativity. Of the 62 patients who achieved ORR, 34% (21/62) proceeded to hematopoietic stem cell transplantation (HSCT). Nine patients resumed revumenib post-HSCT. The median duration of response among the 22 CR/CRh responders was 6.4 months (95% CI: 1.9 mo-NR). Of note, among the 13 CR/CRh responders from the interim analysis, the median duration of CR/CRh extended to 13.0 months (95% CI: 3.4 mo–NR) after seven additional months of follow-up (DCO: February 2024). Five of these patients remained in follow-up with no relapse or death as of the data cutoff. Within the larger safety population of patients with R/R KTM2Ar acute leukemia from the Phase 2 portion of the AUGMENT-101 trial (n=116), revumenib was generally well tolerated and the safety profile was consistent with the Company's previously reported data. Treatment-emergent adverse events (TEAEs) and treatment-related adverse events (TRAEs) leading to treatment discontinuation were low at 14% (16/116) and 5% (6/116), respectively. The most common Grade ≥3 TEAEs were consistent with previously reported data. Grade 3 treatment-emergent differentiation syndrome (DS) was observed in 14% (16/116) of patients and one patient (1%) experienced a Grade 4 DS. Grade 3 treatment-emergent QTc prolongation was observed in 13% (15/116) of patients, with no Grade 4 or Grade 5 events. Details for the oral presentation are as follows: Abstract Number: 211 Title: Updated Results and Longer Follow-up from the AUGMENT-101 Phase 2 Study of Revumenib in All Patients with Relapsed or Refractory (R/R) KMT2Ar Acute Leukemia Presenter: Ibrahim Aldoss, M.D. Session Name: 616. Acute Myeloid Leukemias: Investigational Drug and Cellular Therapies: Menin Inhibitors in AML Session Date: Saturday, December 7, 2024 Session Time: 2:00 PM - 3:30 PM Presentation Time: 2:00 PM New Results from Phase 1/2 SAVE Trial of Revumenib in Combination with Venetoclax and Decitabine/Cedazuridine in R/R AML The Phase 1/2 SAVE trial is an investigator-sponsored trial testing an all-oral regimen of revumenib, venetoclax and the hypomethylating agent (HMA) ASTX727 (decitabine/cedazuridine) in children and adults with R/R AML or mixed-lineage acute leukemia (MPAL) harboring either KMT2Ar, NUP98r or mNPM1 alterations. As of the latest data cutoff (July 2024), 26 patients were enrolled in the trial. The median age was 35 years (range: 12-79). At baseline, 11 patients (42%) had KMT2Ar, 10 patients (38%) had mNPM1, and five patients (20%) had NUP98r. The median prior lines of therapy was three (range: 1-5); 17 patients (65%) had prior venetoclax, 11 (42%) had prior HSCT, and two had received a prior menin inhibitor. The all-oral combination resulted in high rates of remission in patients with R/R KMT2Ar, mNPM1, or NUP98r AML. The ORR was 88% (23/26), with a CR/CRh rate of 58% (15/26). MRD status was available in 14 of the 15 patients who achieved a CR/CRh, 93% (13/14) of whom were MRD negative. In patients with MRD status available who achieved a response, 74% (17/23) were MRD negative. Twelve patients (46%) received HSCT following this combination, with three patients resuming revumenib post-HSCT. With a median follow-up of 6.6 months, the 6-month relapse-free survival was 59% (95% CI: 26%-81%) and overall survival was 74% (95% CI: 39%-83%). The median duration of response in those with CR/CRh was not reached. Two patients had completed maintenance post-HSCT and remained in remission at the time of the data cutoff. The combination was generally well tolerated. The most common (>20%) Grade ≥3 TEAEs were febrile neutropenia (46%) and lung infection (42%), while Grade ≥3 TRAEs (any agent) were thrombocytopenia (12%), neutropenia (8%), QT prolongation (8%), and DS (4%). No patient experienced Grade 4 or 5 DS, and all DS events were resolved with steroids. In addition to the R/R cohort, a frontline cohort is now enrolling patients. Details for the oral presentation are as follows: Abstract Number: 216 Title: Phase I/II Study of the All-Oral Combination of Revumenib (SNDX-5613) with Decitabine/Cedazuridine (ASTX727) and Venetoclax (SAVE) in R/R AML Presenter: Ghayas C. Issa, M.D. Session Name: 616. Acute Myeloid Leukemias: Investigational Drug and Cellular Therapies: Menin Inhibitors in AML Session Date: Saturday, December 7, 2024 Session Time: 2:00 PM - 3:30 PM Presentation Time: 3:15 PM Initial Results from INTERCEPT Trial of Revumenib as Pre-Emptive Therapy for MRD Positive AML INTERCEPT is an investigator-sponsored platform trial evaluating the use of novel therapies, including revumenib, to target MRD and early relapse in AML. This proof-of-concept trial is exploring whether targeting MRD in patients with progressive AML may be an effective approach to maintaining patients in first (CR1) or second remission (CR2). As of the July 2024 data cut off, nine patients with MRD relapse (eight with mNPM1 and one with KMT2Ar) were enrolled in the safety cohort and received revumenib. The median age was 62 years; seven were in CR1, two in CR2; three had prior venetoclax exposure and six had prior intensive therapy. In a preliminary analysis of the eight mNPM1 patients who received revumenib, five of the eight patients had MRD reduction, including three who achieved MRD negativity within six cycles. In the nine-patient safety cohort, dose-limiting toxicities included reversible Grade 3 QTc prolongation in two patients; neither de-escalation nor elimination were mandated and 276 mg of revumenib BID was therefore considered safe for further expansion. These data support revumenib's safety profile and activity in patients with mNPM1 MRD relapse. Details for the oral presentation are as follows: Abstract Number: 223 Title: Revumenib as Pre-emptive Therapy for Measurable Residual Disease in NPM1 mutated or KMT2A-rearranged Acute Myeloid Leukemia: A Domain of the Multi-Arm ALLG AMLM26 Intercept Platform trial Presenter: Sun Loo, M.B.B.S. Session Name: 619. Acute Myeloid Leukemias: Disease Burden and Minimal Residual Disease in Prognosis and Treatment: Measurable Residual Disease in AML in 2024 and Beyond Session Date: Saturday, December 7, 2024 Session Time: 2:00 PM - 3:30 PM Presentation Time: 2:00 PM About Revumenib Revumenib is an oral, small molecule inhibitor of the menin-KMT2A binding interaction that is being developed for the treatment of KMT2A-rearranged (KMT2Ar), also known as mixed lineage leukemia rearranged or MLLr, acute leukemias including acute lymphoid leukemia (ALL) and acute myeloid leukemia (AML), and mutant NPM1 AML. The Journal of Clinical Oncology published results from the Phase 2 AUGMENT-101 trial of revumenib in R/R KMT2Ar acute leukemia showing the trial met its primary endpoint. Revumenib was previously granted Orphan Drug Designation for the treatment of AML, ALL and acute leukemias of ambiguous lineage (ALAL) by the U.S. FDA and for the treatment of AML by the European Commission. The U.S. FDA also granted Fast Track designation to revumenib for the treatment of adult and pediatric patients with R/R acute leukemias harboring a KMT2A rearrangement or NPM1 mutation and Breakthrough Therapy Designation for the treatment of adult and pediatric patients with R/R acute leukemia harboring a KMT2A rearrangement. About Syndax Syndax Pharmaceuticals is a commercial-stage biopharmaceutical company developing an innovative pipeline of cancer therapies. Highlights of the Company's pipeline include revumenib, a selective menin inhibitor, and Niktimvo™ (axatilimab-csfr), an FDA-approved monoclonal antibody that blocks the colony stimulating factor 1 (CSF-1) receptor. Fueled by our commitment to reimagining cancer care, Syndax is working to unlock the full potential of its pipeline and is conducting several clinical trials across the continuum of treatment. For more information, please visit or follow the Company on X (formerly Twitter) and LinkedIn. Syndax Forward-Looking Statements This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Words such as "may," "will," "expect," "plan," "anticipate," "estimate," "intend," "believe" and similar expressions (as well as other words or expressions referencing future events, conditions or circumstances) are intended to identify forward-looking statements. These forward-looking statements are based on Syndax's expectations and assumptions as of the date of this press release. Each of these forward-looking statements involves risks and uncertainties. Actual results may differ materially from these forward-looking statements. Forward-looking statements contained in this press release include, but are not limited to, statements about the progress, timing, clinical development and scope of clinical trials, the reporting of clinical data for Syndax's product candidates, the acceptance of Syndax and its partners' products in the marketplace, sales, marketing, manufacturing and distribution requirements, and the potential use of our product candidates to treat various cancer indications and fibrotic diseases. Many factors may cause differences between current expectations and actual results, including: unexpected safety or efficacy data observed during preclinical or clinical trials; clinical trial site activation or enrollment rates that are lower than expected; changes in expected or existing competition; changes in the regulatory environment; failure of Syndax's collaborators to support or advance collaborations or product candidates; and unexpected litigation or other disputes. Other factors that may cause Syndax's actual results to differ from those expressed or implied in the forward-looking statements in this press release are discussed in Syndax's filings with the U.S. Securities and Exchange Commission, including the "Risk Factors" sections contained therein. Except as required by law, Syndax assumes no obligation to update any forward-looking statements contained herein to reflect any change in expectations, even as new information becomes available. References 1 Overall response rate includes CR, CRh, CRp, CRi, MLFS, and PR; Composite complete remission (CRc) includes CR, CRh, CRp, and CRi CR = Complete remission CRh = Complete remission with partial hematologic recovery CRp = Complete remission with incomplete platelet recovery CRi = Complete remission with incomplete count recovery MLFS = Morphologic leukemia-free state PR = Partial response Syndax Contact: Sharon Klahre [email protected] Tel 781.684.9827 SNDX-G SOURCE Syndax Pharmaceuticals, Inc. 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Clinical ResultPhase 2ASHPriority ReviewFast Track

12 Sep 2024

·www.globenewswire.com

Biosplice Therapeutics Announces Initiation of Acute Myeloid Leukemia (AML) and Myelodysplastic Syndromes (MDS) Trial Sponsored by the National Cancer Institute (NCI)

Biosplice expands its clinical candidate, cirtuvivint, as standalone treatment and combination therapy in patients with AML and MDS, representing next step in ongoing collaboration with the NCISAN DIEGO, Sept. 12, 2024 (GLOBE NEWSWIRE) -- Biosplice Therapeutics, Inc. (“Biosplice”), a clinical-stage biotechnology company pioneering advancements in small molecule inhibition of CDC-like kinases (CLK) and Dual-specificity tyrosine phosphorylation-regulated (DYRK) kinases, is pleased to announce that the U.S. Food and Drug Administration (FDA) has cleared the NCI-sponsored Investigational New Drug (IND) application for cirtuvivint. This small molecule inhibitor of CLK and DYRK kinases is in development for the treatment of hematological malignancies and solid tumors. This clearance allows for the initiation of a new clinical trial of cirtuvivint, both as a standalone treatment for patients with relapsed/refractory AML and MDS as well as in combination with ASTX727 for patients with frontline high-risk MDS. The clinical study (NCI protocol 10674, NCT06484062) will be sponsored by the NCI, part of the National Institutes of Health, with Dr. Maximilian Stahl from the Dana-Farber Cancer Institute serving as principal investigator. This trial will be conducted in participating centers of the NCI’s Experimental Therapeutics Clinical Trials Network including Dana-Farber Cancer Institute and Memorial Sloan Kettering Cancer Center. The study aims to enroll up to 52 patients and will be conducted under the Cooperative Research and Development Agreement (CRADA) executed between Biosplice and the NCI. “We are thrilled that the NCI has received FDA clearance to launch this groundbreaking new Phase 1 trial of cirtuvivint in liquid tumors, both as monotherapy and in combination with ASTX727,” stated Dr. Yusuf Yazici, Chief Medical Officer of Biosplice. “This milestone is a major step forward in our efforts to advance innovative treatments targeting CLKs and DYRKs. Given that dysregulated alternative splicing is commonly implicated in AML and MDS, cirtuvivint’s ability to regulate alternative splicing via CLK and DYRK inhibition may provide a promising new therapeutic pathway for patients. Based on compelling anti-tumor activity across both solid and liquid tumors in in vitro and in vivo models, as well as data from two prior Phase 1 trials in solid tumors, cirtuvivint promises to greatly improve outcomes for patients in these critical and underserved areas.” This milestone highlights the ongoing collaboration between Biosplice and the NCI’s Cancer Therapy Evaluation Program (CTEP) through the NCI Experimental Therapeutics (NCI-NExT) program. After extensive evaluation, cirtuvivint was chosen for inclusion by NCI in the NExT programs following a competitive review. NCI-NExT partners with external researchers and leading scientific experts to accelerate the development of the most promising and innovative therapies, guiding them from early-stage research through to regulatory approval. About Biosplice:Biosplice stands at the forefront of research concentrating on the study and regulation of Cdc2-like kinases (CLKs) and dual-specificity tyrosine-regulated kinases (DYRKs). These kinases play pivotal roles in cell cycle regulation, splicing, and neurodevelopment, marking them as critical targets for therapeutic intervention in a range of diseases, including osteoarthritis, cancer, neurological disorders, and diabetes. With a robust chemical platform for kinase inhibition and a deep understanding of kinase signaling pathways, Biosplice leverages cutting-edge technologies to discover and develop highly selective kinase inhibitors. Biosplice’s drugs in clinical development include lorecivivint for osteoarthritis (completed Phase 3) and cirtuvivint for numerous cancers, with a broad preclinical pipeline that encompasses Alzheimer’s disease, diabetes and other degenerative conditions. About Cirtuvivint:Cirtuvivint is a small molecule inhibitor of CLK and DYRK kinases, which are increasingly recognized as key drivers of various cancers. By targeting these kinases, cirtuvivint modulates alternative pre-mRNA splicing, which may reduce the expression of genes vital for tumor growth, survival, and drug resistance. The compound has shown broad anti-tumor activity across a range of solid and liquid tumors in extensive preclinical studies. Cirtuvivint has also been investigated for the treatment of advanced solid tumors in two clinical trials. The first, SM08502-ONC-01 (NCT03355066), was a first-in-human dose escalation study designed to evaluate safety, tolerability, pharmacokinetics, and pharmacodynamics in patients with advanced solid tumors. The second, SM08502-ONC-03 (NCT05084859), was a Phase 1b trial assessing the efficacy of cirtuvivint in combination with standard treatments for patients with advanced castration-resistant prostate cancer, advanced non-small cell lung cancer, and advanced colorectal cancer. Learn more at https://www.biosplice.com

Phase 1INDPhase 3

20 Jun 2024

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Escend Announces Poster Presentation at the Annual Meeting of the European Hematology Association (EHS) from an Investigator-Initiated Phase I/II study evaluating ES-3000 in Myelodysplastic Syndrome (MDS)

MENLO PARK, Calif., June 20, 2024 /PRNewswire/ -- Escend Pharmaceuticals, Inc., a privately held oncology company, announced today a poster presentation with initial data from the Australasian Leukaemia and Lymphoma Group's (ALLG) investigator-initiated Phase I/II platform study (MYDAS-T MDS05 domain 1) evaluating ES-3000 alone and in combination with ASTX727 at European Hematology Association (EHS) in Madrid, Spain. The poster is entitled, 'Combining oral Wnt/β catenin/inflammasome pathway inhibitor, a bis-benzylisoquinoline alkaloid (ES-3000) with oral decitabine/cedazuridine (ASTX727)* as a treatment strategy for myelodysplasia'. The primary objectives of the initial phase of the trial are to assess the safety profile of ES-3000 and determine the recommended phase 2 dose and dosing schedule of ES-3000 in combination with fixed-dose decitabine/cedazuridine (ASTX727). The results indicate a response in 40% of evaluable patients who received ES-3000 as a single agent. The dose-limiting toxicities as per BION modeling allowed the study to dose escalate. A copy of the poster is available at Escend Pharmaceuticals' website About ES-3000 ES-3000 is a small molecule, oral investigational product that reduces leukemic stem cells by β-catenin and Calmodulin protein-dependent kinase II gamma (CamKIIγ). ES-3000 is being developed for the treatment of myeloid malignancies including acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and myelodysplastic syndrome (MDS). About Escend Escend's development strategy is to select drug candidates with established clinical safety that have not yet achieved US marketing approval and develop them for oncology based on new mechanism of action details, where their effects on specific cellular pathways can be leveraged for the development of novel therapeutics. About Australasian Leukaemia and Lymphoma Group's (ALLG) The Australasian Leukaemia and Lymphoma Group (ALLG) is Australia's and New Zealand's only collaborative clinical trial organisation that sponsors local investigator-initiated clinical trials. Established in 1973, the ALLG's membership of over 1,300 blood cancer health professionals at 94 networked sites includes haematologists, clinician researchers, scientists and nurses treating leukaemia, lymphoma, myeloma, myelodysplastic syndromes and other haematological malignancies. The ALLG plans, designs, conducts, monitors and publishes investigator initiated clinical trials to create better treatments and better lives for patients with blood cancers. For further information about this press release, please contact Saira Bates ([email protected]) or visit *Astex Pharmaceuticals study drug SOURCE Escend Pharmaceuticals, Inc.

Clinical StudyClinical Result

100 Deals associated with Decitabine/Cedazuridine

External Link

KEGG	Wiki	ATC	Drug Bank
-	Decitabine/Cedazuridine	L01XY	DB15694

R&D Status

Approved

10 top approved records.

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Indication	Country/Location	Organization	Date
Acute Myeloid Leukemia	LI	Otsuka Pharmaceutical Netherlands B.V.	15 Sep 2023
Acute Myeloid Leukemia	IS	Otsuka Pharmaceutical Netherlands B.V.	15 Sep 2023
Acute Myeloid Leukemia	NO	Otsuka Pharmaceutical Netherlands B.V.	15 Sep 2023
Acute Myeloid Leukemia	EU	Otsuka Pharmaceutical Netherlands B.V.	15 Sep 2023
Chronic Myelomonocytic Leukemia	AU	Otsuka Australia Pharmaceutical Pty Ltd.	29 Oct 2020
Myelodysplastic Syndromes	US	Otsuka Pharmaceutical Co., Ltd.	07 Jul 2020

Developing

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Acute Myeloid Leukemia	Phase 3	US	Astex Pharmaceuticals, Inc.	15 Feb 2018
Myelodysplastic Syndromes	Phase 3	ES	Astex Pharmaceuticals, Inc.	15 Feb 2018
Myelodysplastic Syndromes	Phase 3	CZ	Astex Pharmaceuticals, Inc.	15 Feb 2018
Myelodysplastic Syndromes	Phase 3	AT	Astex Pharmaceuticals, Inc.	15 Feb 2018
Myelodysplastic Syndromes	Phase 3	GB	Astex Pharmaceuticals, Inc.	15 Feb 2018
Myelodysplastic Syndromes	Phase 3	CA	Astex Pharmaceuticals, Inc.	15 Feb 2018
Myelodysplastic Syndromes	Phase 3	HU	Astex Pharmaceuticals, Inc.	15 Feb 2018
Myelodysplastic Syndromes	Phase 3	DE	Astex Pharmaceuticals, Inc.	15 Feb 2018
Myelodysplastic Syndromes	Phase 3	FR	Astex Pharmaceuticals, Inc.	15 Feb 2018
Myelodysplastic Syndromes	Phase 3	IT	Astex Pharmaceuticals, Inc.	15 Feb 2018

Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT03613532 (1045, ASH2024)	Phase 1	High Risk Myelodysplastic Syndrome Maintenance TP53	30	Venetoclax	babcclpoes(cpgrdvygai) = 6 (23%) rmhjevfsvn (mqgbidsmxq ) View more	Positive	09 Dec 2024
				Decitabine/Cedazuridine
NCT05360160 (ASH2024) Manual	Phase 1/2	Acute Myeloid Leukemia \| \|	26	Revumenib (SNDX-5613) with Decitabine/Cedazuridine (ASTX727) and Venetoclax (SAVE)	(azcvhjocye) = xdbvvqwyms dbjmuyfqvz (ivoekufqzb ) View more	Positive	07 Dec 2024
NCT05835011 (CTgov)	Phase 2	Myelodysplastic Syndromes	2	Decitabine/Cedazuridine+Magrolimab	fviprjoohs(sankkhmrcr) = ediodinnol srqgxjkwgk (swyqdnaweq, niyqzegjmc - ryyrafwzdw) View more	-	02 Oct 2024
NCT05010122 (EHA2024) Manual	Phase 1/2	Acute Myeloid Leukemia \| Myelodysplastic Syndromes First line	26	ASTX727 withVENand GILT (newly diagnosed)	(iyznmpbvtv) = rgoglyrpgf djbgavcfrn (zyeysgugzf ) View more	Positive	14 May 2024
				ASTX727 with VEN and GILT (relapsed/refractory)	(iyznmpbvtv) = ztzqifkofy djbgavcfrn (zyeysgugzf ) View more
NCT02103478 \| NCT03306264 (ASCERTAIN, EHA2024) Manual	Phase 2/3	Myelodysplastic Syndromes	180	DEC-C	(rxfkneiupu) = kcmbegvoqt crdnlzghsj (knaoldyeob ) View more	Positive	14 May 2024
				DEC-C (OR)	(rxfkneiupu) = vwszosbazu crdnlzghsj (knaoldyeob )
EHA2024	Not Applicable	Chronic Myelomonocytic Leukemia	50	Azacitidine	ramvcyidkv(ztygegjokk) = apeurcinca nngolcrwrr (erfswqoulp ) View more	-	14 May 2024
				Decitabine-cedazuridine	ramvcyidkv(ztygegjokk) = kjegqhsezz nngolcrwrr (erfswqoulp ) View more
NCT04746235 (Pubmed) Manual	Phase 2	Acute Myeloid Leukemia	62	ASTX727 + venetoclax 400 mg	(ezqnrgpzib) = rjyqfamwtk wddkdzrujd (fscklrfcub ) View more	Positive	01 Apr 2024
				ASTX727 + venetoclax 400 mg (newly diagnosed acute myeloid leukaemia)	(ezqnrgpzib) = feczjunfwz wddkdzrujd (fscklrfcub, 49 - 77)
NCT04746235 (ASH2023)	Phase 2	Acute Myeloid Leukemia	52	ASTX727 (Decitabine/Cedazuridine) plus Venetoclax	(dicstayaqe) = dsyjwruqiq tirlshzlot (dssekrffzg ) View more	-	11 Dec 2023
ASH2023	Phase 1/2	-	51	ASTX727 + VEN + IVO	(vsgyaclzck) = bstfnksglp qjxakdiyrj (hxbiyesmnj ) View more	-	11 Dec 2023
				ASTX727 + VEN + ENA	(vsgyaclzck) = kdskgcmqgl qjxakdiyrj (hxbiyesmnj ) View more
ASH2023	Not Applicable	Myelodysplastic Syndromes	1,569	Oral Decitabine and Cedazuridine (DEC-C)	biwnajejzp(ymjrqabmyg) = jukdktfwbz rbzformhiz (wpovxdjqho )	-	10 Dec 2023
				Intravenous/Subcutaneous Hypomethylating Agents	biwnajejzp(ymjrqabmyg) = zfxptcamgq rbzformhiz (wpovxdjqho )

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