pevonedistat, venetoclax

Found insideThis volume provides the reader with an overview of the diverse functions of the RUNX family of genes. Found inside – Page 262Pevonedistat (MLN4924), a First-in-Class NEDD8-activating enzyme inhibitor, ... Venetoclax combined with decitabine or azacitidine in treatment-naive, ... Found inside – Page 286... (navitoclax in combination with venetoclax and chemotherapy) Navitoclax I ... R/R B-or T-ALL (pevonedistat in combination with induction chemotherapy) ... This book provides an unprecedented overview of "Targeted Therapies" for acute myeloid leukemias. The supplemental 10 items have 4 responses (1=not at all to 4=very much). Pevonedistat is being tested to treat people who have AML. Open to accrual Jeyakumar Stephanie Osorio Pevonedistat is an investigational drug for . In recent years, we are witnessing the emergence of multiple treatment combinations based on hypomethylating agents (pevonedistat, magrolimab, eprenetapopt, venetoclax) that have proven to be effective in MDS, even those with high-risk factors. How safe and effective any of . The study hypothesis is that the combination of pevonedistat, azacitidine, and venetoclax will be effective, safe, and well tolerated in patients with AML.The primary objective of this portion of the study is to determine a recommended phase 2 dose (RP2D) of pevonedistat, azacitidine, and venetoclax.The investigators will use a variation of the 3+3 design where both escalation and de . The study will enroll approximately 150 patients. Giving azacitidine, venetoclax, and pevonedistat may work better in treating patients with acute myeloid leukemia. Summary: The purpose of this study is to determine whether the combination of pevonedistat + venetoclax + azacitidine improves event-free survival (EFS) compared with venetoclax + azacitidine in patients with newly diagnosed acute myeloid leukemia (AML) who are unfit for intensive chemotherapy. Total bilirubin ≤1.5 times the ULN except in participants with Gilbert's syndrome. CRi is defined as all CR criteria except for residual neutropenia (<1.0×10^9/L [1000/µL]) or thrombocytopenia (<100×10^9/L [100,000/µL]). Participants will be randomly assigned in 1:1 ratio to one of the two treatment groups in 28-day treatment cycles and which will remain disclosed to the patient and study doctor during the study: This multi-center trial will be conducted worldwide. OS is defined as time from randomization to death from any cause. CR rate is defined as the percentage of participants who achieve the CR as evaluated by the independent review committee (IRC). Patients receive venetoclax orally (PO) once daily (QD) on days 1-28, azacitidine intravenously (IV) or subcutaneously (SC) on days 1-7, and pevonedistat IV over 60 minutes on days 1, 3, and 5. Two-year survival rate is defined as the K-M estimate of survival rate at 2-year. These agents added to the HMA/venetoclax doublet include: a combination of cladribine and low-dose cytarabine, the NEDD8-actviating enzyme inhibitor pevonedistat, the anti-CD33 antibody/calicheamicin conjugate gemtuzumab ozogamicin, MDM2 inhibitors, and the anti-programmed death ligand-1 (PDL-1) antibody avelumab . Patients are being randomized 1:1 to receive the combination of pevonedistat 20 mg/m2 intravenously (IV) on days 1, 3, and 5, VEN 400 mg by mouth on days 1-28 in cycle 1 (ramp up schedule of 100 mg on day 1, 200 mg on day 2, 400 mg on days 3-28) and then on days 1-28 (days 1-21 if remission is confirmed; can return to 28-day dosing if well tolerated) in cycle 2 onwards, and AZA 75 mg/m2 (IV or subcutaneously) on days 1-7 or 1-5, 8, and 9, or VEN + AZA, in 28-day cycles until unacceptable toxicity, relapse, or progressive disease. Assessments of disease response are based on the criteria outlined in the ELN 2017 guidelines. Treatment. To determine the safety of the combination regimen. Pevonedistat could spell the end for a rare anticancer mechanism. Nicholas J. 2021; 106:xxx Strong CYP3A4 inducers are not permitted during this study, Systemic antineoplastic therapy or radiotherapy for other malignant conditions within 14 days (or 3 half-lives, whichever is shorter) before the first dose of any study drug, except for hydroxyurea or up to 2 total grams of intravenous cytarabine for cytoreduction. This is a unique book focusing on the management of rare sarcomas, which pose an important challenge in Europe and in the US, as they represent nearly one quarter of all new diagnoses of cancer and have lower survival rates than common ... Study record managers: refer to the Data Element Definitions if submitting registration or results information. Time to first CRi is defined as the time from randomization until the first documented CRi and will be analyzed using the K-M method. Biology College, The Ohio State University, Columbus, OH, USA. 2015). Most items have 4 responses (1=not at all [best] to 4=very much [worst]). If remission is confirmed in Cycle 1 or thereafter, venetoclax 400 mg can be administered on Day 1 through 21 or 28 as per Investigator's discretion, plus azacitidine 75 mg/m^2 IV or subcutaneous (SC) dosing on Day 1 through 7 or Days 1 through 5, Days 8, and 9 in each cycle. Why Should I Register and Submit Results? The drug being tested in this study is called Pevonedistat. 17 Professor DiNardo finished with data demonstrating improved survival outcomes for patients with NPM1 mutated AML treated with an HMA plus venetoclax at three and five years . PR is defined as all hematologic criteria of CR; decrease of bone marrow blast percentage to 5% to 25%; and decrease of pretreatment bone marrow blast percentage by at least 50%. Cell Death Differ 2015). EORTC-QLQ-C30 scale assess HRQOL on 30 items: 5 functional scales (physical, role, cognitive, emotional, and social), 9 symptom scales (fatigue, nausea and vomiting, pain, dyspnea, sleep disturbance, appetite loss, constipation, diarrhea, and financial difficulties), and global quality of life (QOL)/health status scale. Pevonedistat and azacitidine upregulate NOXA (PMAIP1) to increase sensitivity to venetoclax in preclinical models of acute myeloid leukemia. Found insideThis issue of Hematology/Oncology Clinics, edited by Drs. Jorge J. Castillo, Efstathios Kastritis, and Steven P. Treon, will focus on Waldenström Macroglobulinemia. Talk with your doctor and family members or friends about deciding to join a study. CR is defined as bone marrow blasts <5%; absence of circulating blasts and blasts with Auer rods; absence of extramedullary disease; ANC≥ 1.0×10^9/L (1000/µL); platelet count≥100×10^9/L (100,000/µL). Now Viewing. Epub 2021 Sep 27. Everyone in this study will receive pevonedistat, azacitidine and venetoclax. Talk with your doctor and family members or friends about deciding to join a study. The combination of pevonedistat and azacitidine had encouraging clinical activity in patients with higher-risk myelodysplastic syndromes (MDS)/chronic myelomonocytic leukemia (CMML) or low-blast acute myeloid leukemia (AML), according to findings published in Leukemia by Mikkael Sekeres, MD, MS, from Sylvester Comprehensive Cancer Center in Miami, and coauthors. In a phase 1b study in patients aged ≥60 yrs with untreated AML, pevonedistat in combination with azacitidine (AZA) was tolerable and showed clinical activity (Swords et al. Duration of CR + CRh is defined as the time from randomization to CR + CRh and will be summarized descriptively using the K-M method based on the responders. Giving azacitidine, venetoclax, and pevonedistat may work better in treating patients with acute myeloid leukemia.. Will be assessed by Common Terminology Criteria for Adverse Events (CTCAE) version (v)4.03. (Phase I) II. Patients receive venetoclax orally (PO) once daily (QD) on days 1-28, azacitidine intravenously (IV) or subcutaneously (SC) on days 1-7, and pevonedistat IV over 60 minutes on days 1, 3, and 5. Biochem Biophys Res Commun. therapy-related AML or AML with myelodysplastic-related changes per WHO): Male patients, even if surgically sterilized (i.e., status postvasectomy), who: Known human immunodeficiency virus (HIV) positive patients who meet the following criteria will be considered eligible: Known hepatitis B surface antigen seropositive or known or suspected active hepatitis C infection. Daniel Pollyea, MD, MS, discusses the current management of patients with higher-risk myelodysplastic syndrome, the data . The combination of azacitidine and pevonedistat appears less myelosuppressive than azacitidine and venetoclax and more applicable to outpatient treatment . CCR rate is defined as the percentage of participants who achieve the CR + CR with incomplete blood count recovery (CRi) as evaluated by the IRC. Pevonedistat is an inhibitor of the NEDD8-activating enzyme and is being developed for the treatment of malignancies. Participants who discontinue study treatment without evidence of progressive disease (PD) will enter EFS follow-up or response follow-up (study visits every 3 months) or overall survival follow-up (contacted every 3 months to document subsequent therapies and survival status). ), Voluntary written consent must be given before performance of any study related procedure, Treatment with any investigational anti-neoplastic drugs within 2 weeks before the first dose of any study drug (cycle 1 day 1 [C1D1]), AML COHORT ONLY: Patients who are suitable for and agreeable to receive intensive induction chemotherapy, NEWLY DIAGNOSED MDS/CMML COHORT ONLY: Prior treatment with hypomethylating agents, MDS/CMML POST-HMA FAILURE COHORT ONLY: Prior treatment with venetoclax or pevonedistat, Patients whose only site of disease is extramedullary, Acute promyelocytic leukemia as diagnosed by morphologic examination of bone marrow, by fluorescent in situ hybridization or cytogenetics of peripheral blood or bone marrow, or by other accepted analysis, Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of study procedures, Active uncontrolled infection or severe infectious disease, such as severe pneumonia, meningitis, or septicemia, Major surgery within 14 days before the first dose of any study drug, Patients with a prior or concurrent malignancy whose natural history or treatment is not anticipated to interfere with the safety or efficacy assessment of the investigational regimen may be included only after discussion with the PI, Life-threatening illness unrelated to cancer, leading to expected life expectancy (unrelated to leukemia) < 1 year, Patients with severe, uncontrolled coagulopathy or bleeding disorder not related to leukemia, Maintained on modern therapeutic regimens utilizing non-CYP-interactive agents, No history of acquired immunodeficiency syndrome (AIDS)-defining opportunistic infections, Note: Patients who have isolated positive hepatitis B core antibody (i.e., in the setting of negative hepatitis B surface antigen and negative hepatitis B surface antibody) must have an undetectable hepatitis B viral load. CRi is defined as all CR criteria except for residual neutropenia (<1.0×10^9/L [1000/µL]) or thrombocytopenia (<100×10^9/L [100,000/µL]). EFS is defined as time from study randomization to date of failure to achieve complete remission (CR), relapse from CR, or death. 613.ACUTE MYELOID LEUKEMIA: CLINICAL STUDIES | NOVEMBER 5, 2020 A Randomized Phase 2 Study of Pevonedistat, Venetoclax, and Azacitidine Versus Venetoclax Plus Azacitidine in Adults with Newly Diagnosed Acute Myeloid Leukemia (AML) Who Are Unfit for Intensive Chemotherapy Nicholas J. Pevonedistat is a compound that inhibits neddylation that has been studied in multiple trials encompassing both MDS and AML. I. Participants in Arm A will receive the study drug pevonedistat in combination with venetoclax and azacitidine. Search for other works by this author on: © 2020 by The American Society of Hematology, Copyright ©2020 by American Society of Hematology, 613.Acute Myeloid Leukemia: Clinical Studies, https://doi.org/10.1182/blood-2020-136968. Upregulation of MCL-1 is thought to be a primary mode of resistance to VEN. The drug being tested in this study is called Pevonedistat. 6: The Future of Myelodysplastic Syndrome. Participants may have newly diagnosed primary de novo AML or secondary AML (sAML), defined as AML after myelodysplastic syndromes (MDS) or myeloproliferative neoplasm (MPN), or therapy-related AML (t-AML) following cytotoxic therapy, and/or radiotherapy for a malignant or nonmalignant disease. PR is defined as all hematologic criteria of CR; decrease of bone marrow blast percentage to 5% to 25%; and decrease of pretreatment bone marrow blast percentage by at least 50%. Assessments of disease response are based on the criteria outlined in the ELN 2017 guidelines. CRh is defined as bone marrow with <5% blasts, peripheral blood neutrophil count >0.5×10^3/µL and peripheral blood platelet count >0.5×10^5/µL. CRi is defined as all CR criteria except for residual neutropenia (<1.0×10^9/L [1000/µL]) or thrombocytopenia (<100×10^9/L [100,000/µL]). Nicholas Short, MD, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, discusses a Phase II trial (NCT04266795) of a pevonedistat, venetoclax (Ven) and azacitadine (aza) triplet combination in newly-diagnosed acute myeloid leukemia (AML) patients unfit for intensive chemotherapy. This screening and multi-sub-study Phase 1b/2 trial will establish a method for genomic screening followed by assigning and accruing simultaneously to a multi-study "Master Protocol (BAML-16-001-M1)." The specific subtype of acute myeloid leukemia will determine which sub-study, within this protocol, a participant will be assigned to . CCR is defined as the percentage of participants who achieve the CR + CRi as evaluated by the IRC. CR is defined as bone marrow blasts <5%; absence of circulating blasts and blasts with Auer rods; absence of extramedullary disease; absolute neutrophil count (ANC)≥1.0×10^9/L (1000/µL); platelet count≥100×10^9/L (100,000/µL). Participants will be randomly assigned in. Had diagnosed or treated for another malignancy (except for adequately treated carcinoma in situ of any organ or nonmelanoma skin cancer) within 1 year before randomization or previously diagnosed with another malignancy and have any evidence of residual disease that may compromise the administration of pevonedistat, venetoclax or azacitidine. Zhao:Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Current Employment. However, the future for MDS patients is promising. In a randomized phase 2 study of pevonedistat + AZA vs AZA alone in patients with higher-risk myelodysplastic syndromes/chronic myelomonocytic leukemia and low-blast AML, pevonedistat + AZA improved event-free survival (EFS) and overall survival (OS), had a similar safety profile to AZA alone, did not increase myelosuppression, and maintained AZA dose intensity (Adès et al. We will also evaluate how well this combination works in patients with AML. This is likely mediated through pevonedistat-induced neutralization of prosurvival proteins including myeloid leukemia cell differentiation protein (MCL-1). Found insideAt the heart of this book is the editor’s and authors’ desire to overcome the controversies and barriers to practice that usually emerge following the appearance of new data. Drugs used in chemotherapy . Familial acute myeloid leukemia with mutated CEBPA, Cytogenetically normal acute myeloid leukemia, Core binding factor acute myeloid leukemia, Genetic and Rare Diseases Information Center, U.S. Department of Health and Human Services, The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Participants will attend the end-of-treatment visit 30 days after the last dose of study drug or before the start of subsequent anti-neoplastic therapy if that occurs sooner. CR is defined as bone marrow blasts <5%; absence of circulating blasts and blasts with Auer rods; absence of extramedullary disease; ANC≥1.0×10^9/L (1000/µL); platelet count≥100×10^9/L (100,000/µL). Found insideIn this book, leading experts in cancer immunotherapy join forces to provide a comprehensive guide that sets out the main principles of oncoimmunology and examines the latest advances and their implications for clinical practice, focusing ... Pevonedistat-2002. 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Is promising Lodzi, Szpital Uniwersytecki Nr 2 im biomarkers of response will be chosen at random to alive..., date of randomization ( except who died before assessment ) ALT ) and aspartate aminotransferase ( AST ) times. 0 ) future for MDS patients is promising study team decides that an individual eligible... Modification of Diet in Renal disease [ MDRD ] study equation ) be primary... A compilation of articles written by and about Suleika Jaouad and a journey through cancer age! In Adults with acute myeloid leukemias we will also evaluate how well this combination works in patients AML-MRC! Group when compared with single-agent azacitidine best ] ) survival, leading to cell death in cancers including. Likely mediated through pevonedistat-induced neutralization of prosurvival proteins including myeloid leukemia who cytoreduced... The NAE reaction cycle progression and cell survival adenosine 59-monophosphate ( AMP ) —a binding...
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