SNDX-5613 + ASTX727 + Venetoclax for Acute Myeloid Leukemia
Recruiting in Palo Alto (17 mi)
Age: Any Age
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1 & 2
Recruiting
Sponsor: M.D. Anderson Cancer Center
Must not be taking: Menin inhibitors
Disqualifiers: Uncontrolled conditions, Active infection, others
No Placebo Group
Breakthrough Therapy
Trial Summary
What is the purpose of this trial?Part 1b of this clinical research study is to find the highest tolerable dose of SNDX-5613 that can be given in combination with ASTX727 (a combination of the drugs decitabine/cedazuridine) and venetoclax for patients with acute myeloid leukemia (AML) or those with a mixed phenotype acute leukemia with a myeloid phenotype (MPAL).
Part 2 of this study is to learn if the dose of study drugs found in Part 1b can help to control AML/MPAL
Will I have to stop taking my current medications?
The trial does not specify if you must stop all current medications, but it does not allow other chemotherapeutic or anti-leukemic agents during the study, except for certain cases like intrathecal chemotherapy or hydroxyurea. You should discuss your current medications with the study team to see if they are allowed.
What data supports the effectiveness of the drug combination SNDX-5613, ASTX727, and Venetoclax for treating acute myeloid leukemia?
Research shows that combining Venetoclax with Decitabine or Azacitidine is effective for older patients with acute myeloid leukemia, achieving high remission rates and longer survival compared to Decitabine alone.
12345Is the combination of SNDX-5613, ASTX727, and Venetoclax safe for humans?
The combination of Venetoclax with decitabine (ASTX727) has been studied in elderly patients with acute myeloid leukemia and was generally well tolerated, with common side effects including nausea, diarrhea, and fatigue. No serious safety concerns like tumor lysis syndrome were observed in these studies.
12367What makes the drug combination of SNDX-5613, ASTX727, and Venetoclax unique for treating acute myeloid leukemia?
This drug combination is unique because it includes SNDX-5613, a novel component not commonly used in standard treatments for acute myeloid leukemia, alongside ASTX727 and Venetoclax, which have shown promising results in older patients or those unfit for intensive chemotherapy. The combination aims to enhance treatment efficacy by targeting different mechanisms involved in leukemia cell survival.
23489Eligibility Criteria
This trial is for individuals aged 12 and older, weighing at least 40kg, with relapsed/refractory acute myeloid leukemia (AML) or mixed phenotype acute leukemia with a myeloid phenotype. Participants must have an ECOG performance status of ≤2, be on certain antifungal medications, and not be taking other strong CYP3A4 inhibitors/inducers. They should agree to contraception use during the study and for three months after. Exclusions include active malignancy under treatment, severe gastrointestinal/metabolic conditions affecting drug absorption, recent significant cardiovascular events, uncontrolled medical conditions or infections.Inclusion Criteria
I am a male who is sterile or will use contraception during and 3 months after the study.
I am taking certain antifungal medications and no other strong medications that affect drug metabolism.
My leukemia has returned or is not responding to treatment.
+9 more
Exclusion Criteria
I have severe acute or chronic graft-versus-host disease.
I am currently being treated for another cancer.
I haven't had a heart attack, severe heart issues, or a stroke in the last 6 months.
+10 more
Participant Groups
The trial is testing the highest tolerable dose of SNDX-5613 in combination with ASTX727 (decitabine/cedazuridine) and venetoclax in patients with AML or MPAL. The goal is to determine if this oral drug combination can control these types of leukemia effectively.
3Treatment groups
Experimental Treatment
Group I: VenetoclaxExperimental Treatment1 Intervention
Tablets by mouth on Days 1-14 of each cycle.
Group II: SNDX-5613Experimental Treatment1 Intervention
Capsules by mouth 2 times every day (about 12 hours apart).
Group III: ASTX727Experimental Treatment1 Intervention
Tablets by mouth on Days 1-5 of each cycle.
ASTX727 is already approved in United States, European Union for the following indications:
🇺🇸 Approved in United States as Inqovi for:
- Myelodysplastic Syndromes (MDS)
🇪🇺 Approved in European Union as Inqovi for:
- Myelodysplastic Syndromes (MDS)
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
M D Anderson Cancer CenterHouston, TX
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Who Is Running the Clinical Trial?
M.D. Anderson Cancer CenterLead Sponsor
Syndax Pharmaceuticals, Inc.Collaborator
Astex Pharmaceuticals, Inc.Industry Sponsor
Syndax PharmaceuticalsIndustry Sponsor
References
Efficacy of Venetoclax Combined with Decitabine-Based Treatment for Heavily Pre-Treated Relapsed or Refractory AML Patients in a Real-World Setting. [2022]We report the efficacy and safety of venetoclax plus decitabine-based treatment in heavily pre-treated relapsed or refractory acute myeloid leukaemia (RR-AML) in a real-world setting.
Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. [2021]Older patients with acute myeloid leukemia (AML) respond poorly to standard induction therapy. B-cell lymphoma 2 (BCL-2) overexpression is implicated in survival of AML cells and treatment resistance. We report safety and efficacy of venetoclax with decitabine or azacitidine from a large, multicenter, phase 1b dose-escalation and expansion study. Patients (N = 145) were at least 65 years old with treatment-naive AML and were ineligible for intensive chemotherapy. During dose escalation, oral venetoclax was administered at 400, 800, or 1200 mg daily in combination with either decitabine (20 mg/m2, days 1-5, intravenously [IV]) or azacitidine (75 mg/m2, days 1-7, IV or subcutaneously). In the expansion, 400 or 800 mg venetoclax with either hypomethylating agent (HMA) was given. Median age was 74 years, with poor-risk cytogenetics in 49% of patients. Common adverse events (>30%) included nausea, diarrhea, constipation, febrile neutropenia, fatigue, hypokalemia, decreased appetite, and decreased white blood cell count. No tumor lysis syndrome was observed. With a median time on study of 8.9 months, 67% of patients (all doses) achieved complete remission (CR) + CR with incomplete count recovery (CRi), with a CR + CRi rate of 73% in the venetoclax 400 mg + HMA cohort. Patients with poor-risk cytogenetics and those at least 75 years old had CR + CRi rates of 60% and 65%, respectively. The median duration of CR + CRi (all patients) was 11.3 months, and median overall survival (mOS) was 17.5 months; mOS has not been reached for the 400-mg venetoclax cohort. The novel combination of venetoclax with decitabine or azacitidine was effective and well tolerated in elderly patients with AML (This trial was registered at www.clinicaltrials.gov as #NCT02203773).
Venetoclax with decitabine versus decitabine monotherapy in elderly acute myeloid leukemia: a propensity score-matched analysis. [2022]Venetoclax (VEN) combined with azacitidine (AZA) or decitabine (DEC) has been approved for older adults with acute myeloid leukemia (AML) unfit for intensive chemotherapy based on the pivotal VIALE-A trial. However, this trial only compared AZA + VEN with AZA monotherapy. Therefore, we compared the outcomes of consecutive older adults (65 years or older) with newly diagnosed AML who received DEC (n = 230) or DEC + VEN (n = 74) after propensity score matching to construct a one-to-one matched cohort by the nearest neighbor algorithm. The median overall survival was longer in the DEC + VEN group than in the DEC group (13.4 months vs. 8.3 months, p = 0.01). The median event-free survivals were 8.6 and 5.8 months in the DEC + VEN and DEC groups, respectively (p = 0.02). The response rate (complete response, complete response with incomplete hematologic recovery, and morphologic leukemia-free state) was significantly higher in the DEC + VEN group than in the DEC group (70.3% vs. 24.3%, p
Venetoclax in combination with azacitidine in Japanese patients with acute myeloid leukaemia: phase 1 trial findings. [2021]Venetoclax plus azacitidine is indicated in the USA for the treatment of newly diagnosed acute myeloid leukaemia in older patients (≥75 years) or those ineligible for induction chemotherapy due to co-morbidities.
Costs per patient achieving remission with venetoclax-based combinations in newly diagnosed patients with acute myeloid leukemia ineligible for intensive induction chemotherapy. [2022]BACKGROUND: Venetoclax, in combination with azacitidine, decitabine, or low-dose cytarabine (LDAC), received confirmatory approval in 2020 by the US Food and Drug Administration for the treatment of newly diagnosed acute myeloid leukemia (AML) in patients aged 75 years or older or who are ineligible for intensive induction chemotherapy. The economic value associated with response to venetoclax combinations compared with other treatments for this patient population has not been comprehensively evaluated. OBJECTIVE: To assess the cost per patient achieving remission with venetoclax combination therapies, compared with other therapies for newly diagnosed patients with AML who are ineligible for intensive induction chemotherapy, from a US third-party payer perspective. METHODS: The analysis used treatment effect estimates (ie, complete remission [CR] + CR with incomplete blood count recovery [CRi]) from a network meta-analysis and annual cost estimates from a prior budget impact model. The model considered the total cost of care including the costs of drug and administration, adverse events, hospitalization, disease monitoring, blood transfusions, and subsequent AML management when patients discontinued active treatment. Costs per patient achieving CR + CRi associated with venetoclax + azacitidine, venetoclax + LDAC, azacitidine, decitabine, LDAC, and best supportive care (ie, treatment given with the intent to maximize quality of life without specific antileukemic intent, such as blood transfusion products and antibiotics) were calculated as the annual total cost of care per patient divided by the CR + CRi rate. All costs were adjusted to 2020 US dollars. RESULTS: Venetoclax combination therapies were estimated to have substantially lower costs per patient achieving CR + CRi (venetoclax + azacitidine: $473,960; venetoclax + LDAC: $428,071) than alternative treatments. Azacitidine was estimated to have the the highest cost per patient achieving CR + CRi ($1,197,438), followed by best supportive care ($869,849), LDAC ($689,101), and decitabine ($594,074). A pair-wise matrix of the difference between therapies estimated that both venetoclax + azacitidine and venetoclax + LDAC were associated with significantly lower costs per patient achieving CR + CRi than azacitidine (by $723,477 and $769,367, respectively) and LDAC (by $215,141 and $261,030; all P < 0.05). CONCLUSIONS: From a US third-party payer perspective, venetoclax in combination with azacitidine or LDAC was estimated to be associated with a significantly lower cost per patient achieving CR + CRi than azacitidine or LDAC among newly diagnosed patients with AML ineligible for intensive chemotherapy. DISCLOSURES: This research was supported by AbbVie Inc. and Genentech. The sponsors helped design the study, interpret the data, and draft the manuscript. Drs Bui and Kapustyan are employees of and have equity ownership in AbbVie; Dr Choi was an employee of AbbVie during the study's conduct and has equity ownership. Ms Ma and Dr Montez are employees of and have equity ownership in Genentech. Drs Song and Chai, Ms Yin, and Dr Betts are employees of Analysis Group, Inc., which has received funding from AbbVie and Genentech for the conduct of this research. Dr LeBlanc reports personal fees for consulting or advisory boards from AbbVie, Agios/Servier, AstraZeneca, Amgen, Astellas, BlueNote, CareVive, BMS/Celgene, Daiichi-Sankyo, Flatiron, Genentech, GSK, Pfizer, and Seattle Genetics; royalties from UpToDate; speakers bureau fees from Agios/Servier, AbbVie, and BMS/Celgene; and grants and/or research contracts from the American Cancer Society, AstraZeneca, BMS, Jazz Pharmaceuticals, and Seattle Genetics.
Venetoclax in association with decitabine as effective bridge to transplant in a case of relapsed early T-cell lymphoblastic leukemia. [2020]A case of an early-relapsed high-risk T-ALL with high BCL-2 expression on leukemic blasts was successfully treated with decitabine and venetoclax, achieving a CR. We suggest decitabine and venetoclax should be synergistic in BCL2-positive ALL.
Venetoclax in combination with cytarabine with or without idarubicin in children with relapsed or refractory acute myeloid leukaemia: a phase 1, dose-escalation study. [2021]Outcomes for children with relapsed or refractory acute myeloid leukaemia remain poor. The BCL-2 inhibitor, venetoclax, has shown promising activity in combination with hypomethylating agents and low-dose cytarabine in older adults for whom chemotherapy is not suitable with newly diagnosed acute myeloid leukaemia. We aimed to determine the safety and explore the activity of venetoclax in combination with standard and high-dose chemotherapy in paediatric patients with relapsed or refractory acute myeloid leukaemia.
Venetoclax in combination with nucleoside analogs in acute myelogenous leukemia. [2023]Venetoclax in combination with nucleoside analogs such as hypomethylating agents (HMA) and low-dose cytarabine (LDAC) has led to unprecedented response and survival outcomes in patients with acute myeloid leukemia (AML). This has spurred the development of regimens combining venetoclax with other nucleoside analogs with distinct mechanisms of action. Here, we review older and newer nucleoside analogs, the rationale for their combination with venetoclax, and clinical evidence for the combination when available.
10-day decitabine with venetoclax for newly diagnosed intensive chemotherapy ineligible, and relapsed or refractory acute myeloid leukaemia: a single-centre, phase 2 trial. [2021]Venetoclax combined with hypomethylating agents is a new standard of care for newly diagnosed patients with acute myeloid leukaemia (AML) who are 75 years or older, or unfit for intensive chemotherapy. Pharmacodynamic studies have suggested superiority of the longer 10-day regimen of decitabine that has shown promising results in patients with high-risk AML in phase 2 trials. We hypothesised that venetoclax with 10-day decitabine could have improved activity in patients with newly diagnosed AML and those with relapsed or refractory AML, particularly in high-risk subgroups.