Ziftomenib Combinations for Acute Myeloid Leukemia
Recruiting in Palo Alto (17 mi)
+24 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: Kura Oncology, Inc.
Must not be taking: Immunosuppressive drugs
Disqualifiers: Acute promyelocytic leukemia, CNS leukemia, uncontrolled infection, others
No Placebo Group
Approved in 1 Jurisdiction
Trial Summary
What is the purpose of this trial?
The safety, tolerability, and antileukemic response of ziftomenib in combination with standard of care treatments for patients with relapsed/refractory acute myeloid leukemia will be examined with the following agents: FLAG-IDA, low-dose cytarabine, and gilteritinib.
Will I have to stop taking my current medications?
The trial does not specify if you need to stop taking your current medications, but it does mention that you should not have received any anticancer therapy within 14 days before starting the study treatment. It's best to discuss your specific medications with the trial team.
What data supports the effectiveness of the drug combination including Ziftomenib for treating acute myeloid leukemia?
The combination of cytarabine with other drugs has been a standard treatment for acute myeloid leukemia (AML), showing response rates of up to 70% in younger patients. Additionally, the approval of novel drugs like Gemtuzumab Ozogamicin in combination with cytarabine has provided new treatment opportunities, suggesting that combining traditional and new agents can improve outcomes in AML.12345
What safety data exists for Ziftomenib and its combinations in treating acute myeloid leukemia?
What makes the drug Ziftomenib unique for treating acute myeloid leukemia?
Eligibility Criteria
This trial is for adults with relapsed/refractory acute myeloid leukemia (AML) who have specific genetic changes like NPM1 mutation or KMT2A rearrangement. Participants need to be in a stable physical condition, have good liver and kidney function, and agree to use contraception. It's not suitable for those with poor heart function.Inclusion Criteria
My liver and kidney functions are within normal ranges.
Your ejection fraction is above the predetermined limit.
You (or your legal representative) must be able to comprehend and submit written consent before the initial screening process.
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Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Phase 1a Treatment
Participants receive oral ziftomenib in combination with standard of care treatments in sequential cohorts to identify safety and tolerability
28 days per cycle
Multiple visits per cycle
Phase 1b Treatment
Following determination of maximum tolerated dose, participants receive oral ziftomenib in combination with standard of care treatments in dose validation/expansion cohorts
28 days per cycle
Multiple visits per cycle
Follow-up
Participants are monitored for safety and effectiveness after treatment, including assessments for transfusion independence, overall survival, and remission rates
Up to 12 months
Treatment Details
Interventions
- Cytarabine (Anti-metabolites)
- Fludarabine (Anti-metabolites)
- Gilteritinib (Other)
- Granulocyte colony-stimulating factor (Other)
- Idarubicin (Anti-tumor antibiotic)
- Ziftomenib (Other)
Trial OverviewThe trial tests the safety and effectiveness of Ziftomenib combined with other AML treatments: FLAG-IDA regimen, low-dose Cytarabine, or Gilteritinib. The goal is to see how well patients respond to these combinations when their AML has come back or hasn't improved after treatment.
Participant Groups
2Treatment groups
Experimental Treatment
Group I: Phase 1bExperimental Treatment6 Interventions
Oral ziftomenib; Following the determination of the maximum tolerated dose in Phase 1a, participants will be enrolled in 1 of 5 dose validation/expansion cohorts:
A-1: Participants with a NPM1 mutation: ziftomenib plus FLAG-IDA
A-2: Participants with a NPM1 mutation: ziftomenib plus low-dose cytarabine (LDAC)
A-3: Participants with a NPM1 mutation: ziftomenib plus gilteritinib
B-1: Participants with a KMT2A rearrangement: ziftomenib plus FLAG-IDA
B-2: Participants with a KMT2A rearrangement: ziftomenib plus low-dose cytarabine (LDAC)
Group II: Phase 1aExperimental Treatment6 Interventions
Oral ziftomenib; sequential cohorts of escalating dose levels of ziftomenib to identify the safety and tolerability of the combination regimens. Participants will be enrolled in 1 of 5 dose escalation cohorts:
A-1: Participants with a NPM1 mutation: ziftomenib plus FLAG-IDA
A-2: Participants with a NPM1 mutation: ziftomenib plus low-dose cytarabine (LDAC)
A-3: Participants with a NPM1 mutation: ziftomenib plus gilteritinib
B-1: Participants with a KMT2A rearrangement: ziftomenib plus FLAG-IDA
B-2: Participants with a KMT2A rearrangement: ziftomenib plus low-dose cytarabine (LDAC)
Ziftomenib is already approved in United States for the following indications:
🇺🇸 Approved in United States as Ziftomenib for:
- None - Investigational for Acute Myeloid Leukemia (AML)
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
OU Health Stephenson Cancer CenterOklahoma City, OK
MD Anderson Cancer CenterHouston, TX
The University of KansasKansas City, KS
UCI Health Chao Family Comprehensive Cancer CenterOrange, CA
More Trial Locations
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Who Is Running the Clinical Trial?
Kura Oncology, Inc.Lead Sponsor
References
Acute myeloid leukemia: focus on novel therapeutic strategies. [2022]Acute myeloid leukemia (AML) is a heterogeneous disease with variable clinical outcomes. Cytogenetic analysis reveals which patients may have favorable risk disease, but 5-year survival in this category is only approximately 60%, with intermediate and poor risk groups faring far worse. Advances in our understanding of the biology of leukemia pathogenesis and prognosis have not been matched with clinical improvements. Unsatisfactory outcomes persist for the majority of patients with AML, particularly the elderly. Novel agents and treatment approaches are needed in the induction, post-remission and relapsed settings. The additions of clofarabine for relapsed or refractory disease and the hypomethylating agents represent recent advances. Clinical trials of FLT3 inhibitors have yielded disappointing results to date, with ongoing collaborations attempting to identify the optimal role for these agents. Potential leukemia stem cell targeted therapies and treatments in the setting of minimal residual disease are also under investigation. In this review, we will discuss recent advances in AML treatment and novel therapeutic strategies.
Therapeutic Targeting of Acute Myeloid Leukemia by Gemtuzumab Ozogamicin. [2021]Acute myeloid leukemia (AML) is a complex hematological malignancy characterized by genetic and clinical heterogeneity and high mortality. Despite the recent introduction of novel pharmaceutical agents in hemato-oncology, few advancements have been made in AML for decades. In the last years, the therapeutic options have rapidly changed, with the approval of innovative compounds that provide new opportunities, together with new challenges for clinicians: among them, on 1 September, 2017 the Food and Drug Administration granted approval for Gemtuzumab Ozogamicin (GO) in combination with daunorubicin and cytarabine for the treatment of adult patients affected by newly diagnosed CD33+ AML. Benefits of GO-based regimens were also reported in the pre- and post-transplantation settings. Moreover, several biomarkers of GO response have been suggested, including expression of CD33 and multidrug resistance genes, cytogenetic and molecular profiles, minimal residual disease and stemness signatures. Among them, elevated CD33 expression on blast cells and non-adverse cytogenetic or molecular risk represent largely validated predictors of good response.
Treatment of acute myeloid leukemia: state-of-the-art and future directions. [2019]Despite major recent advances in the understanding of the molecular biology of the disease, the treatment of acute myeloid leukemia (AML) in adults remains challenging. For the 75% of AML patients older than 60 years, currently available treatments produce significant toxicity with poor overall response rates and survival. In younger patients, standard regimens using cytarabine and an anthracycline for induction followed by some form of intensive postremission therapy can produce response rates of 70% with 5-year relapse-free survival rates of 25% to 40%. Chromosomal analyses define three prognostic categories with favorable, intermediate, and unfavorable risk. In older adults, AML appears to be an intrinsically resistant disorder of proximal pluripotent hematopoietic stem cells. A variety of targeted therapies currently in development include modulators of MDR1-mediated drug resistance, immunotherapeutics, angiogenesis inhibitors, proapoptotic antisense oligonucleotides, and specific small molecule inhibitors of tyrosine kinase and farnesyltransferase. For example, oral farnesyltransferase inhibitors have demonstrated activity and tolerability in patients with refractory AML and are now in phase II testing. Such targeted therapeutics offer the promise of novel antileukemic activity combined with an improved therapeutic index.
A personalized approach to acute myeloid leukemia therapy: current options. [2020]Therapeutic options for acute myeloid leukemia (AML) have remained unchanged for nearly the past 5 decades, with cytarabine and anthracyclines and use of hypomethylating agents for less intensive therapy. Implementation of large-scale genomic studies in the past decade has unraveled the genetic landscape and molecular etiology of AML. The approval of several novel drugs for targeted therapy, including midostaurin, enasidenib, ivosidenib, gemtuzumab-ozogamicin, and CPX351 by the US Food and Drug Administration has widened the treatment options for clinicians treating AML. This review focuses on some of these novel therapies and other promising agents under development, along with key clinical trial findings in AML.
Acute myeloid leukaemia: optimal management and recent developments. [2022]The current treatment of patients with acute myeloid leukaemia yields poor results, with expected cure rates in the order of 30-40% depending on the biological characteristics of the leukaemic clone. Therefore, new agents and schemas are intensively studied in order to improve patients' outcomes. This review summarizes some of these new paradigms, including new questions such as which anthracycline is most effective and at what dose. High doses of daunorubicin have shown better responses in young patients and are well tolerated in elderly patients. Monoclonal antibodies are promising agents in good risk patients. Drugs blocking signalling pathways could be used in combination with chemotherapy or in maintenance with promising results. Epigenetic therapies, particularly after stem cell transplantation, are also discussed. New drugs such as clofarabine and flavopiridol are reviewed and the results of their use discussed. It is clear that many new approaches are under study and hopefully will be able to improve on the outcomes of the commonly used '7+3' regimen of an anthracycline plus cytarabine with daunorubicin, which is clearly an ineffective therapy in the majority of patients.
Updated safety of midostaurin plus chemotherapy in newly diagnosed FLT3 mutation-positive acute myeloid leukemia: the RADIUS-X expanded access program. [2021]Approval of midostaurin, a multikinase inhibitor, in combination with chemotherapy for the treatment of adults with newly diagnosed FLT3 mutation-positive acute myeloid leukemia, was based on the phase 3 RATIFY trial results. RADIUS-X (NCT02624570) was an expanded access program providing access to midostaurin during regulatory review and extending the understanding of the safety and tolerability of midostaurin. Patients aged ≥18 years received midostaurin with 1-2 cycles of induction therapy (cytarabine plus daunorubicin or idarubicin) and ≤4 cycles of high-dose cytarabine consolidation chemotherapy or as single-agent maintenance therapy. The study enrolled 103 patients. No new safety events were observed; toxicities were not influenced by age, anthracycline choice, or coadministration of CYP3A4 inhibitors. The most common adverse events (AEs) were febrile neutropenia, nausea, and diarrhea. During maintenance, 46% of patients reported AEs. Midostaurin demonstrated a manageable safety profile and was associated with high transplant and low on-treatment relapse rates.
The Time Has Come for Targeted Therapies for AML: Lights and Shadows. [2020]Acute myeloid leukemia (AML) is a complex disease characterized by genetic and clinical heterogeneity and high mortality. After 40 years during which the standard of care for patients evolved very little, the therapeutic landscape has recently seen rapid changes, with the approval of eight new drugs by the Food and Drug Administration (FDA) within the last 2 years, providing new opportunities, as well as new challenges, for treating clinicians. These therapies include FLT3 inhibitors midostaurin and gilteritinib, CPX-351 (liposomal cytarabine and daunorubicin), gemtuzumab ozogamicin (GO, anti-CD33 monoclonal antibody conjugated with calicheamicin), IDH1/IDH2 inhibitors ivosidenib and enasidenib, Hedgehog inhibitor glasdegib, and BCL-2 inhibitor venetoclax. In this review, we summarize currently available data on these new drugs and discuss the rapidly evolving therapeutic armamentarium for AML, focusing on targeted therapies.
Updates on the Management of Acute Myeloid Leukemia. [2023]Acute myeloid leukemia is a heterogeneous disease defined by a large spectrum of genetic aberrations that are potential therapeutic targets. New targeted therapies have changed the landscape for a disease with poor outcomes. They are more effective than standard chemotherapy with a good safety profile. For "fit patients" in first-line, the combination of gemtuzumab ozogamicin or midostaurin with intensive chemotherapy or Vyxeos is now considered the "standard of care" for selected patients. On the other hand, for "unfit patients", azacitidine-venetoclax has been consolidated as a frontline treatment, while other combinations with magrolimab or ivosidenib are in development. Nevertheless, global survival results, especially in relapsed or refractory patients, remain unfavorable. New immunotherapies or targeted therapies, such as Menin inhibitors or sabatolimab, represent an opportunity in this situation. Future directions will probably come from combinations of different targeted therapies ("triplets") and maintenance strategies guided by measurable residual disease.
New and emerging therapies for acute myeloid leukaemia. [2020]The treatment of acute myeloid leukemia (AML) has remained relatively unchanged for the past 3-4 decades with generally poor outcomes, especially in elderly populations unfit for intensive therapy. Recent advancements, however, have identified several cytogenetic and molecular markers that have not only improved prognostication but have also led to the development of several new targeted therapies for specific subpopulations. In 2017, the US Food and Drug Administration approved four new treatments with indications for fms like tyrosine kinase 3 (FLT3)-mutated AML (midostaurin), newly diagnosed or relapsed/refractory CD33+AML (gemtuzumab ozogamicin), newly diagnosed therapy-related AML or AML with myelodysplasia-related changes (CPX-351) and relapsed/refractory AML with an isocitrate dehydrogenase (IDH)2 mutation (enasidenib). These newly approved therapies have demonstrated improved response in their target populations in several pivotal clinical trials with some also demonstrating improved overall survival. Additional novel therapies in development for AML include agents that target B cell lymphoma 2, FLT3, IDH1, the ubiquitination pathway, as well as cell therapy using engineered T cells with chimeric antigen receptors. This review provides a summary of the four newly approved therapies for AML, as well as several promising therapies currently in development.
Novel agents and regimens in acute myeloid leukemia: latest updates from 2022 ASH Annual Meeting. [2023]Developments in investigational agents and novel regimens in acute myeloid leukemia (AML) were reported in the 2022 American Society of Hematology (ASH) annual meeting. Encouraging efficacy data were presented from first-in-human studies of two investigational menin inhibitors, SNDX-5613 and KO-539, in relapsed and refractory (R/R) acute myeloid leukemia (AML) with KMT2A rearrangement or mutant NPM1, with overall response rates (ORR) of 53% (32/60) and 40% (8/20), respectively. The addition of the novel drug pivekimab sunirine, a first-in-class antibody-drug conjugate targeting CD123, to azacitidine and venetoclax in R/R AML resulted in an ORR of 45% (41/91), which rose to 53% in those who were venetoclax naïve. Additional novel triplet treatment combinations included the addition of magrolimab, an anti-CD47 antibody, to azacitidine and venetoclax, with an ORR of 81% (35/43) in newly diagnosed AML, including an ORR of 74% (20/27) in TP53 mutated AML. The addition of the FLT3 inhibitor gilteritinib to azacitidine/venetoclax was also featured, with an ORR of 100% (27/27) in newly diagnosed AML and an ORR of 70% (14/20) in R/R AML.
Ivosidenib Boosts OS with Azacitidine in AML. [2022]A recent phase III study shows that the combination of azacitidine with the IDH1 inhibitor ivosidenib is more effective than azacitidine alone in patients with acute myeloid leukemia who aren't eligible for intensive chemotherapy. The drug duo tripled overall survival and increased complete remission and event-free survival rates.
A phase 1-2 study of a farnesyltransferase inhibitor, tipifarnib, combined with idarubicin and cytarabine for patients with newly diagnosed acute myeloid leukemia and high-risk myelodysplastic syndrome. [2021]The authors conducted a phase 1/2 study of tipifarnib in combination with idarubicin and cytarabine (IA) in 95 patients with previously untreated acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome.
Rationale and design of the 2 by 2 factorial design GnG-trial: a randomized phase-III study to compare two schedules of gemtuzumab ozogamicin as adjunct to intensive induction therapy and to compare double-blinded intensive postremission therapy with or without glasdegib in older patients with newly diagnosed AML. [2022]Overall survival remains poor in older patients with acute myeloid leukemia (AML) with less than 10% being alive after 5 years. In recent studies, a significant improvement in event-free, relapse-free and overall survival was shown by adding gemtuzumab ozogamicin (GO), a humanized antibody-drug conjugate directed against CD33, to intensive induction therapy once or in a sequential dosing schedule. Glasdegib, the small-molecule inhibitor of smoothened (SMO), also showed improved overall survival in patients not eligible for intensive chemotherapy when combined with low-dose cytarabine compared to low-dose cytarabine alone. These findings warrant further investigations in the phase III GnG trial.