Ziftomenib Combinations for Acute Myeloid Leukemia
Recruiting in Palo Alto (17 mi)
+27 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: Live vaccines
Disqualifiers: Leukostasis, CNS involvement, active infection, others
No Placebo Group
Breakthrough Therapy
Trial Summary
What is the purpose of this trial?This Phase 1 study will assess the safety, tolerability, and preliminary antileukemic activity of ziftomenib in combination with venetoclax and azacitidine (ven/aza), ven, and 7+3 for two different molecularly-defined arms, NPM1-m and KMT2A-r.
Will I have to stop taking my current medications?
The trial protocol does not specify if you need to stop taking your current medications. However, if you are in the relapsed/refractory cohort, you should not have received chemotherapy, immunotherapy, or investigational therapy within 14 days before starting the trial.
What evidence supports the effectiveness of the drug combination including Ziftomenib for treating acute myeloid leukemia?
Research shows that combining venetoclax with azacitidine improves remission rates and survival in patients with acute myeloid leukemia, especially those who are older or not fit for intensive chemotherapy. This suggests that similar drug combinations, like those including Ziftomenib, may also be effective.
12345Is the combination of Ziftomenib and other drugs safe for treating acute myeloid leukemia?
The combination of venetoclax and azacitidine has been studied for safety in patients with acute myeloid leukemia, showing that while it can cause some serious side effects like low white blood cell counts (neutropenia), low platelet counts (thrombocytopenia), and low red blood cell counts (anemia), these side effects are generally considered tolerable.
24678What makes the Ziftomenib combination drug unique for treating acute myeloid leukemia?
The Ziftomenib combination drug is unique because it includes Ziftomenib, a novel component not commonly used in standard treatments for acute myeloid leukemia. This combination also incorporates venetoclax and azacitidine, which have shown improved remission rates and survival in older or unfit patients compared to azacitidine alone.
12789Eligibility Criteria
This trial is for adults with a specific type of leukemia (AML) that's either new or has come back after treatment. They must have certain genetic changes (NPM1 mutation or KMT2A rearrangement), be in decent physical shape, and agree to use birth control. People can't join if they have other active cancers, uncontrolled infections, heart problems, CNS involvement by AML, high white blood cell counts without management options like hydroxyurea or leukapheresis, HIV/Hepatitis B/C infection, or if women are pregnant/breastfeeding.Inclusion Criteria
I agree to use birth control or abstain from sex as required.
My liver, kidneys, and heart are working well.
My AML is either new or has returned, and tests show I have an NPM1 mutation or KMT2A rearrangement.
+1 more
Exclusion Criteria
I have a known BCR-ABL gene change.
Mean corrected QT interval corrected for heart rate by Fredericia's formula (QTcF) >480 ms on triplicate ECGs
I have not received any live vaccines within the last 14 days and won't until my B-cell levels recover.
+12 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Participants receive ziftomenib in combination with venetoclax/azacitidine, venetoclax, or 7+3 chemotherapy
28 days per cycle, multiple cycles
Regular visits per cycle
Follow-up
Participants are monitored for safety and effectiveness after treatment
Up to 1 year
Long-term follow-up
Participants are assessed for overall survival and other long-term outcomes
Up to 1 year following end of treatment
Participant Groups
The study tests the safety and potential effectiveness of Ziftomenib combined with Venetoclax/Azacitidine ('ven/aza'), just Venetoclax ('ven'), or standard chemo ('7+3') in patients with Acute Myeloid Leukemia (AML). It focuses on those who have NPM1 mutations or KMT2A rearrangements.
11Treatment groups
Experimental Treatment
Group I: Dose Validation/Expansion: Ziftomenib/Venetoclax/Azacitidine in R/R NPM1-m (A-1)Experimental Treatment3 Interventions
Ziftomenib/Venetoclax/Azacitidine in relapsed/refractory NPM1-m AML patients who have failed at least one prior line of therapy
Group II: Dose Validation/Expansion: Ziftomenib/Venetoclax/Azacitidine in R/R KMT2A-r (B-1)Experimental Treatment3 Interventions
Ziftomenib/Venetoclax/Azacitidine in relapsed/refractory KMT2A-r AML patients who have failed at least one prior line of therapy
Group III: Dose Validation/Expansion: Ziftomenib/Venetoclax/Azacitidine in 1L NPM1-m (A-4)Experimental Treatment3 Interventions
Ziftomenib/Venetoclax/Azacitidine in newly diagnosed NPM1-m AML patients
Group IV: Dose Validation/Expansion: Ziftomenib/Venetoclax/Azacitidine in 1L KMT2A-r (B-3)Experimental Treatment3 Interventions
Ziftomenib/Venetoclax/Azacitidine in newly diagnosed KMT2A-r AML patients
Group V: Dose Validation/Expansion: Ziftomenib/Venetoclax in R/R NPM1-m (A-3)Experimental Treatment2 Interventions
Ziftomenib/Venetoclax in relapsed/refractory NPM1-m AML patients who have failed at least one prior line of therapy
Group VI: Dose Validation/Expansion: Ziftomenib/7+3 in 1L NPM1-m (A-2)Experimental Treatment3 Interventions
Ziftomenib/7+3 in newly diagnosed NPM1-m AML patients who are candidates for intensive chemotherapy and meet the protocol definition of high-risk disease
Group VII: Dose Validation/Expansion: Ziftomenib/7+3 in 1L KMT2A-r (B-2)Experimental Treatment3 Interventions
Ziftomenib/7+3 in newly diagnosed KMT2A-r AML patients who are candidates for intensive chemotherapy
Group VIII: Dose Escalation: Ziftomenib/Venetoclax/Azacitidine in R/R NPM1-m (A-1)Experimental Treatment3 Interventions
Ziftomenib/Venetoclax/Azacitidine in relapsed/refractory NPM1-m AML patients who have failed at least one prior line of therapy
Group IX: Dose Escalation: Ziftomenib/Venetoclax/Azacitidine in R/R KMT2A-r (B-1)Experimental Treatment3 Interventions
Ziftomenib/Venetoclax/Azacitidine in relapsed/refractory KMT2A-r AML patients who have failed at least one prior line of therapy
Group X: Dose Escalation: Ziftomenib/7+3 in 1L NPM1-m (A-2)Experimental Treatment3 Interventions
Ziftomenib/7+3 in newly diagnosed NPM1-m AML patients who are candidates for intensive chemotherapy and meet the protocol definition of high-risk disease
Group XI: Dose Escalation: Ziftomenib/7+3 in 1L KMT2A-r (B-2)Experimental Treatment3 Interventions
Ziftomenib/7+3 in newly diagnosed KMT2A-r AML patients who are candidates for intensive chemotherapy and meet the protocol definition of high-risk disease
Azacitidine is already approved in European Union, United States, Canada, Japan, Australia for the following indications:
🇪🇺 Approved in European Union as Vidaza for:
- Acute myeloid leukemia
- Chronic myelomonocytic leukemia
- Myelodysplastic syndromes
🇺🇸 Approved in United States as Vidaza for:
- Myelodysplastic syndromes
- Chronic myelomonocytic leukemia
🇨🇦 Approved in Canada as Vidaza for:
- Myelodysplastic syndromes
- Acute myeloid leukemia
🇯🇵 Approved in Japan as Vidaza for:
- Myelodysplastic syndromes
- Acute myeloid leukemia
🇦🇺 Approved in Australia as Vidaza for:
- Myelodysplastic syndromes
- Acute myeloid leukemia
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Karmanos Cancer InstituteDetroit, MI
Robert H. Lurie Comprehensive Cancer Center of Northwestern UniversityChicago, IL
Moores UC San Diego Cancer CenterLa Jolla, CA
Sarah Cannon Research Institute - St. David's South Austin Medical Center / Texas Oncology South AustinAustin, TX
More Trial Locations
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Who Is Running the Clinical Trial?
Kura Oncology, Inc.Lead Sponsor
References
Phase II Study of Venetoclax Added to Cladribine Plus Low-Dose Cytarabine Alternating With 5-Azacitidine in Older Patients With Newly Diagnosed Acute Myeloid Leukemia. [2023]The combination of venetoclax and 5-azacitidine (5-AZA) for older or unfit patients with acute myeloid leukemia (AML) improves remission rates and survival compared with 5-AZA alone. We hypothesized that the addition of venetoclax to cladribine (CLAD)/low-dose araC (low-dose cytarabine [LDAC]) alternating with 5-AZA backbone may further improve outcomes for older patients with newly diagnosed AML.
The efficacy and safety of venetoclax and azacytidine combination treatment in patients with acute myeloid leukemia and myelodysplastic syndrome: systematic review and meta-analysis. [2023]The meta-analysis sought to evaluate the efficacy and safety of a combination of venetoclax (Ven) and azacitidine (AZA) in the treatment of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS).
Venetoclax plus azacitidine in Japanese patients with untreated acute myeloid leukemia ineligible for intensive chemotherapy. [2023]The phase 3 VIALE-A trial (NCT02993523) reported that venetoclax-azacitidine significantly prolonged overall survival compared with placebo-azacitidine in patients with newly diagnosed acute myeloid leukemia ineligible for intensive chemotherapy. Herein, efficacy and safety of venetoclax-azacitidine are analyzed in the Japanese subgroup of VIALE-A patients.
[Efficacy of venetoclax combined azacitidine in newly diagnosed acute myeloid leukemia unfit for standard chemotherapy: a single center experience]. [2023]Objective: To investigate the effectiveness and safety of the VA regimen, which combines venetoclax with azacitidine in the treatment of patients with newly diagnosed acute myeloid leukemia (AML) who are not suitable candidates for conventional chemotherapy. Methods: In the Department of Hematology at the Second Hospital of Hebei Medical University, 66 AML patients who received venetoclax and azacitidine treatment from May 2020 to March 2022 were the subject of a retrospective study. The complete remission (CR) rate, cCR rate, ORR rate, MRD negative rate, the incidence of adverse events,1-year EFS, and OS were retrospectively analyzed. Patients subgroups with varying ages, ECOG scores, primary and secondary, risk stratifications, and gene mutation were compared for differences in efficacy and survival. Results: The median follow-up was 4.25 (0.9-19.9) months, and the median number of treatment courses was 2 (1-8) cycles. After the first cycle, the cCR rate was 78.8% , and the MRD negative rate was 51.9% . After prolonged treatment, the cCR rate was 81.8% and MRD negative rate was 66.7% . The median EFS and OS, respectively, were13.2 and 15.3 months. Secondary AML showed inferior efficacy and prognosis. IDH1/2 or NPM1 mutation groups had a significantly higher rate of CR than the control group (P<0.05) . The CR rate and MRD negative rate of patients with rebound thrombocytosis were significantly higher than those without rebound thrombocytosis (P<0.05) . Those who had epigenetic modification mutations (DNMT3, ASXL1, TET2) were more likely to benefit from ongoing therapy. The most common grade 3 and 4 adverse reactions were neutropenia, thrombocytopenia, and anemia. Conclusions: In real-world patients with newly diagnosed AML who are not candidates for standard chemotherapy, the VA regimen produces rapid deep remission. Primary AML patients, rebound thrombocytosis, IDH1/2, and NPM1 gene mutations are favorable factors for treatment benefit, and adverse reactions were tolerable.
Clinical and molecular predictors of response and survival following venetoclax therapy in relapsed/refractory AML. [2021]Azacitidine + venetoclax, decitabine + venetoclax, and low-dose cytarabine + venetoclax are now standard treatments for newly diagnosed older or unfit patients with acute myeloid leukemia (AML). Although these combinations are also commonly used in relapsed or refractory AML (RR-AML), clinical and molecular predictors of response and survival in RR-AML are incompletely understood. We retrospectively analyzed clinical and molecular characteristics and outcomes for 86 patients with RR-AML who were treated with venetoclax combinations. The complete remission (CR) or CR with incomplete hematologic recovery (CRi) rate was 24%, and the overall response rate was 31% with the inclusion of a morphologic leukemia-free state. Azacitidine + venetoclax resulted in higher response rates compared with low-dose cytarabine + venetoclax (49% vs 15%; P = .008). Median overall survival (OS) was 6.1 months, but it was significantly longer with azacitidine + venetoclax compared with low-dose cytarabine + venetoclax (25 vs 3.9 months; P = .003). This survival advantage of azacitidine + venetoclax over low-dose cytarabine + venetoclax persisted when patients were censored for subsequent allogeneic stem cell transplantation (8.1 vs 3.9 months; P = .035). Mutations in NPM1 were associated with higher response rates, whereas adverse cytogenetics and mutations in TP53, KRAS/NRAS, and SF3B1 were associated with worse OS. Relapse was driven by diverse mechanisms, including acquisition of novel mutations and an increase in cytogenetic complexity. Venetoclax combination therapy is effective in many patients with RR-AML, and pretreatment molecular characteristics may predict outcomes. Trials that evaluate novel agents in combination with venetoclax therapy in patients with RR-AML that have adverse risk genomic features are warranted.
[Short-term efficacy of venetoclax combined with azacitidine in acute myeloid leukemia: a single-institution experience]. [2022]Objective: To explore the safety and short-term efficacy of venetoclax combined with azacitidine (Ven+AZA) in previously untreated patients unfit for standard chemotherapy and patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) in China. Methods: A retrospective study was conducted in 60 previously untreated patients unfit for standard chemotherapy and patients with R/R AML who received Ven+ AZA (venetoclax, 100 mg D1, 200 mg D2, 400 mg D3-28; azacitidine, 75 mg/m(2) D1- 7) at the Peking University Institute of Hematology from June 1, 2019 to May 31, 2021. The incidence of adverse events, complete remission (CR) /CR with incomplete hematological recovery (CRi) rate, objective remission rate (ORR) , and minimal residual disease (MRD) status in patients with different risk stratification and gene subtypes were analyzed. Results: The median age of the patients was 54 (18-77) years, 33 (55.0%) were males, and the median follow-up time was 4.8 (1.4-26.3) months. Among the 60 patients, 24 (40.0%) were previously untreated patients unfit for standard chemotherapy, and 36 (60.0%) were R/R patients. The median mumber cycles of Ven+AZA in the two groups were both 1 (1-5) . According to the prognostic risk stratification of the National Comprehensive Cancer Network, it was divided into 8 cases of favorable-risk, 2 cases of intermediate risk, and 14 cases of poor-risk. In previously untreated patients unfit for standard chemotherapy, after the first cycle of Ven+AZA, 17/24 (70.8%) cases achieved CR/CRi, 3/24 (12.5%) achieved partial remission (PR) , and the ORR was 83.3%. Among them, nine patients received a second cycle chemotherapy and two received a third cycle. Among CR/CRi patients, 8/17 (47.1%) achieved MRD negativity after two cycles of therapy. In the R/R group, after the first cycle of Ven+AZA, 21/36 (58.3%) cases achieved CR/CRi (7/21 achieved MRD negativity) , 3 achieved PR, and the ORR was 66.7%. Among R/R patients, 12 were treated for more than two cycles. There were no new CR/CRi patients after the second treatment cycle, and 14 cases (66.7%) achieved MRD negativity. According to the time from CR to hematological recurrence, the R/R group was divided into 12 cases in the favorable-risk group (CR to hematological recurrence ≥18 months) and 24 in the poor-risk group (CR to hematological recurrence<18 months, no remission after one cycle of therapy, and no remission after two or more cycles of therapy) . Eleven of 24 (45.8%) cases achieved CR/CRi after one cycle of Ven+AZA in the poor-risk R/R group, and 10 of 12 (83.3%) achieved CR/CRi in the favorable-risk R/R group, which was significantly superior to the poor-risk group (P=0.031) . After one cycle of treatment, 13 patients with IDH1/2 mutations and 4 that were TP53-positive all achieved CR/CRi. The CR/CRi rate of 18 patients with NPM1 mutations was 77.8%. Five patients with RUNX1-RUNX1T1 combined with KIT D816 mutation (two initial diagnoses and three recurrences) had no remission. Ven+ AZA was tolerable for AML patients. Conclusion: Ven+AZA has acceptable safety in previously untreated patients unfit for standard chemotherapy, patients with R/R AML can achieve a high response rate, and some patients can achieve MRD negativity. It is also effective in NPM1-, IDH1/IDH2-, and TP53-positive patients. The long-term efficacy remains to be observed.
SARS-CoV-2 Infection in Patients Treated with Azacitidine and Venetoclax for Acute Leukemia: A Report of a Case Series Treated in a Single Institution. [2023]Venetoclax combined with azacitidine (AZA-VEN) constitutes an option for the treatment of acute myeloid leukemia. There are, however, no data on the COVID-19 incidence and outcome in patients treated with AZA-VEN.
Venetoclax plus 3 + 7 daunorubicin and cytarabine chemotherapy as first-line treatment for adults with acute myeloid leukaemia: a multicentre, single-arm, phase 2 trial. [2022]Adults with acute myeloid leukaemia have unsatisfactory clinical outcomes and rates of complete remission. Venetoclax combined with azacytidine or low-dose cytarabine has shown efficacy in adults aged 75 years or older (or 18-74 years with comorbidities precluding intensive chemotherapy) with acute myeloid leukaemia. We aimed to investigate the activity and safety of venetoclax plus 3+7 daunorubicin and cytarabine chemotherapy in adults with acute myeloid leukaemia.
Venetoclax-based combinations for acute myeloid leukemia: optimizing their use in Latin-America. [2022]Objectives: Venetoclax combinations are a new standard for patients with acute myeloid leukemia (AML). We aimed to evaluate the safety and efficacy of these combinations in a period of accelerated approval in Latin-America.Methods: This observational study evaluated adults with acute myeloid leukemia who received venetoclax-based therapy in 11 public or private centers in Mexico and Peru for both newly diagnosed or relapsed and refractory AML.Results: Fifty patients were included; 28 with newly diagnosed (ND) AML and 22 with relapsed/refractory (RR) disease. ND patients were older (64 vs. 40 years; p < 0.001) with a lower functional capacity (ECOG ≥2 64.3% vs 9%; p < 0.001). Venetoclax was frequently combined with azacytidine (60%) and prophylactic azoles (82%) with a median maximum dose of 200 mg (range, 100-600 mg). Hematologic toxicities were common. Complete response rates including patients with incomplete hematopoietic recovery were 78.6% in ND and 45.5% in RR patients, with a median overall survival of 9.6 (95% CI 3.7-15.5) and 8 months (95% CI 4.8-11.2).Discussion: Our study showed a preferred use of venetoclax plus azacytidine over cyatrabine. Patients in the first-line setting were similar to those in the landmark studies, while most patients with relapsed disease had received prior intensive therapies. Responses were favorable, with a median survival in agreement to other reports, albeit shorter than that observed in the randomized phase-3 trials.Conclusion: Venetoclax-based therapy in AML was effective despite dose reductions and prophylactic antifungals in two middle-income countries outside of a clinical trial setting.