Targeted Therapies for Acute Myeloid Leukemia

Recruiting at 12 trial locations

Overseen By Ashley Yocum, PhD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Beat AML, LLC

Must not be taking: Hypomethylating agents

Disqualifiers: Myeloid sarcoma, Promyelocytic leukemia, CNS involvement, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 1

Duration: Up to 12 months

2000 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, it mentions that prior treatment with certain medications is allowed, so it's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the drug Venetoclax in treating acute myeloid leukemia?

Venetoclax, when combined with azacitidine, has shown effectiveness in treating acute myeloid leukemia (AML), particularly in newly diagnosed elderly or unfit patients, with complete remission rates of 28.3% and an improvement in overall survival. It has also demonstrated activity in relapsed/refractory AML, with remission rates of 33-46%, although these remissions are often short-lived. ^{1 2 3 4 5}

Is the treatment generally safe for humans?

Venetoclax, when combined with low-dose cytarabine or azacitidine, has shown lower toxicity compared to intensive chemotherapy for acute myeloid leukemia (AML) patients who cannot receive standard treatment. Common side effects include neutropenia (low white blood cell count), thrombocytopenia (low platelet count), and anemia, but these adverse reactions are generally considered tolerable. ^{2 5 6 7 8}

What makes the drug combination for acute myeloid leukemia unique?

This treatment combines several targeted therapies, including venetoclax, which is a BCL2 inhibitor, and azacitidine, a hypomethylating agent, to enhance effectiveness against acute myeloid leukemia. The combination is particularly beneficial for older patients or those unfit for intensive chemotherapy, offering a novel approach by targeting specific genetic mutations and pathways involved in the disease. ^{3 4 5 9 10}

What is the purpose of this trial?

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 evaluate investigational therapies or combinations with the ultimate goal of advancing new targeted therapies for approval. The study also includes a marker negative sub-study which will include all screened patients not eligible for any of the biomarker-driven sub-studies.

Research Team

John C Byrd, MD

Principal Investigator

Beat AML

Eligibility Criteria

This trial is for adults with acute myeloid leukemia (AML). Group A includes those who haven't been treated before, except possibly with hydroxyurea. People over 60 or certain younger adults with specific genetic markers can join. Group B is for those whose AML has returned or didn't respond to treatment. You can't join if you have brain involvement by AML, active bleeding disorders, isolated myeloid sarcoma without blood/marrow involvement, a type of leukemia called acute promyelocytic leukemia, or other serious medical conditions.

Inclusion Criteria

I am 60 or older, or I am 18 or older with specific genetic factors.

Subjects must be able to understand and provide written informed consent

My AML has come back or didn't respond to treatment, and I am 18 or older.

Exclusion Criteria

I have a blood clotting disorder with active bleeding or signs of clotting.

Patients with psychological, familial, social, or geographic factors that otherwise preclude them from giving informed consent, following the protocol, or potentially hamper compliance with study treatment and follow-up

I have been diagnosed with acute promyelocytic leukemia.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

1 visit (in-person)

Treatment

Participants are assigned to sub-studies based on genomic screening to evaluate investigational therapies or combinations

Up to 12 months

Monthly visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 5 years

Periodic visits (in-person)

Treatment Details

Interventions

• AG-120
• AG-221
• Azacitidine
• AZD5153
• AZD5991
• BI 836858
• Cytarabine
• Daunorubicin
• Entospletinib
• Gilteritinib
• Laboratory Biomarker Analysis
• Pevonedistat
• SNDX-5613
• TP-0903
• Venetoclax

Trial Overview The study tests different treatments based on patients' specific genetic types of AML. It's part of a larger 'Master Protocol' that assigns people to sub-studies testing various drugs and combinations like SNDX-5613, Gilteritinib, Venetoclax and others alongside standard therapies such as Azacitidine and Cytarabine.

Participant Groups

Group I: BAML-16-001-S9 (Closed) Experimental Treatment 3 Interventions

This is an open-label phase 2 clinical trial of a stepwise approach to the treatment of patients with TP53 mutation AML. On day 1, all enrolled participants will be initiated on therapy with pevonedistat (20 mg/m2) day 1, 3 and 5 together with azacitidine (75 mg/m2 days 1-7 or day 1-5 then day 8, 9) every 28 days. During cycle 1, patients with rapidly progressive disease or severe organ dysfunction, not correctable by hydroxyurea cytoreduction will not be eligible to continue. Those patients who achieved a response, defined as complete response or complete response with incomplete blood count recovery, by the end of cycle 4 will continue on pevonedistat and azacitidine until disease progression, unacceptable toxicity, or 12 cycles of therapy. After 12 months of combined therapy, pevonedistat will be continued until progression of disease, unacceptable toxicity, or up to 2 years of total therapy.

Group II: BAML-16-001-S8 (Closed) Experimental Treatment 6 Interventions

This is an open-label Phase 1b/2 clinical study of gilteritinib monotherapy, gilteritinib in combination with decitabine, or gilteritinib in combination with decitabine and venetoclax in untreated FLT3 mutated AML with high and low variant allele frequency. Initially, the combination of gilteritinib and decitabine was tested (Group 1); however, subsequently the combination of decitabine and venetoclax was shown to be a highly effective therapy for older AML patients, so the triple combination of gilteritinib in combination with decitabine and venetoclax (Group 2) is now being evaluated in this study.

Group III: BAML-16-001-S6 (Closed) Experimental Treatment 4 Interventions

The study is an open-label phase 2 study of entospletinib in younger and older AML patients with NPM1+/FLT3ITD-AML. It includes patients age ≥18 years who are able and willing to receive 7 + 3 intensive chemotherapy. Entospletinib is administered daily with IV daunorubicin (days 1-3 for Cycle 1) and cytarabine (days 1-7 for Cycle 1). If a second induction is required, it is given with IV daunorubicin (days 1-2 for Cycle 2) and cytarabine (days 1-5 for Cycle 2).

Group IV: BAML-16-001-S5 (Closed) Experimental Treatment 3 Interventions

This is a phase 2 clinical trial to assess the feasibility and efficacy of a stepwise approach to the treatment of patients with TP53 mutations (identified molecularly) with/without complex karyotype (Cohort A) or complex karyotype (3 or greater metaphase abnormalities without TP53) (Cohort B). All enrolled participants will be initiated on entospletinib 400 mg orally twice daily. This dose will be administered continuously in 28 day cycles.

Group V: BAML-16-001-S4 (Closed) Experimental Treatment 3 Interventions

This is a 2 cohort phase 1b/2 clinical trial to assess the feasibility and efficacy of entospletinib (ENTO) stepwise approach to the treatment of patients with balanced translocations of MLL identified cytogenetically (Cohort 1) and patients with MLL-partial tandem duplications identified molecularly (Cohort 2). All enrolled participants will be initiated on monotherapy with ENTO 400 mg PO BID. This dose will be administered continuously in 28 day cycles.

Group VI: BAML-16-001-S3 (Closed) Experimental Treatment 3 Interventions

This is a phase 2 clinical trial to assess the feasibility and efficacy of a stepwise approach to the treatment of IDH2-mutant AML. On day 1 of the trial, all enrolled participants will be initiated on therapy with the IDH2 inhibitor AG-221 for IDH2 R140 and R172-mutant patients. The dosing will be based on phase 1 experience of AG-221, which has established 100 mg daily as a safe and tolerated dose, with preliminary suggestion of efficacy. These will be administered continuously in 28 day cycles. Hydroxyurea will be allowed for the purposes of cytoreduction.

Group VII: BAML-16-001-S21 Experimental Treatment 1 Intervention

This is a Phase 1, open-label, multicenter, dose escalation, and dose optimization study to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of ZE46-0134 in adult patients with relapsed or refractory AML with FLT3-ITD and/or FLT3-TKD mutations. Patients with AML that are out-patients or hospitalized due to their AML can be enrolled in the study. The study will be run in 2 parts: Part 1 will be dose escalation and determination of the maximum tolerated dose, and Part 2 will be dose expansion.

Group VIII: BAML-16-001-S2 (Closed) Experimental Treatment 3 Interventions

This is an open-label Phase 1b/2 clinical study of BI 836858 given in combination with azacitidine, followed by BI 836858 plus azacitidine maintenance, in newly diagnosed acute myeloid leukemia. The target population is assigned by the Beat AML Master Protocol (the "umbrella" study). Eligible patients will have previously untreated acute myeloid leukemia, age greater than or equal to 60, with any 1 of the following: mutated TET2, IDH1, IDH2, or WT1, or "marker negative" as defined by the overall Beat AML umbrella protocol.

Group IX: BAML-16-001-S18 (Closed) Experimental Treatment 3 Interventions

This is an open-label Phase 1b clinical study of AZD5991 + azacitidine in patients aged ≥60 years with newly diagnosed, previously untreated, hypermethylated and marker-negative AML. The phase 1b1 study will adopt a standard 3+3 design with dose escalation based upon dose limiting toxicities. The recommended Phase 2 dose (RP2D) is defined in this study as the highest dose level where less than 2 dose limiting toxicities (DLT) are observed out of 6 patients. Once the RP2D is defined, patients will be enrolled into 2 separate cohorts (hypermethylation and marker negative group) for the phase 1b2 expansion. These 2 groups will both be treated at the RP2D determined from phase 1b1.

Group X: BAML-16-001-S17 Experimental Treatment 4 Interventions

This is an open-label Phase 1b dose escalation and expansion clinical trial to determine the safety and recommended dose of SNDX-5613 combined with azacitidine and venetoclax in newly diagnosed, untreated AML patients age ≥ 60 years who are not candidates or do not wish to pursue intensive induction therapy and who have NPM1 mutated or MLL-rearranged disease. After determination of the recommended dose of SNDX-5613, the study will have an expansion cohort to be treated at the recommended dose in combination with azacitidine and venetoclax in the same patient population.

Group XI: BAML-16-001-S16 (Closed) Experimental Treatment 3 Interventions

This is an open-label phase 2 clinical study to assess the feasibility and efficacy of a combination based approach to the treatment of IDH1 mutant AML. On day 1 of the trial, all enrolled participants will be initiated on therapy with the IDH1 inhibitor AG-120 given daily together with azacitidine (days 1-5 and 8-9 or 7 consecutive days 1-7) in 28 day cycles for IDH1 mutant patients. Those patients who have achieved a response, defined as complete response or complete response with incomplete blood count recovery, by the end of cycle 6, will continue on combination therapy for a total of 12 cycles and then patients will go onto receive monotherapy with AG-120 until disease progression or unacceptable side effects that mandate discontinuation of therapy. Patients who cannot complete 12 cycles of azacitidine may proceed onto monotherapy with AG-120.

Group XII: BAML-16-001-S14 (Closed) Experimental Treatment 3 Interventions

The study is an open-label Phase 1b/2 clinical study of TP-0903 given in addition to decitabine in patients ≥ 60 years with newly diagnosed, previously untreated AML with TP53 mutations and/or complex karyotype. The Phase 1b portion of this study will use a standard 3 + 3 design with dose escalation based upon dose limiting toxicities. The maximum tolerated dose will be defined as the highest dose where at most 1 patient in 6 experiences dose-limiting toxicity, and this is generally the recommended Phase 2 dose (RP2D). Once the RP2D is determined from Phase 1b, patients will be enrolled at this dose level to initiate the Phase 2 portion of the study.

Group XIII: BAML-16-001-S12 (Arm B) Experimental Treatment 2 Interventions

This is an open label phase 2 randomized study in which eligible AML patients will be randomly assigned (1:1) to receive either the FDA label-approved regimen of 28-day Venetoclax + Azacitidine (Arm A) or the 14-day regimen of Venetoclax + Azacitidine (Arm B). Newly diagnosed acute myeloid leukemia (AML) patients ≥ 60 years will be enrolled.

Group XIV: BAML-16-001-S10 (Closed) Experimental Treatment 3 Interventions

This is a phase 1b/2 clinical trial to assess the safety and efficacy of the combination of AZD5153 and venetoclax. In a phase 1b component, safety and tolerability of the combination will be assessed in relapsed/refractory AML patients ≥ 18 years of age. Following determination of the recommended Phase 2 dose (RP2D), newly diagnosed, marker negative patients age ≥ 60 will be enrolled in the phase 2 component; these patients will be treated at the previously identified RP2D for the combination. The RP2D will be the highest dose level with ≤ 1 out of 6 patients with dose limiting toxicity and defined as the maximum tolerated dose.

Group XV: BAML-16-001-S1 (Closed) Experimental Treatment 4 Interventions

This is an open-label Phase 1b/2 clinical study of Samalizumab given in addition to standard induction chemotherapy/consolidation, followed by Samalizumab maintenance, in newly diagnosed acute myeloid leukemia. Patients that are marker negative, as defined based on the Beat AML Master Protocol assignment or with CBF karyotype/interphase cytogenetics/molecular testing defined by presence of t(8;21)(q22;q22) or the molecular equivalent RUNX1/RUNX1T1 fusion transcript or inv(16)(p13q22) or t(16;16)(p13;q22) or the molecular equivalent CBFB/MYH11 fusion transcript based on the Beat AML will receive Samalizumab in combination with induction therapy followed by Samalizumab maintenance.

Group XVI: BAML-16-001-S12 (Arm A) Active Control 2 Interventions

This is an open label phase 2 randomized study in which eligible AML patients will be randomly assigned (1:1) to receive either the FDA label-approved regimen of 28-day Venetoclax + Azacitidine (Arm A) or the 14-day regimen of Venetoclax + Azacitidine (Arm B). Newly diagnosed acute myeloid leukemia (AML) patients ≥ 60 years will be enrolled.

AG-120 is already approved in United States for the following indications:

Approved in United States as Tibsovo for:

• Acute myeloid leukemia (AML) with a susceptible IDH1 mutation

Who Is Running the Clinical Trial?

Beat AML, LLC

Lead Sponsor

Trials

1

Recruited

2,000+

Findings from Research

In a study of 35 patients with relapsed or refractory acute myeloid leukaemia (R/R AML) treated with venetoclax-azacitidine (VEN-AZA), the complete remission rate was significantly higher at 48.6% compared to 15% in a historical cohort treated with azacitidine (AZA).

Patients receiving VEN-AZA also showed a trend towards longer overall survival (12.8 months) compared to those treated with AZA (7.3 months), indicating that VEN-AZA may offer a more effective treatment option for R/R AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Azacitidine-venetoclax versus azacitidine salvage treatment for primary induction failure or first relapsed acute myeloid leukaemia patients. Petit, C., Saillard, C., Mohty, B., et al.[2023]

In a pooled analysis of treatment-naïve patients with FLT3-mutant acute myeloid leukemia, the combination of venetoclax and azacitidine resulted in a significantly higher composite complete remission rate (67%) compared to azacitidine alone (36%), with a median overall survival of 12.5 months versus 8.6 months.

The treatment was found to be safe, with no unexpected toxicities reported, indicating that venetoclax + azacitidine is a promising option for older patients or those with comorbidities who are ineligible for intensive therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of FLT3 Mutation on Outcomes after Venetoclax and Azacitidine for Patients with Treatment-Naïve Acute Myeloid Leukemia. Konopleva, M., Thirman, MJ., Pratz, KW., et al.[2023]

Two investigational menin inhibitors, SNDX-5613 and KO-539, showed promising efficacy in treating relapsed and refractory acute myeloid leukemia (AML), with overall response rates of 53% and 40%, respectively, in patients with specific genetic mutations.

The combination of pivekimab sunirine with azacitidine and venetoclax achieved a 45% overall response rate in relapsed and refractory AML, which increased to 53% in patients who had not previously received venetoclax, highlighting the potential of novel treatment combinations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Novel agents and regimens in acute myeloid leukemia: latest updates from 2022 ASH Annual Meeting. DiNardo, KW., LeBlanc, TW., Chen, H.[2023]

In a study of 16 patients with FLT3-ITD mutated relapsed/refractory acute myeloid leukemia (AML), the combination of venetoclax (VEN) and azacitidine (AZA) showed some efficacy, with 14.3% of FLT3-ITDmut patients achieving complete remission, similar to the 22.2% in the FLT3-ITD wild-type group.

Patients with FLT3-ITD mutations had a significantly shorter median overall survival (130 days) compared to those without the mutation (300 days), suggesting that additional treatments, like transplantation, may be necessary for better outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Efficacy of Venetoclax Plus Azacitidine in Relapsed/Refractory Acute Myeloid Leukemia Patients with FLT3-ITD Mutation]. Weng, GY., You, WW., Liu, HX., et al.[2023]

Venetoclax (VEN) is FDA approved for treating newly diagnosed elderly or unfit patients with acute myeloid leukemia (AML) when combined with hypomethylating agents, showing complete remission rates of 28.3% and overall survival improvements in a phase-3 study.

While VEN has demonstrated effectiveness in various myeloid malignancies, including relapsed AML and high-risk myelodysplastic syndromes, remissions are often short-lived, typically lasting less than a year, but can facilitate transitions to allogeneic stem cell transplants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax-based chemotherapy in acute and chronic myeloid neoplasms: literature survey and practice points. Gangat, N., Tefferi, A.[2023]

In a study of 26 adult patients with relapsed/refractory acute myeloid leukemia (R/R AML), the combination of venetoclax (VEN) with demethylating agents (azacitidine or decitabine) resulted in a 57.7% overall response rate, including 13 complete responses, indicating its efficacy as a salvage therapy.

Patients who achieved minimal residual disease negativity had significantly better overall survival and event-free survival, highlighting the importance of this outcome in improving long-term prognosis for R/R AML patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Clinical Observation of Venetoclax Combined with Demethylating Agents on the Treatment of Relapsed/Refractory Acute Myeloid Leukemia]. Wang, Y., Huang, SL., Zhang, XX., et al.[2023]

The VA regimen, combining venetoclax and azacitidine, demonstrated a high complete remission (cCR) rate of 78.8% after the first treatment cycle and 81.8% after prolonged treatment in 66 patients with newly diagnosed acute myeloid leukemia (AML) who were not suitable for conventional chemotherapy.

The treatment was generally safe, with manageable adverse effects, primarily neutropenia, thrombocytopenia, and anemia, and showed better outcomes in patients with specific gene mutations (IDH1/2 or NPM1) and those experiencing rebound thrombocytosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Efficacy of venetoclax combined azacitidine in newly diagnosed acute myeloid leukemia unfit for standard chemotherapy: a single center experience]. Sun, L., Ye, SJ., Zhou, N., et al.[2023]

Venetoclax combined with low-dose cytarabine (VEN + LDAC) offers a promising low-intensity treatment option for older patients with acute myeloid leukaemia (AML) who cannot tolerate intensive chemotherapy, showing lower toxicity and the potential for comparable remission and survival rates for specific genotypes.

The VICTOR trial is a phase II study designed to assess the effectiveness of VEN + LDAC compared to standard intensive chemotherapy in patients aged 60 and older, with a focus on maintaining quality of life and reducing healthcare costs, while employing an adaptive design to potentially include younger patients if results are favorable.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax combined with low dose cytarabine compared to standard of care intensive chemotherapy for the treatment of favourable risk adult acute myeloid leukaemia (VICTOR): Study protocol for an international, open-label, multicentre, molecularly-guided randomised, phase II trial. Dillon, R., Maycock, S., Jackson, A., et al.[2022]

The combination of vosaroxin and venetoclax synergistically induces apoptosis in acute myeloid leukemia (AML) cell lines and primary patient samples, suggesting a potent anti-leukemic effect.

This combination treatment effectively targets AML progenitor cells while sparing normal hematopoietic progenitor cells, indicating a potentially safer therapeutic option for elderly patients with AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax Synergistically Enhances the Anti-leukemic Activity of Vosaroxin Against Acute Myeloid Leukemia Cells Ex Vivo. Liu, F., Knight, T., Su, Y., et al.[2020]

The BCL2 inhibitor venetoclax, when combined with low-dose cytarabine or hypomethylating agents, is both safe and effective for older patients with newly diagnosed acute myeloid leukemia (AML) who cannot undergo intensive chemotherapy.

New targeted therapies, such as glasdegib and CPX-351, have shown improved survival rates in specific patient populations, highlighting the importance of genomic characterization in selecting the most effective treatment for AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Single-agent and combination biologics in acute myeloid leukemia. Richard-Carpentier, G., DiNardo, CD.[2022]

References

1. England pubmed.ncbi.nlm.nih.gov

Azacitidine-venetoclax versus azacitidine salvage treatment for primary induction failure or first relapsed acute myeloid leukaemia patients. [2023]

2. United States pubmed.ncbi.nlm.nih.gov

Impact of FLT3 Mutation on Outcomes after Venetoclax and Azacitidine for Patients with Treatment-Naïve Acute Myeloid Leukemia. [2023]

3. England pubmed.ncbi.nlm.nih.gov

Novel agents and regimens in acute myeloid leukemia: latest updates from 2022 ASH Annual Meeting. [2023]

4. China pubmed.ncbi.nlm.nih.gov

[Efficacy of Venetoclax Plus Azacitidine in Relapsed/Refractory Acute Myeloid Leukemia Patients with FLT3-ITD Mutation]. [2023]

5. United States pubmed.ncbi.nlm.nih.gov

Venetoclax-based chemotherapy in acute and chronic myeloid neoplasms: literature survey and practice points. [2023]

6. China pubmed.ncbi.nlm.nih.gov

[Clinical Observation of Venetoclax Combined with Demethylating Agents on the Treatment of Relapsed/Refractory Acute Myeloid Leukemia]. [2023]

7. China pubmed.ncbi.nlm.nih.gov

[Efficacy of venetoclax combined azacitidine in newly diagnosed acute myeloid leukemia unfit for standard chemotherapy: a single center experience]. [2023]

8. England pubmed.ncbi.nlm.nih.gov

Venetoclax combined with low dose cytarabine compared to standard of care intensive chemotherapy for the treatment of favourable risk adult acute myeloid leukaemia (VICTOR): Study protocol for an international, open-label, multicentre, molecularly-guided randomised, phase II trial. [2022]

9. France pubmed.ncbi.nlm.nih.gov

Venetoclax Synergistically Enhances the Anti-leukemic Activity of Vosaroxin Against Acute Myeloid Leukemia Cells Ex Vivo. [2020]

10. United States pubmed.ncbi.nlm.nih.gov

Single-agent and combination biologics in acute myeloid leukemia. [2022]