FLAG-Ida + Pivekimab for Acute Myeloid Leukemia

Overseen By Jacob Appelbaum, MD, PhD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Fred Hutchinson Cancer Center

Must not be taking: Investigational agents

Disqualifiers: Blast phase CML, FLT3-mutated AML, others

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

Compensation: Varies

Number of Visits: 1

30 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial seeks to determine the optimal dose and effectiveness of a new treatment combination for acute myeloid leukemia (AML), especially in high-risk cases. The study combines a new drug, Pivekimab Sunirine (PVEK), which directly targets cancer cells, with existing chemotherapy drugs to improve treatment outcomes. Individuals recently diagnosed with AML or similar blood cancers, who have specific markers on their cancer cells, may be suitable candidates for this trial. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new therapy.

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 does allow the use of hydroxyurea before starting the study therapy and mentions that patients may have received low-intensity treatment for a previous condition.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that the FLAG-Ida treatment has helped people with acute myeloid leukemia (AML) and achieved some success. Studies found that many patients responded well to FLAG-Ida. However, in one study, about 14% of patients experienced severe side effects that led to death.

Regarding Pivekimab Sunirine (PVEK), early research suggests it is generally safe. In studies with newly diagnosed AML patients, PVEK demonstrated strong effects against leukemia and was mostly well-tolerated. Some patients experienced side effects, but these were usually manageable.

In summary, both FLAG-Ida and PVEK have shown promise in past studies, focusing on balancing effectiveness and safety. Understanding the potential risks and discussing them with a healthcare provider is important. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of FLAG-Ida and Pivekimab Sunirine for treating Acute Myeloid Leukemia because it introduces a novel approach to targeting cancer cells. While standard treatments often rely on chemotherapy to kill rapidly dividing cells, Pivekimab Sunirine is an antibody-drug conjugate that specifically targets the CD123 protein found on leukemia cells, potentially reducing damage to healthy cells. This targeted mechanism could lead to more effective treatment with fewer side effects, offering hope for improved patient outcomes.

What evidence suggests that this trial's treatments could be effective for acute myeloid leukemia?

Studies have shown that the FLAG-Ida treatment works well for acute myeloid leukemia (AML). In earlier studies, over 80% of patients who received FLAG-Ida responded positively and were more likely to achieve remission after just one round of treatment. Pivekimab Sunirine (PVEK) targets specific parts of cancer cells called CD123 receptors, delivering chemotherapy directly to them. Research has demonstrated that PVEK is highly effective against AML in early tests and may improve treatment success rates. This trial will evaluate the combination of PVEK with FLAG-Ida to determine if it could enhance treatment effectiveness for patients with high-risk AML. ^{1 2 3 6 7}

Who Is on the Research Team?

Jacob Appelbaum, MD, PhD

Principal Investigator

Fred Hutch/University of Washington Cancer Consortium

Are You a Good Fit for This Trial?

Adults diagnosed with high-risk acute myeloid leukemia (AML) or related conditions, who haven't been treated yet. They must have normal heart function and kidney clearance, no severe infections, and agree to use contraception. Excluded are those with certain other leukemias, FLT3-mutated AML, life-threatening illnesses, known drug allergies, or pregnant/breastfeeding women.

Inclusion Criteria

I have a specific type of untreated AML, not including APL.

My leukemia is considered high-risk based on specific tests.

My cancer cells show CD123 presence.

Exclusion Criteria

Known hypersensitivity to any study drug or prior >= grade 3 hypersensitivity reactions to monoclonal antibodies

You cannot be currently receiving any other experimental treatment for leukemia.

I have a health condition that may reduce my life expectancy to less than a year.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Induction Therapy

Patients receive PVEK IV on day 1 or day 1 and 22, G-CSF SC on days 0-5, fludarabine IV on days 1-5, cytarabine IV on days 1-5, and idarubicin IV on days 1-3. Additional cycle may be given if cancer persists.

6 weeks

Multiple visits (in-person)

Post-Remission Therapy

Patients receive PVEK IV on day 1 or day 1 and 22, and high-dose cytarabine IV every 12 hours on days 1-6. Treatment repeats every 42 days for up to 3 cycles.

18 weeks

Multiple visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment completion every 3 months for 5 years.

5 years

Quarterly visits (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• FLAG-Ida
• Pivekimab Sunirine

Trial Overview

The trial is testing the best dose of Pivekimab Sunirine combined with a chemotherapy regimen called FLAG-Ida for treating newly diagnosed adverse risk AML. It aims to see if this combination therapy is more effective than chemotherapy alone in killing cancer cells.

How Is the Trial Designed?

Group I: Treatment (PVEK, FLAG-Ida) Experimental Treatment 10 Interventions

See Detailed Description.

FLAG-Ida is already approved in United States, European Union for the following indications:

Approved in United States as Pivekimab Sunirine for:

• Refractory acute myeloid leukemia
• Refractory B Acute Lymphoblastic Leukemia
• Refractory Mixed Phenotype Acute Leukemia
• Refractory T Acute Lymphoblastic Leukemia
• Relapsing acute myeloid leukemia
• CD123 Positive Acute Myeloid Leukemia

Approved in European Union as Pivekimab Sunirine for:

• CD123 Positive Acute Myeloid Leukemia

Who Is Running the Clinical Trial?

Fred Hutchinson Cancer Center

Lead Sponsor

Trials

583

Recruited

1,341,000+

ImmunoGen, Inc.

Industry Sponsor

Trials

33

Recruited

4,000+

AbbVie

Industry Sponsor

Trials

1,079

Recruited

535,000+

Founded

2013

Headquarters

North Chicago, USA

Known For

Immunology treatments

Top Products

Humira (adalimumab), Skyrizi (risankizumab), Rinvoq (upadacitinib)

Dr. Roopal Thakkar

AbbVie

Chief Medical Officer since 2023

MD from Wayne State University School of Medicine

Robert A. Michael

AbbVie

Chief Executive Officer

Bachelor's degree in Finance from the University of Illinois

Published Research Related to This Trial

The combination of venetoclax (VEN) with intensive chemotherapy (FLAG-IDA) shows promising efficacy in treating high-risk acute myeloid leukemia (AML), with complete remission rates ranging from 53% to 89% in newly diagnosed and relapsed/refractory patients across six studies involving 221 patients.

Safety outcomes indicate a significant risk of infections, with rates of neutropenic fever and bacteremia reported between 44-55% and 24-48%, respectively, suggesting that while the regimen is effective, careful monitoring for infections is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of FLAG-Ida-based therapy combined with venetoclax for the treatment for newly diagnosed and relapsed/refractory patients with AML - A systematic review. Sherban, A., Fredman, D., Shimony, S., et al.[2023]

High-density immunophenotyping and proteogenomics revealed unique expression of the RNA helicase U5 snRNP200 on AML cells, which is not found on normal hematopoietic precursors, suggesting it could be a specific target for therapy.

Anti-U5 snRNP200 antibodies showed effectiveness in treating AML in immunocompetent models, especially when combined with azacitidine, indicating a promising approach for developing Fc-optimized therapeutics against AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Systematic evaluation of AML-associated antigens identifies anti-U5 SNRNP200 therapeutic antibodies for the treatment of acute myeloid leukemia. Knorr, K., Rahman, J., Erickson, C., et al.[2023]

The study established a 24-color full-spectrum flow cytometry panel that significantly improves the detection of minimal residual disease (MRD) in acute myeloid leukemia (AML), allowing for better observation and clustering of various bone marrow cells.

Key immune markers, such as CD96 and CD200, showed altered expression in AML-MRD samples compared to normal bone marrow, suggesting their potential role in diagnosis, prognosis, and treatment guidance for AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Twenty-four-color full spectrum flow cytometry panel for minimal residual disease detection in acute myeloid leukemia. Chen, M., Fu, M., Gong, M., et al.[2023]

In a study of 42 adult patients with relapsed or refractory acute myeloid leukemia (AML) treated with the FLAG ± Ida chemotherapy regimen, the complete remission (CR) rate was 47.6%, which aligns with historical rates of 52% to 63%.

The median overall survival (OS) for patients achieving CR was not reached, with an estimated 48-month survival rate of 56%, indicating that FLAG ± Ida remains an effective salvage treatment for R/R AML, despite common adverse effects like pancytopenia and infection.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Retrospective Analysis of Adult Patients With Relapsed/Refractory Acute Myeloid Leukemia Treated with FLAG at a Comprehensive Cancer Center. Tenold, ME., Moskoff, BN., Krishnan, R., et al.[2022]

In a study of 32 acute myeloid leukemia (AML) blast samples, the selective inhibitors PCN5603 and U0126 effectively killed AML progenitor cells in a dose-dependent manner while sparing normal progenitors, indicating a targeted therapeutic approach.

The combination of U0126 and PCN5603 showed synergistic effects in killing AML cells, with the inhibitors being significantly more effective against AML than normal cells, suggesting a potential strategy for minimizing damage to healthy tissue during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined inhibition of the phosphoinosityl-3-kinase (PI3Kinase) P110δ subunit and mitogen-extracellular activated protein kinase (MEKinase) shows synergistic cytotoxicity against human acute myeloid leukemia progenitors. Xing, Y., Hogge, DE.[2019]

The FLAG-IDA chemotherapy regimen was administered to seven children with refractory acute myeloid leukemia (AML), and while it was tolerable with no early deaths, the efficacy remains uncertain due to high relapse rates and limited patient numbers.

Hematological toxicity was common among patients, with one case of severe non-hematological toxicity (bacterial meningitis), highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fludarabine, cytarabine, granulocyte colony-stimulating factor and idarubicin for relapsed childhood acute myeloid leukemia. Nakayama, H., Tomizawa, D., Tanaka, S., et al.[2018]

In a study of 45 patients with high-risk myeloid malignancies, the FLAG-IDA treatment regimen resulted in a 53% complete remission rate, demonstrating its effectiveness against these aggressive cancers.

Despite some serious side effects, including pulmonary toxicity and mucositis, the FLAG-IDA regimen showed an overall survival rate of 40% at 12 months, indicating it has an acceptable safety profile for high-risk patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FLAG-IDA regimen (fludarabine, cytarabine, idarubicin and G-CSF) in the treatment of patients with high-risk myeloid malignancies. de la Rubia, J., Regadera, A., Martín, G., et al.[2019]

Pim1 overexpression in the U937 acute myeloid leukemia (AML) cell line enhances cell proliferation and inhibits apoptosis, indicating its role in promoting cancer cell survival.

The study found that Pim1 increases the chemotactic ability of AML cells through the phosphorylation of CXCR4 and increased calcium influx, suggesting a mechanism by which Pim1 contributes to leukemia progression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Role of Pim1 Gene Overexpression in Pathogenesis of Acute Myeloid Leukemia]. Li, Q., Sun, RX., Ou, Y., et al.[2019]

In a study of 45 patients with newly diagnosed or relapsed/refractory acute myeloid leukemia (AML), the combination of FLAG-IDA and venetoclax achieved a remarkable overall response rate of 98%, with 89% of patients reaching a composite complete remission.

The treatment was associated with manageable non-hematologic adverse events, and after 20 months of follow-up, the estimated 24-month event-free survival and overall survival rates were 64% and 76%, respectively, indicating a favorable outcome compared to historical benchmarks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax combined with FLAG-IDA induction and consolidation in newly diagnosed acute myeloid leukemia. DiNardo, CD., Lachowiez, CA., Takahashi, K., et al.[2023]

APVO436, a bispecific antibody, demonstrated promising single-agent activity in 14 patients with relapsed or refractory acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) who had previously failed other treatments, with 50% of AML patients achieving stable disease or complete remission.

The treatment activated T-cells and reduced the number of certain cancerous cells, leading to a median survival of 282 days for the group, indicating its potential as an effective immunotherapy for these difficult-to-treat conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Post-hoc Analysis of Pharmacodynamics and Single-Agent Activity of CD3xCD123 Bispecific Antibody APVO436 in Relapsed/Refractory AML and MDS Resistant to HMA or Venetoclax Plus HMA. Watts, J., Lin, TL., Mims, A., et al.[2022]

In a study of leukemic cells from 54 acute myeloid leukemia (AML) patients, RANK was found to be expressed on the surface of AML cells in 35% of cases, indicating its potential role in the disease.

RANK signaling was linked to the release of cytokines that promote cell growth and survival, contributing to resistance against common AML treatments like doxorubicin and cytarabine, and correlating with poorer patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Receptor Activator of NF-κB (RANK) Confers Resistance to Chemotherapy in AML and Associates with Dismal Disease Course. Clar, KL., Weber, LM., Schmied, BJ., et al.[2021]

A high-throughput flow-cytometry method was developed to assess phospho-protein activation in 166 pediatric acute myeloid leukemia (pedAML) samples, revealing specific signaling patterns that correlate with relapse risk in intermediate and high-risk subtypes.

The signaling inhibitor midostaurin was found to be the most effective against AML blasts, blocking multiple phospho-proteins and significantly prolonging disease latency in a mouse model, suggesting its potential for individualized therapy in pedAML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phospho-Profiling Linking Biology and Clinics in Pediatric Acute Myeloid Leukemia. Schumich, A., Prchal-Murphy, M., Maurer-Granofszky, M., et al.[2020]

IRAK1 is overexpressed in acute myeloid leukemia (AML) and plays a crucial role in promoting the survival of leukemia cells, as shown by genetic knockdown experiments in primary AML samples and xenograft models.

The multikinase inhibitor pacritinib effectively inhibits IRAK1 and demonstrates potent activity against AML cells, reducing leukemia burden and showing greater efficacy compared to other targeted therapies like quizartinib and ruxolitinib.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inhibition of interleukin-1 receptor-associated kinase-1 is a therapeutic strategy for acute myeloid leukemia subtypes. Hosseini, MM., Kurtz, SE., Abdelhamed, S., et al.[2021]

High expression levels of immune checkpoints PD-1, PD-L1, and PD-L2 in bone marrow cells of acute myeloid leukemia (AML) patients are associated with poor overall survival, based on analysis of RNA-seq and mutation data from 176 patients and validation in 62 additional patients.

Co-expression patterns of immune checkpoints, such as PD-1/CTLA-4 and PD-1/PD-L1, correlate with significantly lower survival rates, suggesting these patterns could serve as potential biomarkers for developing new therapies for AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Expression patterns of immune checkpoints in acute myeloid leukemia. Chen, C., Liang, C., Wang, S., et al.[2021]

Citations

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pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC11012572/

FLAG/FLAG-Ida Regimen in Secondary and Relapsed ...

The studies of patients treated with FLAG-Ida as frontline therapy demonstrated response rates exceeding 80% but generally included younger ...

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FLAG-IDA in the treatment of refractory/relapsed acute ...

In our experience, FLAG-IDA is a well-tolerated and effective regimen in relapsed/refractory AML. The toxicity is acceptable, enabling most patients to receive ...

3.

sciencedirect.com

sciencedirect.com/science/article/abs/pii/S0145212623006331

Safety and efficacy of FLAG-Ida-based therapy combined ...

In our systematic review, FLAG-Ida plus VEN proved to be a potentially tolerable and effective regimen in ND and R/R AML patients.

4.

ashpublications.org

ashpublications.org/blood/article/132/Supplement%201/82/265975/The-Choice-of-Induction-Regimen-Affects-Post

The Choice of Induction Regimen Affects Post Remission ...

Patients in the FLAG-Ida group were more likely to achieve remission after one course of induction (74% vs 62%, p<0.001) and had a faster time ...

5.

ascopubs.org

ascopubs.org/doi/10.1200/JCO.23.00943

Fludarabine, Cytarabine, Granulocyte Colony-Stimulating ...

Overall, FLAG-Ida + GO significantly reduced relapse without improving OS. However, exploratory analyses show that patients with NPM1 and FLT3 ...

6.

ashpublications.org

ashpublications.org/blood/article/144/Supplement%201/55/530356/A-Randomized-Comparison-of-CPX-351-and-FLAG-Ida-in

A Randomized Comparison of CPX-351 and FLAG-Ida in ...

AEs led to death in 2 patients (7%) in the CPX-351 arm and 4 (14%) in the FLAG-Ida arm. Conclusions: This exploratory subgroup analysis of the ...

7.

haematologica.org

haematologica.org/article/view/haematol.2023.282912

Fludarabine, cytarabine, and idarubicin with or without ...

Thirty-seven and 81 sequentially treated patients received FLAVIDA and FLA-IDA, respectively, and had safety and efficacy outcomes reported.