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

Trial Summary

What is the purpose of this trial?

This phase I trial finds the best dose of PVEK when given together with fludarabine, cytarabine, granulocyte colony-stimulating factor (G-CSF), and idarubicin, (FLAG-Ida) regimen and studies the effectiveness of this combination therapy in treating patients with newly diagnosed adverse risk acute myeloid leukemia (AML) and other high-grade myeloid neoplasms. PVEK is a monoclonal antibody linked to a chemotherapy drug. PVEK is a form of targeted therapy because it attaches to specific molecules (receptors) on the surface of cancer cells, known as CD123 receptors, and delivers the chemotherapy drug to kill them. Chemotherapy drugs, such as idarubicin, fludarabine, high-dose cytarabine work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. G-CSF helps the bone marrow make more white blood cells in patients with low white blood cell count due to cancer treatment. Giving PVEK with the FLAG-Ida regimen may be a safe and effective treatment for patients with acute myeloid leukemia and other high-grade myeloid neoplasms.

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.

What data supports the effectiveness of the drug FLAG-Ida + Pivekimab for Acute Myeloid Leukemia?

The research on APVO436, a similar type of drug, showed promising results in patients with relapsed or refractory acute myeloid leukemia (AML), with some achieving stable disease or complete remission. This suggests potential effectiveness for similar treatments in AML. ^{1 2 3 4 5}

Is the FLAG-Ida + Pivekimab treatment safe for humans?

The FLAG-Ida regimen, used for treating acute myeloid leukemia, has shown some common side effects like infections, fever, and pneumonia, but these are generally manageable. Safety data from studies indicate that while there are risks, the treatment is considered tolerable with careful monitoring. ^{6 7 8 9 10}

What makes the drug Pivekimab Sunirine unique for treating acute myeloid leukemia?

Pivekimab Sunirine is unique because it targets CD123, a protein often overexpressed in acute myeloid leukemia (AML) cells, potentially offering a more targeted approach compared to traditional chemotherapy. This specificity may help in reducing the leukemia burden by directing the immune system to attack the cancer cells more effectively. ^{1 11 12 13 14}

Research Team

Jacob Appelbaum, MD, PhD

Principal Investigator

Fred Hutch/University of Washington Cancer Consortium

Eligibility Criteria

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 am 18 years old or older.

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

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

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

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)

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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 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]

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]

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]

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]

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]

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]

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]

References

1. Switzerland 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. [2022]

2. England pubmed.ncbi.nlm.nih.gov

Systematic evaluation of AML-associated antigens identifies anti-U5 SNRNP200 therapeutic antibodies for the treatment of acute myeloid leukemia. [2023]

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

Expression patterns of immune checkpoints in acute myeloid leukemia. [2021]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Receptor Activator of NF-κB (RANK) Confers Resistance to Chemotherapy in AML and Associates with Dismal Disease Course. [2021]

5. Poland pubmed.ncbi.nlm.nih.gov

Twenty-four-color full spectrum flow cytometry panel for minimal residual disease detection in acute myeloid leukemia. [2023]

6. Australia pubmed.ncbi.nlm.nih.gov

Fludarabine, cytarabine, granulocyte colony-stimulating factor and idarubicin for relapsed childhood acute myeloid leukemia. [2018]

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

Retrospective Analysis of Adult Patients With Relapsed/Refractory Acute Myeloid Leukemia Treated with FLAG at a Comprehensive Cancer Center. [2022]

8. England 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. [2023]

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

Venetoclax combined with FLAG-IDA induction and consolidation in newly diagnosed acute myeloid leukemia. [2023]

10. England pubmed.ncbi.nlm.nih.gov

FLAG-IDA regimen (fludarabine, cytarabine, idarubicin and G-CSF) in the treatment of patients with high-risk myeloid malignancies. [2019]

11. England 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. [2019]

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

Phospho-Profiling Linking Biology and Clinics in Pediatric Acute Myeloid Leukemia. [2020]

13. England pubmed.ncbi.nlm.nih.gov

Inhibition of interleukin-1 receptor-associated kinase-1 is a therapeutic strategy for acute myeloid leukemia subtypes. [2021]

14. China pubmed.ncbi.nlm.nih.gov

[Role of Pim1 Gene Overexpression in Pathogenesis of Acute Myeloid Leukemia]. [2019]