Nerofe for Acute Myeloid Leukemia and Myelodysplastic Syndrome

Overseen By Amber Thomassen, APRN-BC

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Immune System Key Ltd

Must not be taking: Investigational drugs, Antineoplastics

Disqualifiers: APL, Cardiopulmonary disease, HIV, others

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

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 2

Duration: 12 cycles (each cycle is 4 weeks)

18 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called Nerofe for individuals with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS), both types of blood cancer. The trial aims to determine the safest dose for future studies. Participants will receive Nerofe through an IV three times a week. The trial seeks individuals whose previous treatments for AML or MDS have not succeeded or who cannot undergo standard treatments. 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 treatment.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you can continue using hydroxyurea if needed. If you are on systemic steroids or other immunosuppressants, you may need to stop them before starting the trial.

Is there any evidence suggesting that Nerofe is likely to be safe for humans?

Research has shown that Nerofe may help treat certain blood cancers, such as Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS). Studies have examined how Nerofe, when combined with another drug called DOX, can destroy cancer cells by altering specific cell signals.

Although detailed information about Nerofe's safety is limited, this trial aims to find a safe dose for future research. In early trials like this, researchers primarily focus on how well patients tolerate the drug and what side effects may occur. Therefore, while detailed safety data is not yet available, this trial is crucial for understanding Nerofe's safety profile. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Nerofe is unique because it offers a new approach to treating Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS) with its novel mechanism of action. Unlike standard chemotherapy treatments like cytarabine and daunorubicin that broadly attack dividing cells, Nerofe specifically targets cancer cells, potentially reducing damage to healthy cells. Researchers are excited about Nerofe because it may provide a more targeted therapy with fewer side effects, making it a promising option for patients who struggle with the harsh impacts of traditional treatments.

What evidence suggests that Nerofe might be an effective treatment for acute myeloid leukemia and myelodysplastic syndrome?

Research suggests that Nerofe, the investigational treatment in this trial, may help treat Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS) by promoting cancer cell death. Studies have shown that Nerofe enhances the natural process of cell death in cancer cells by affecting specific pathways in the body. Specifically, it reduces KRAS signaling, which cancer cells require for survival, leading to increased cell death. Early findings also indicate that Nerofe may aid the immune system in fighting cancer. While more research is needed, these early results offer promise for patients with AML and MDS. ^{1 2 5 6 7}

Are You a Good Fit for This Trial?

Adults with advanced Myelodysplastic Syndrome (MDS) or Acute Myeloid Leukemia (AML) who haven't responded to standard treatments can join. They must have a certain level of disease risk, be in fair health, and their organs need to function well. People with severe liver or kidney issues, very high white blood cell counts without control measures, or poor venous access for blood sampling cannot participate.

Inclusion Criteria

My MDS did not improve after 4 HMA cycles, or I can't tolerate HMA.

Suitable venous access to allow for all study related blood sampling (safety and research).

Total bilirubin < 1.5 x greater upper limit of normal (UNL). Elevated indirect bilirubin associated with post-transfusion hemolysis is allowed.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

NEROFE is administered three times per week on alternate days for up to 12 cycles, with dosage determined by body surface area.

12 cycles (each cycle is 4 weeks)

Multiple visits per cycle (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, with a minimum follow-up of 30 days after the last dose.

4 weeks

1 visit (in-person)

Long-term follow-up

Participants are followed for the resolution of any ongoing adverse events after the initial follow-up period.

What Are the Treatments Tested in This Trial?

Interventions

• Nerofe

Trial Overview The trial is testing NEROFE, a new hormone-peptide treatment for MDS and AML. It's given intravenously three times weekly based on body size. The study aims to find the safest dose that works best (RP2D).

How Is the Trial Designed?

Group I: NEROFE Experimental Treatment 1 Intervention

Dose Level - Nerofe Dose -1 - 6mg/m2 1. \- 12 mg/m2 2. \- 24 mg/m2 3. \- 48 mg/m2 4. \- 96 mg/m2 5. \- 150mg/m2

Nerofe is already approved in United States for the following indications:

Approved in United States as Nerofe for:

• Acute Myelogenous Leukemia (AML)
• Myelodysplastic Syndrome (MDS)

Who Is Running the Clinical Trial?

Immune System Key Ltd

Lead Sponsor

Trials

5

Recruited

70+

University of Miami Sylvester Comprehensive Cancer Center

Collaborator

Trials

11

Recruited

2,700+

Published Research Related to This Trial

The novel recombinant chimeric fusion toxin DTctGMCSF effectively targets and kills acute myeloid leukemia (AML) cells that are resistant to conventional therapies, including those with multi-drug resistance and p53 deficiencies, with an IC50 of 1-10 ng/ml.

DTctGMCSF demonstrated selective cytotoxicity against over 99% of primary leukemic progenitor cells from therapy-refractory AML patients while sparing normal hematopoietic progenitor cells, suggesting a promising therapeutic option for resistant myeloid leukemias.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Granulocyte-macrophage colony-stimulating factor receptor-targeted therapy of chemotherapy- and radiation-resistant human myeloid leukemias. Perentesis, JP., Bendel, AE., Shao, Y., et al.[2019]

In a study of 70 patients with core-binding factor acute myeloid leukaemia (CBF AML), age and a white blood cell count greater than 40 were identified as significant risk factors for poorer overall survival and higher relapse rates.

Consolidation treatment with more than three cycles of intermediate- to high-dose cytarabine was found to improve overall survival and relapse-free survival, highlighting its importance in the treatment regimen for CBF AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prognostic markers in core-binding factor AML and improved survival with multiple consolidation cycles of intermediate-/high-dose cytarabine. Prabahran, A., Tacey, M., Fleming, S., et al.[2019]

Core-binding factor (CBF) acute myeloid leukemia (AML) affects about 13% of adults with primary AML and, while it has a relatively favorable prognosis, only half of the patients achieve a cure.

Recent research has identified several genetic and epigenetic alterations, such as mutations in KIT, FLT3, and JAK2, which could serve as new prognostic markers and therapeutic targets, potentially leading to better treatment outcomes for CBF-AML patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Advances in molecular genetics and treatment of core-binding factor acute myeloid leukemia. Mrózek, K., Marcucci, G., Paschka, P., et al.[2022]

In a study of 23 newly diagnosed CBF AML patients, distinct subgroups were identified based on gene expression profiling, revealing differences in apoptotic signaling and sensitivity to treatments like BV6 and ABT-737.

The findings suggest that targeting apoptotic signaling pathways could lead to novel therapeutic strategies for CBF leukemias, particularly for patients in the unfavorable subgroup who show resistance to certain treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Deregulated apoptosis signaling in core-binding factor leukemia differentiates clinically relevant, molecular marker-independent subgroups. Lück, SC., Russ, AC., Botzenhardt, U., et al.[2013]

The study demonstrated that a diphtheria toxin (DT) fused to murine GM-CSF effectively targets and kills leukemia cells in a rat model, achieving a significant 3 log reduction in leukemic cells with a specific dose of 75 microg/kg/day.

While higher doses of the DT-mGM-CSF fusion protein caused severe toxicity to vital organs like the liver, kidney, and lung, the lower dose used did not affect hemopoietic progenitor cells, indicating a potential therapeutic window for treating acute myeloid leukemia (AML) without harming normal blood cell production.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In vivo targeting of leukemic cells using diphtheria toxin fused to murine GM-CSF. Rozemuller, H., Rombouts, EJ., Touw, IP., et al.[2019]

Amifostine has shown efficacy in treating human acute megakaryocytic leukemia by inducing cell cycle arrest in the G2/M phase and promoting apoptosis in Dami cells, indicating its potential as a therapeutic agent.

The mechanism of action involves the modulation of gene expression related to the CCND1-BCL2-CASP3 network, suggesting that targeting this pathway could be a novel approach for treating various subtypes of acute myeloid leukemia (AML).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CCND1-BCL2 Gene Network: A direct target of Amifostine in human acute megakaryocytic leukemia cells. Zhang, F., Yang, B., Zhang, K., et al.[2018]

Myeloid growth factors, such as granulocyte-colony stimulating factors, are safe and well-tolerated in patients with acute leukemias, effectively reducing the duration of neutropenia during chemotherapy.

While these growth factors help shorten neutropenia and improve disease-free survival in some patients, they do not significantly impact overall survival or complete remission rates in acute myeloid and lymphoblastic leukemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The role of myeloid growth factors in acute leukemia. Wadleigh, M., Stone, RM.[2019]

CBF leukemias, a subtype of acute myelogenous leukemia (AML), show the highest response rates to therapy and the longest remission durations among AML types.

Despite having different clinical presentations (AML M2 and AML M4eo), CBF leukemias share a common molecular pathophysiology linked to abnormalities in the core-binding factor (CBF), a crucial transcription factor in blood cell development.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Diagnosis and management of core-binding factor leukemias. Seiter, K.[2007]

In a study of 130 pediatric patients with core binding factor acute myeloid leukemia (CBF-AML), KIT mutations were found in 31% of cases, with exon 17 mutations linked to significantly worse outcomes, including a 36% cumulative incidence of relapse and 40% overall survival at 3 years.

A high variant-allele frequency (VAF) of KIT mutations (>33%) was associated with a higher risk of disease relapse and poorer overall survival, highlighting the importance of KIT mutational analysis in risk assessment for pediatric CBF-AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

KIT exon 17 mutations are predictive of inferior outcome in pediatric acute myeloid leukemia with RUNX1::RUNX1T1. Srinivasan, S., Dhamne, C., Patkar, N., et al.[2023]

The recombinant diphtheria toxin-human granulocyte macrophage colony-stimulating factor chimeric fusion protein (DTctGMCSF) effectively targets and induces rapid cell death in chemotherapy-resistant acute myeloid leukemia (AML) cells, showing promise for patients with resistant forms of the disease.

DTctGMCSF may offer a new treatment option for AML patients whose leukemia has recurred and become resistant to standard chemotherapy, potentially improving outcomes for this challenging patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Induction of apoptosis in multidrug-resistant and radiation-resistant acute myeloid leukemia cells by a recombinant fusion toxin directed against the human granulocyte macrophage colony-stimulating factor receptor. Perentesis, JP., Waddick, KG., Bendel, AE., et al.[2007]

In a multicenter trial involving 640 patients with newly diagnosed acute myeloid leukemia (AML), the addition of granulocyte colony-stimulating factor (G-CSF) to chemotherapy improved disease-free survival rates, showing 42% at four years compared to 33% without G-CSF.

While G-CSF did not significantly enhance overall survival for all patients, it notably benefited those with standard-risk AML, leading to a 45% survival rate at four years versus 35% for those not receiving G-CSF.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of priming with granulocyte colony-stimulating factor on the outcome of chemotherapy for acute myeloid leukemia. Löwenberg, B., van Putten, W., Theobald, M., et al.[2022]

In a study of 13,203 elderly patients with non-Hodgkin lymphoma, the use of colony-stimulating factors (CSF) during chemotherapy was associated with a 53% increased risk of developing therapy-related myelodysplastic syndromes or acute myeloid leukemia (t-MDS/AML).

The 5-year incidence of t-MDS/AML was higher in patients receiving CSF (14.1 per 1000 person-years) compared to those not receiving it (8.3 per 1000 person-years), indicating a significant association, particularly for those also receiving antimetabolite chemotherapy, who had a 2.5-fold increased risk.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of white blood cell growth factors and risk of acute myeloid leukemia or myelodysplastic syndrome among elderly patients with non-Hodgkin lymphoma. Gruschkus, SK., Lairson, D., Dunn, JK., et al.[2021]

In a study of 67 adult AML patients, the Smac mimetic BV6 demonstrated significant antileukemic activity, with 51% of primary AML samples showing sensitivity to BV6, especially in cases resistant to standard chemotherapy (cytarabine).

The effectiveness of BV6 was linked to specific gene expression profiles, including higher TNF levels and lower XIAP levels, suggesting that these markers could help predict which patients might benefit from Smac mimetic therapies in AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Smac mimetic induces cell death in a large proportion of primary acute myeloid leukemia samples, which correlates with defined molecular markers. Lueck, SC., Russ, AC., Botzenhardt, U., et al.[2021]

Citations

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Nerofe for Acute Myeloid Leukemia and Myelodysplastic ... What data supports the effectiveness of the drug Nerofe for treating Acute Myeloid Leukemia and Myelodysplastic Syndrome? Research on similar treatments ...

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A Phase 2a, Open-Label, Two Stage Study of Nerofe or ... This is a Phase 2a, Open-label, one arm study in which the eligible patients will be treated with IV Nerofe, three times a week in 28 days cycles (up to 12 ...

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Tumour cells apoptosis factor (Immune System Key) It was observed that the combination of Nerofe and DOX downregulated KRAS signaling via miR217 upregulation, resulting in enhanced apoptosis of tumor cells. In ...

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Apoptosis and anti-apoptotic mechanisms in the progression ... These observations and the data on NF-κB activity are consistent with results by other investigators who showed that cells from patients with early stage MDS, ...

5. hematologyandoncology.net hematologyandoncology.net/files/2019/08/ho0118BrunnerREV.pdf

Implications for New Therapeutic Approaches Similar transplantation outcomes for acute myeloid leukemia and myelodysplastic syndrome patients with haploidenti- cal versus 10/10 human ...

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a novel human hormone-peptide with anti-cancer activity TCApF was identified through screening of the human genome with bioinformatics tools, and was found to have anticancer activity in acute myeloid ...

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Acute Myeloid Leukemia and Myelodysplastic Syndromes ... Clinical trial and observational data show that for older adults, chemotherapy can provide a survival advantage over supportive care, even among selected ...