Nerofe for Acute Myeloid Leukemia and Myelodysplastic Syndrome

Recruiting in Palo Alto (17 mi)

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: Immune System Key Ltd

Must not be taking: Investigational drugs, Antineoplastics

Disqualifiers: APL, Cardiopulmonary disease, HIV, others

No Placebo Group

Approved in 1 Jurisdiction

Trial Summary

What is the purpose of this trial?

This trial tests NEROFE, a new drug given through an IV, on patients with certain blood cancers to find a safe dose and see if it helps control their cancer.

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.

What data supports the effectiveness of the drug Nerofe for treating Acute Myeloid Leukemia and Myelodysplastic Syndrome?

Research on similar treatments shows that targeting specific receptors on leukemia cells can effectively kill drug-resistant cancer cells. For example, a fusion protein targeting GMCSF receptors has been shown to kill chemotherapy-resistant leukemia cells, suggesting that Nerofe, which may work in a similar way, could be effective. ^{1 2 3 4 5}

Is Nerofe safe for humans?

The research mentions that a similar treatment using a diphtheria toxin fusion protein showed severe dose-dependent toxicity to organs like the liver, kidney, and lung in animal studies, but lower doses were used to avoid these effects. This suggests that while there may be potential safety concerns at higher doses, lower doses might be safer. ^{1 5 6 7 8}

How is the drug Nerofe different from other treatments for acute myeloid leukemia and myelodysplastic syndrome?

Nerofe, also known as Tumor-Cells Apoptosis Factor (TCApF), is unique because it targets apoptotic signaling pathways, which are involved in the process of programmed cell death. This approach may offer a novel way to treat acute myeloid leukemia and myelodysplastic syndrome by potentially overcoming chemotherapy resistance seen in some patients. ^{9 10 11 12 13}

Research Team

Eligibility Criteria

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).

I am able to care for myself and perform daily activities.

Trial Timeline

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.

Treatment Details

Interventions

• Nerofe (Hormone Therapy)

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).

Participant Groups

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

Find a Clinic Near You

Research Locations Nearby Select from list below to view details:

University of Miami Hospital and Clinics / Sylvester Comprehensive Cancer Center Miami, FL

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+

Findings from Research

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 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]

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]

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]

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 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]

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]

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]

References

1. United States 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. [2007]

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

Effect of priming with granulocyte colony-stimulating factor on the outcome of chemotherapy for acute myeloid leukemia. [2022]

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

Granulocyte-macrophage colony-stimulating factor receptor-targeted therapy of chemotherapy- and radiation-resistant human myeloid leukemias. [2019]

4. United States 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. [2021]

5. England pubmed.ncbi.nlm.nih.gov

In vivo targeting of leukemic cells using diphtheria toxin fused to murine GM-CSF. [2019]

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

The role of myeloid growth factors in acute leukemia. [2019]

7. England pubmed.ncbi.nlm.nih.gov

CCND1-BCL2 Gene Network: A direct target of Amifostine in human acute megakaryocytic leukemia cells. [2018]

8. United States 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. [2021]

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

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

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

Prognostic markers in core-binding factor AML and improved survival with multiple consolidation cycles of intermediate-/high-dose cytarabine. [2019]

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

KIT exon 17 mutations are predictive of inferior outcome in pediatric acute myeloid leukemia with RUNX1::RUNX1T1. [2023]

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

Advances in molecular genetics and treatment of core-binding factor acute myeloid leukemia. [2022]

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

Deregulated apoptosis signaling in core-binding factor leukemia differentiates clinically relevant, molecular marker-independent subgroups. [2013]