CRD3874 for AML

Overseen By Sunita Philip

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: University of Maryland, Baltimore

Must not be taking: Immunosuppressants, Chemotherapy

Disqualifiers: Acute promyelocytic leukemia, CNS leukemia, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 6 months

36 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial requires that any prior therapy must be completed at least 2 weeks before starting the study treatment, and certain medications like myeloid growth factors and hydroxyurea must be stopped 1-2 weeks before starting. If you are on systemic immunosuppressive therapy or certain other treatments, you may need to stop them before joining the trial.

How does the drug CRD3874 differ from other treatments for AML?

CRD3874 is unique because it targets leukemic stem cells (LSCs) that are resistant to chemotherapy and likely responsible for relapse, focusing on cells that overexpress the CD123 marker, which is not a common target in standard AML treatments. ^{1 2 3 4 5}

What is the purpose of this trial?

This clinical research study is being done to answer questions about how to treat cancer. To clear cancer cells from the body, the immune system needs the action of proteins called Type 1 interferons. The protein STING (for STimulator of INterferon Genes) stimulates the body to make Type 1 interferons. Type 1 interferons activate key molecules in cancer immunity to kill cancer cells. CRD3874 is a synthetic drug that activates STING, and STING stimulates the immune system to kill cancer cells. In experiments on blood from humans, CRD3874 makes blood cells produce molecules responsible for anti-cancer activity. CRD3874 was tested in mice with cancers including leukemia, head and neck cancer, lung cancer, pancreatic cancer and sarcoma. In these mice, CRD3874 made tumors shrink or disappear, and some mice developed long-lasting immunity against cancer. Also, when CRD3874 was given with other anti-cancer treatments, it increased their anti-cancer effects.

Eligibility Criteria

This trial is for patients with relapsed or refractory Acute Myeloid Leukemia (AML) who have tried other treatments without success. Participants must meet specific health criteria to join, but these details are not provided here.

Inclusion Criteria

Able to understand and willing to provide written informed consent

Willing to comply with clinical study instructions and requirements

Peripheral blast count <50 × 10^9/L

Exclusion Criteria

Severe hypersensitivity to study drug components

Current participation in other studies or use of investigational agents

Evidence of clinically significant immunosuppression

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive CRD3874-SI via IV infusion once weekly for 28-day cycles

6 months

Weekly visits for infusion

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 years

Treatment Details

Interventions

• CRD3874

Trial Overview The study tests CRD3874, a synthetic drug designed to activate the STING protein in the body's immune system, potentially helping it produce molecules that fight cancer cells and improve responses to other anti-cancer treatments.

Participant Groups

Group I: STING agonist CRD3874-SI in patients with relapsed/refractory acute myeloid leukemia Experimental Treatment 1 Intervention

Drug Product: CRD3874 solution for injection (CRD3874-SI) Type of drug: Synthetic small molecule Formulation: Sterile solution of CRD3874 for injection Route of Administration: IV infusion over one hour Strength: 6 mg/mL Schedule: Cycle: once weekly infusion x 4 (Days 1, 8, 15 and 22) over 28-day for Cycles 1 and 2. For Cycle 3 and onward, weekly infusion x 3 (Days 1, 8 and 15), until they develop unacceptable toxicities or disease progression, or do not achieve at least a morphologic leukemia-free state response after 6 cycles.

Who Is Running the Clinical Trial?

University of Maryland, Baltimore

Lead Sponsor

Trials

729

Recruited

540,000+

Findings from Research

In a study of 34 acute myeloid leukemia (AML) cases, CD123 was found to be significantly overexpressed in leukemic stem cells (LSCs), specifically in the CD34+/CD38-/CD123+ subpopulation, indicating its potential as a therapeutic target.

FLT3/ITD mutations, which are important in leukemia development, were exclusively detected in the CD34+/CD38-/CD123+ LSCs, suggesting that targeting CD123 with antibodies and combining it with FLT3 inhibitors could enhance treatment effectiveness against these resistant cancer cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunoprofiling of leukemic stem cells CD34+/CD38-/CD123+ delineate FLT3/ITD-positive clones. Al-Mawali, A., Gillis, D., Lewis, I.[2018]

In a study of 142 acute myeloid leukemia (AML) patients, high CXCR4 expression was found to correlate with increased leukemic burden and other clinical features such as high platelet count and organ enlargement.

CXCR4 expression serves as an independent prognostic factor in AML, suggesting that targeting CXCR4 could be a promising therapeutic strategy for improving patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CXCR4 expression accounts for clinical phenotype and outcome in acute myeloid leukemia. Mannelli, F., Cutini, I., Gianfaldoni, G., et al.[2021]

In a study of 304 AML patients, those with CD7 expression showed higher levels of HLA-DR and CD33, indicating a distinct immunophenotype that suggests these cells originate from earlier stages of blood cell development.

Patients with CD4 expression exhibited higher levels of CD15, CD64, and CD33, indicating a more mature hematological development, and the study suggests that the expression levels of CD4 and CD7 can help in quantitatively detecting minimal residual disease (MRD) in AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Features of Immunophenotypes and Characteristics of Molecular Biology and Cellular Genetics of AML Patients with CD4 and CD7 Expression]. Liu, TQ., Huang, S., Yao, B., et al.[2018]

In a study of 105 acute myeloid leukaemia (AML) cases, CDw131 expression levels helped identify two subgroups: one with low expression (75 cases) and another with high expression (30 cases), which correlated with distinct biological characteristics.

AMLs with high CDw131 expression were associated with increased cell cycling, specific receptor expressions (like CD11b and CD14), and mutations such as FLT3 internal tandem duplication, suggesting potential targets for new therapeutic strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Interleukin (IL)-3/granulocyte macrophage-colony stimulating factor/IL-5 receptor alpha and beta chains are preferentially expressed in acute myeloid leukaemias with mutated FMS-related tyrosine kinase 3 receptor. Riccioni, R., Diverio, D., Riti, V., et al.[2022]

LINC00324 is down-regulated in the peripheral blood leukocytes of acute myeloid leukemia (AML) patients and its expression correlates significantly with important immunophenotypes like CD33, as well as red blood cell and platelet counts.

The study suggests that LINC00324 may play a role in regulating immune cell differentiation and function, indicating its potential as a target for new drug development in AML treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Correlation analysis between LINC00324 and immunophenotype in peripheral blood leukocytes in patients with acute myeloid leukemia]. Liu, Y., Zhang, Y., Xie, J., et al.[2020]

References

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

Immunoprofiling of leukemic stem cells CD34+/CD38-/CD123+ delineate FLT3/ITD-positive clones. [2018]

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

CXCR4 expression accounts for clinical phenotype and outcome in acute myeloid leukemia. [2021]

3. China pubmed.ncbi.nlm.nih.gov

[Features of Immunophenotypes and Characteristics of Molecular Biology and Cellular Genetics of AML Patients with CD4 and CD7 Expression]. [2018]

4. England pubmed.ncbi.nlm.nih.gov

Interleukin (IL)-3/granulocyte macrophage-colony stimulating factor/IL-5 receptor alpha and beta chains are preferentially expressed in acute myeloid leukaemias with mutated FMS-related tyrosine kinase 3 receptor. [2022]

5. China pubmed.ncbi.nlm.nih.gov

[Correlation analysis between LINC00324 and immunophenotype in peripheral blood leukocytes in patients with acute myeloid leukemia]. [2020]