Gene Therapy for Acute Lymphoblastic Leukemia

Recruiting at 5 trial locations

Overseen By Allen Reha

Age: Any Age

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Vironexis Biotherapeutics Inc.

Disqualifiers: Hepatoxicity, Thrombotic microangiopathy, Cardiomyopathy, others

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

Compensation: Varies

Number of Visits: Unknown

32 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a Phase 1/2, first-in-human, open-label, dose-escalating trial designed to assess the safety and efficacy of VNX-101 in patients with relapsed or refractory CD19-positive hematologic malignancies.

Will I have to stop taking my current medications?

The trial protocol mentions that chemotherapy must be stopped within certain timelines, but it does not specify about other medications. It's best to discuss your current medications with the trial team to get a clear answer.

What data supports the effectiveness of the treatment VNX-101, GP101 for acute lymphoblastic leukemia?

The research highlights that new treatments like gene-modified T cells and monoclonal antibodies have shown success in treating resistant or relapsed leukemia, suggesting that similar innovative therapies could be effective for acute lymphoblastic leukemia. ^{1 2 3 4 5}

Is gene therapy for acute lymphoblastic leukemia, known as VNX-101 or GP101, safe for humans?

The research articles provided do not contain specific safety data for gene therapy treatments like VNX-101 or GP101 for acute lymphoblastic leukemia or other conditions. ^{2 3 6 7 8}

How is the treatment VNX-101 unique for acute lymphoblastic leukemia?

VNX-101 is a gene therapy that uses engineered leukemia cells to stimulate the immune system to fight the cancer, which is different from traditional chemotherapy drugs that directly kill cancer cells. ^{9 10 11 12 13}

Research Team

Vironexis Clinical Trials

Principal Investigator

Vironexis Biotherapeutics Inc.

Eligibility Criteria

This trial is for adults and teens with B-cell acute lymphoblastic leukemia that has come back or hasn't responded to treatment. They should have a certain amount of cancer cells in their bone marrow, can't be treated with CAR-T therapy or didn't improve after it, and must meet specific health criteria for major organs and blood.

Inclusion Criteria

My cancer cells are still CD19 positive after blinatumomab treatment.

I am between 13 and 90 years old.

AAVrh74 total antibody <1:400

Exclusion Criteria

I have moderate to severe acute GvHD or any grade of chronic GvHD.

History of hypersensitivity to corticosteroids or history of corticosteroid-related toxicity

Hepatoxicity (AST or ALT > 2x upper limit of normal)

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose-finding (Part 1)

Dose-finding PK study to determine the minimal dose that achieves target PK serum levels of GP101 at steady state without dose-limited toxicities

8 weeks

Treatment (Part 2)

Determine the safety and pharmacokinetics of VNX-101 at the recommended Part 2 dose in a broader array of subjects with higher leukemic burden

Up to 5 years

Long-term Follow-up

Long-term follow-up assessments for safety conducted post VNX-101 dosing

6 to 15 years

Treatment Details

Interventions

• VNX-101

Trial Overview The study tests different doses of VNX-101, a gene therapy drug, to see how safe it is and how well it works against leukemia. It's an early-stage trial where patients receive increasing amounts of the drug to find the best dose.

Participant Groups

Group I: Group 1/Group 2/Group 3/Group 4 Experimental Treatment 4 Interventions

Who Is Running the Clinical Trial?

Vironexis Biotherapeutics Inc.

Lead Sponsor

Trials

1

Recruited

30+

Findings from Research

Recent advancements in the treatment of acute lymphoblastic leukemia (ALL) include the use of novel agents like blinatumomab, which have shown promising results in patients with relapsed/refractory disease and minimal residual disease (MRD).

The integration of targeted therapies, such as tyrosine kinase inhibitors for Philadelphia chromosome-like ALL and bcl-2/bcl-xl inhibitors for relapsed cases, is expected to enhance treatment outcomes and management strategies for ALL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Navigating the nexus of MRD and novel agents in ALL. Advani, AS., Copelan, EA.[2023]

Acute lymphoblastic leukemia (ALL) remains a leading cause of childhood cancer-related deaths, but advancements in treatment, including risk stratification based on early response, have improved outcomes significantly.

New immunotherapeutic approaches, such as monoclonal antibodies and gene-modified T cells, show promise in treating resistant cases of ALL and may be integrated with traditional chemotherapy to enhance cure rates while aiming to reduce treatment-related toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recent advances in the management of pediatric acute lymphoblastic leukemia. Starý, J., Hrušák, O.[2022]

The cure rate for childhood acute lymphoblastic leukemia (ALL) has surpassed 90% in recent clinical trials, but further improvements will depend on molecular therapies and precise risk stratification rather than just increasing chemotherapy doses.

Specific genetic markers, such as ETV6-RUNX1 and Philadelphia chromosome positivity, guide treatment decisions, with targeted therapies like dasatinib and venetoclax showing promise for high-risk subtypes, while innovative treatments like CAR-T cell therapy are being explored for better outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Precision medicine in acute lymphoblastic leukemia. Pui, CH.[2022]

Recent advancements in treating childhood acute lymphoblastic leukemia (ALL) have improved disease-free survival rates, particularly for high-risk groups, but ALL still remains the leading cause of cancer-related deaths in children.

Challenges persist in standardizing staging systems, ensuring adequate patient numbers for clinical studies, and accurately assessing treatment responses, which complicates the delivery of optimal therapy and supportive care for ALL patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Remaining problems in the staging and treatment of childhood lymphoblastic leukemia. Bleyer, WA.[2007]

A new 2-tier genetic classification for acute lymphoblastic leukemia (ALL) was developed using data from 809 patients, identifying good-risk (GR) and poor-risk (PR) genetic profiles based on specific genetic features.

Patients with a GR profile, which includes favorable genetic markers, showed a significantly higher event-free survival rate of 94% compared to 79% for those with a PR profile, indicating that genetic profiling can help tailor treatment intensity for better outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A novel integrated cytogenetic and genomic classification refines risk stratification in pediatric acute lymphoblastic leukemia. Moorman, AV., Enshaei, A., Schwab, C., et al.[2023]

3-5% of childhood acute lymphoblastic leukaemia (ALL) cases are linked to germline mutations, which can significantly impact treatment and necessitate genetic counseling for affected families.

Patients with ALL who have cancer predisposition mutations may face unique treatment challenges due to their reduced tolerance to chemotherapy and increased risk of organ toxicities, but many still have a good chance of being cured with appropriate chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment-related toxicities in children with acute lymphoblastic leukaemia predisposition syndromes. Schmiegelow, K.[2017]

Survival rates for acute lymphoblastic leukemia (ALL) in children have dramatically improved from about 10% in the 1960s to over 90% today, thanks to advancements in multi-agent chemotherapy, CNS prophylaxis, and supportive care.

Novel immunotherapies, such as blinatumomab and CAR T-cell therapy, have shown promise in treating relapsed or refractory B-ALL, offering better remission rates and lower toxicity compared to traditional chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[PEDIATRIC ACUTE LYMPHOBLASTIC LEUKEMIA]. Elitzur, S., Izraeli, S.[2023]

The CCCG-ALL 2015 chemotherapy protocol for pediatric acute lymphoblastic leukemia (ALL) resulted in significantly lower rates of serious adverse events (SAE) and treatment-related mortality compared to the CCLG-ALL 2008 protocol, indicating a safer treatment option.

While the remission rates were similar between the two protocols, the CCCG-ALL 2015 group had a lower negative conversion rate of minimal residual disease (MRD), suggesting that while it is safer, its early efficacy in eliminating residual leukemia cells may need improvement.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Comparison of the Early Efficacy and Serious Adverse Events between CCCG-ALL 2015 and CCLG-ALL 2008 in the Treatment of Pediatric Patients with Acute Lymphoblastic Leukemia]. Pan, LL., Zheng, YZ., LE, SH., et al.[2022]

In a study of 135 children with newly diagnosed acute lymphoblastic leukemia (ALL), the PEG-Asp containing VDPAP regimen showed similar efficacy to the L-asparaginase containing VDLP regimen, with complete remission rates of 84.6% and 89.4%, respectively.

PEG-Asp demonstrated a longer half-life of about 7 days, providing a more prolonged therapeutic effect, while both regimens had comparable rates of adverse effects, primarily allergic reactions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Comparison of polyethylene glycol conjugated asparaginase and L-asparaginase for treatment of childhood acute lymphoblastic leukemia]. [2018]

Asparaginase is a crucial part of treatment for acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LBL), with pegaspargase being the preferred option due to its better pharmacokinetic profile and lower risk of immunogenic reactions compared to native E. coli asparaginase.

For patients who experience hypersensitivity reactions to asparaginase, switching to an Erwinia-derived formulation is recommended to maintain the benefits of treatment, highlighting the importance of managing side effects to ensure effective therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Asparaginase therapy in patients with acute lymphoblastic leukemia: expert opinion on use and toxicity management. Sandley, M., Angus, J.[2023]

The study demonstrated that using HIV-1-based lentiviral vectors can achieve over 90% gene transfer efficiency in B-precursor acute lymphoblastic leukemia (ALL) cell lines, indicating a highly effective method for engineering leukemia cells for immunotherapy.

Transduction of primary human B-precursor ALL cells also showed high efficiency with both MoMuLV-based retrovirus and HIV-1-based lentivirus vectors, suggesting potential for developing personalized immunotherapies for leukemia patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gene delivery to human B-precursor acute lymphoblastic leukemia cells. Mascarenhas, L., Stripecke, R., Case, SS., et al.[2021]

The combination of vincristine, dexamethasone, and L-asparaginase (VXL) showed synergistic effects in treating pediatric acute lymphoblastic leukemia (ALL) in both laboratory and mouse models, significantly delaying disease progression by up to 146 days.

Pharmacokinetic analysis indicated that the combination therapy increased the systemic exposure of dexamethasone, which may enhance the effectiveness of the treatment, providing a promising platform for testing new drugs in clinical trials for relapsed or refractory ALL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetic modeling of an induction regimen for in vivo combined testing of novel drugs against pediatric acute lymphoblastic leukemia xenografts. Szymanska, B., Wilczynska-Kalak, U., Kang, MH., et al.[2021]

The study found that Wnt16 does not activate canonical Wnt signaling in E2A-PBX1-positive B-ALL cells, despite high levels of Wnt16 and beta-catenin present in these cells.

Beta-catenin plays a crucial role in cell adhesion to the bone marrow stroma through N-cadherin, indicating that leukemia-stroma interactions may be mediated by this N-cadherin-dependent mechanism.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

beta-catenin is involved in N-cadherin-dependent adhesion, but not in canonical Wnt signaling in E2A-PBX1-positive B acute lymphoblastic leukemia cells. Nygren, MK., Døsen-Dahl, G., Stubberud, H., et al.[2009]

References

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

Navigating the nexus of MRD and novel agents in ALL. [2023]

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

Recent advances in the management of pediatric acute lymphoblastic leukemia. [2022]

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

Precision medicine in acute lymphoblastic leukemia. [2022]

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

Remaining problems in the staging and treatment of childhood lymphoblastic leukemia. [2007]

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

A novel integrated cytogenetic and genomic classification refines risk stratification in pediatric acute lymphoblastic leukemia. [2023]

6. Netherlands pubmed.ncbi.nlm.nih.gov

Treatment-related toxicities in children with acute lymphoblastic leukaemia predisposition syndromes. [2017]

7. Israel pubmed.ncbi.nlm.nih.gov

[PEDIATRIC ACUTE LYMPHOBLASTIC LEUKEMIA]. [2023]

8. China pubmed.ncbi.nlm.nih.gov

[Comparison of the Early Efficacy and Serious Adverse Events between CCCG-ALL 2015 and CCLG-ALL 2008 in the Treatment of Pediatric Patients with Acute Lymphoblastic Leukemia]. [2022]

9. China pubmed.ncbi.nlm.nih.gov

[Comparison of polyethylene glycol conjugated asparaginase and L-asparaginase for treatment of childhood acute lymphoblastic leukemia]. [2018]

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

Asparaginase therapy in patients with acute lymphoblastic leukemia: expert opinion on use and toxicity management. [2023]

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

Gene delivery to human B-precursor acute lymphoblastic leukemia cells. [2021]

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

Pharmacokinetic modeling of an induction regimen for in vivo combined testing of novel drugs against pediatric acute lymphoblastic leukemia xenografts. [2021]

13. Netherlands pubmed.ncbi.nlm.nih.gov

beta-catenin is involved in N-cadherin-dependent adhesion, but not in canonical Wnt signaling in E2A-PBX1-positive B acute lymphoblastic leukemia cells. [2009]