Gene Therapy + Chemotherapy for AIDS-Related Lymphoma

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: City of Hope Medical Center

Must be taking: Antiretrovirals

Must not be taking: Investigational agents

Disqualifiers: Opportunistic infections, CMV retinitis, others

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

Compensation: Varies

Number of Visits: 22

10 Participants Needed

Trial Summary

What is the purpose of this trial?

This pilot clinical trial studies gene therapy following combination chemotherapy in treating patients with acquired immune deficiency syndrome (AIDS)-related non-Hodgkin lymphoma. Placing genes that have been shown in the laboratory to inhibit the growth and spread of the immunodeficiency virus (HIV) into the patient's peripheral blood stem cells may improve the body's ability to fight HIV. Drugs used in chemotherapy 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. Giving gene therapy after combination chemotherapy may improve the body's ability to fight HIV and AIDS-related non-Hodgkin lymphoma.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you must be on antiretroviral therapy (ART) as per standard guidelines and cannot be on any other investigational agents or concurrent chemotherapy, biological, or radiation therapy.

What data supports the effectiveness of the treatment Gene Therapy + Chemotherapy for AIDS-Related Lymphoma?

Research shows that high-dose chemotherapy with stem cell transplantation has been successful in treating HIV-negative lymphomas, and gene therapy approaches may help control HIV infection, which is crucial for long-term survival in HIV-related lymphomas. Additionally, gene-modified stem cells have shown potential in introducing HIV resistance, suggesting a promising approach for treating HIV-related malignancies. ^{1 2 3 4 5}

Is the combination of gene therapy and chemotherapy safe for treating AIDS-related lymphoma?

The combination of gene therapy and chemotherapy for AIDS-related lymphoma has been studied, and while there were no unexpected toxicities from the gene-modified cells, chemotherapy can increase toxicity, especially when combined with antiretroviral therapy. Some patients experienced bone marrow toxicity, but gene therapy showed stable expression in blood cells without unexpected side effects. ^{1 3 6 7 8}

How does the treatment Gene Therapy + Chemotherapy for AIDS-Related Lymphoma differ from other treatments?

This treatment is unique because it combines gene therapy with chemotherapy, using genetically modified stem cells to potentially control HIV infection while treating lymphoma. This approach aims to improve long-term outcomes by addressing both the lymphoma and the underlying HIV infection, which is not typically targeted in standard chemotherapy regimens. ^{1 2 3 9 10}

Research Team

Amrita Krishnan, MD

Principal Investigator

City of Hope Medical Center

Mark J. Roschewski, MD

Principal Investigator

NCI Lymphoid Malignancy Branch

Eligibility Criteria

This trial is for HIV-positive patients with specific types of AIDS-related non-Hodgkin lymphoma, who have not had other cancers (except certain skin cancers or those treated curatively over 2 years ago), no history of severe brain conditions or seizures, and are not pregnant. They must be able to follow the study plan, use effective birth control, and show a significant reduction in their lymphoma after initial chemotherapy.

Inclusion Criteria

My kidney function is within the required range for the study.

I am HIV positive and will receive standard HIV treatment during the study.

My lymphoma is confirmed by biopsy and suitable for R-EPOCH treatment.

Exclusion Criteria

I do not have any uncontrolled illnesses or active infections, except for HIV.

I am not currently on any experimental treatments or other cancer therapies.

Any AIDS-related opportunistic infection occurring within the past year and for which treatment has been unsuccessful would be considered exclusionary, but this is done on a case-by-case basis as determined by the principal investigator (PI)

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Chemotherapy

Patients receive R-EPOCH chemotherapy regimen including prednisone, rituximab, etoposide, doxorubicin, vincristine, and cyclophosphamide, followed by filgrastim until neutrophil count recovers. Treatment repeats every 21 days for 6 courses.

18 weeks

6 cycles, each with multiple visits for drug administration

Gene Therapy

Patients receive lentivirus vector rHIV7-shI-TAR-CCR5RZ-transduced hematopoietic stem/progenitor cells IV 48 hours after the final chemotherapy course.

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment completion, with follow-up visits at 1, 2, 3, 6, 9, 12, 18, and 24 months, every 6 months for 3 years, and then annually for 10 years.

Up to 15 years

Multiple visits over 15 years

Treatment Details

Interventions

• Doxorubicin Hydrochloride, Vincristine Sulfate, Prednisone, Etoposide, Cyclophosphamide
• Lentivirus Vector rHIV7-shI-TAR-CCR5RZ-transduced Hematopoietic Stem/Progenitor Cells

Trial Overview The trial tests gene therapy combined with chemotherapy in AIDS-related non-Hodgkin lymphoma patients. It involves inserting genes that may inhibit HIV into stem cells after standard chemo drugs like rituximab and doxorubicin. The goal is to see if this can boost the body's fight against both cancer and HIV.

Participant Groups

Group I: Treatment (R-EPOCH, rHIV7-shI-TAR-CCR5RZ-transduced HSPC) Experimental Treatment 8 Interventions

Patients receive prednisone PO BID on days 1-5; rituximab IV on day 1; etoposide IV over 96 hours, doxorubicin hydrochloride IV over 96 hours and vincristine sulfate IV over 96 hours on days 1-4; and cyclophosphamide IV over 30-60 minutes on day 5. Patients then receive filgrastim SC QD beginning on day 6 and continuing until absolute neutrophil count recovers. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients then receive lentivirus vector rHIV7-shI-TAR-CCR5RZ-transduced hematopoietic stem/progenitor cells IV on day 0 (48 hours after the final combination chemotherapy course.)

Who Is Running the Clinical Trial?

City of Hope Medical Center

Lead Sponsor

Trials

614

Recruited

1,924,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

In a study of 37 patients with poor-prognosis AIDS-related non-Hodgkin's lymphoma, a reduced-dose chemotherapy regimen combined with zidovudine resulted in a 52% objective response rate, indicating some efficacy in this high-risk population.

However, the treatment was associated with significant bone marrow toxicity, leading to two treatment-related deaths, highlighting the need for careful monitoring and management of side effects in this vulnerable group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prospective study with combined low-dose chemotherapy and zidovudine in 37 patients with poor-prognosis AIDS-related non-Hodgkin's lymphoma. French-Italian Cooperative Study Group. Tirelli, U., Errante, D., Oksenhendler, E., et al.[2020]

In a dose-escalation trial involving 47 patients with aggressive HIV-related non-Hodgkin's lymphoma, the maximum tolerated doses of doxorubicin and etoposide were not reached, indicating that the chemotherapy regimen was well-tolerated even when combined with antiretroviral therapy.

The treatment resulted in a 30% complete response rate and a 28% overall survival rate at 42 months, suggesting that the VACOP-B regimen is an effective option for managing this type of lymphoma in HIV-infected patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A prospective, non-randomised phase 1-2 trial of VACOP-B with filgrastim support for HIV-related non-Hodgkin's lymphoma. Sawka, CA., Shepherd, FA., Franssen, E., et al.[2015]

In a study of 19 HIV patients undergoing chemotherapy for non-Hodgkin's lymphoma, HAART did not significantly alter the pharmacokinetics of doxorubicin (DOX), suggesting that the way the body processes DOX remains consistent regardless of HAART treatment.

However, the area under the concentration curve (AUC) of DOX was linked to higher levels of hematologic toxicity in patients receiving CHOP alone, indicating that other factors may contribute to increased toxicity when HAART is also administered.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of highly active antiretroviral therapy (HAART) on pharmacokinetics and pharmacodynamics of doxorubicin in patients with HIV-associated non-Hodgkin's lymphoma. Toffoli, G., Corona, G., Cattarossi, G., et al.[2020]

References

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

Stem cell transplantation and gene therapy for HIV-related lymphomas. [2012]

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

Hematologic Aspects of HIV/AIDS. [2019]

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

Prospective study with combined low-dose chemotherapy and zidovudine in 37 patients with poor-prognosis AIDS-related non-Hodgkin's lymphoma. French-Italian Cooperative Study Group. [2020]

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

Transplantation in HIV-infected subjects: is cure possible? [2016]

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

Gene therapy-based treatment for HIV-positive patients with malignancies. [2017]

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

A prospective, non-randomised phase 1-2 trial of VACOP-B with filgrastim support for HIV-related non-Hodgkin's lymphoma. [2015]

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

RNA-based gene therapy for HIV with lentiviral vector-modified CD34(+) cells in patients undergoing transplantation for AIDS-related lymphoma. [2022]

8. England pubmed.ncbi.nlm.nih.gov

Effect of highly active antiretroviral therapy (HAART) on pharmacokinetics and pharmacodynamics of doxorubicin in patients with HIV-associated non-Hodgkin's lymphoma. [2020]

9. Germany pubmed.ncbi.nlm.nih.gov

Treatment of acquired immunodeficiency syndrome-related lymphoma with a standard chemotherapy regimen. [2019]

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

Treatment of HIV-Associated Lymphomas: The Latest Approaches for Optimizing Outcomes. [2019]