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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new approach to treating AIDS-related non-Hodgkin lymphoma, a cancer affecting the lymphatic system. It combines chemotherapy, which targets and kills cancer cells, with gene therapy using a lentivirus vector to help the body better fight HIV. The researchers hope this combination will more effectively combat both the cancer and the virus. Individuals with HIV who have been diagnosed with certain types of lymphoma, such as Burkitt lymphoma or diffuse large B-cell lymphoma, might be suitable candidates for this trial. 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 innovative therapy.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that the chemotherapy drugs used in this trial, such as doxorubicin, vincristine, prednisone, etoposide, and cyclophosphamide, are generally well-tolerated and have been effective in many patients. Past studies reported high success rates, with many patients experiencing complete or partial remission of their cancer. However, like all chemotherapy, these drugs can cause side effects, such as tiredness, nausea, and changes in blood cell levels.

Regarding the gene therapy, which involves altering stem cells with a lentivirus, promising evidence exists. Previous studies found that this type of gene therapy can remain effective in the body for up to two years. While this is encouraging, it's important to understand that this trial is in an early stage. This means that while some safety information is available, the complete safety profile is still being studied.

Overall, both treatments have shown potential in earlier research, but as with any medical treatment, risks are involved. Participants will be closely monitored for any side effects. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard chemotherapy treatments for AIDS-related lymphoma, which typically involve drugs like doxorubicin, vincristine, and prednisone, this innovative approach includes a cutting-edge gene therapy component. The treatment uses lentivirus vector rHIV7-shI-TAR-CCR5RZ-transduced hematopoietic stem/progenitor cells, which are designed to enhance the body's immune response against the cancer. Researchers are excited because this gene therapy targets specific genetic pathways, potentially improving treatment effectiveness and reducing the risk of cancer recurrence. By integrating gene therapy with traditional chemotherapy, this approach promises a more comprehensive attack on the cancer cells, offering hope for better outcomes in patients.

What evidence suggests that this trial's treatments could be effective for AIDS-related lymphoma?

Research has shown that a new gene therapy using a modified virus to deliver genes into stem cells holds potential for treating AIDS-related conditions. This therapy, administered to participants in this trial, involves adding genes to stem cells that can block HIV, potentially enhancing the body's ability to combat the virus. Studies have found that this gene therapy remains active in the blood for up to two years, suggesting it might help the immune system fight HIV more effectively. Participants will also receive chemotherapy drugs like doxorubicin and vincristine, which have long been used to stop cancer cells from growing and spreading. This combined approach in the trial aims to effectively address both HIV infection and lymphoma. ^{6 7 8 9 10}

Who Is on the Research Team?

Amrita Krishnan, MD

Principal Investigator

City of Hope Medical Center

Mark J. Roschewski, MD

Principal Investigator

NCI Lymphoid Malignancy Branch

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT00569985

NCT00569985 | Gene Therapy-Treated Stem Cells in ... This pilot clinical trial studies biological therapy in treating patients with acquired immune deficiency syndrome (AIDS)-related lymphoma undergoing stem ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC3130552/

RNA-based gene therapy for HIV with lentiviral vector ... Stem cell gene therapy for HIV results in sustained RNA expression in the blood of patients for up to 2 years following transplant.

3. clinicaltrials.gov clinicaltrials.gov/study/NCT01961063

Gene Therapy After Frontline Chemotherapy in Treating ... Patients receive busulfan IV over 3 hours on day -2 followed by lentivirus vector rHIV7-shI-TAR-CCR5RZ-transduced hematopoietic progenitor cells IV on day 0.

4. cancer.gov cancer.gov/publications/dictionaries/cancer-drug/def/730576

lentivirus vector rHIV7-shI-TAR-CCR5RZ-transduced ... The 3 RNA products produced by the lentilvirus are: a short hairpin RNA (shRNA) targeted to an exon of the HIV-1 genes tat/rev, designated as shI; a decoy for ...

5. sciencedirect.com sciencedirect.com/science/article/pii/S2352304222000800

Ready for translation into targeted cancer gene therapy? Among them, lentiviral vectors (LVs) have emerged as powerful tools for stable gene delivery due to several advantages including the ability to transduce both ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/8750155/

Vincristine, doxorubicin, cyclophosphamide, prednisone ... Results: 57/73 patients achieved CR (78%), and the overall response rate (CR-PR) was 95%. The median observation time is 40 months (10+-74+). The 1-, 3- and 5- ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT02538926

NCT02538926 | Etoposide, Prednisone, Vincristine Sulfate ... This phase II trial studies how well etoposide, prednisone, vincristine sulfate, cyclophosphamide, and doxorubicin hydrochloride with asparaginase work in ...

8. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/11458812/

Cyclophosphamide, doxorubicin, vincristine, prednisone, and ... In cohort I, 92% of patients achieved a complete response (CR) or partial response (PR) with four cycles of CHOPE and 85% were in CR after four additional ...

9. clinicaltrials.gov clinicaltrials.gov/study/NCT03220022

Study Details | NCT03220022 | Ibrutinib, Rituximab, ... This phase I trial studies the side effect and best dose of ibrutinib in combination with rituximab, etoposide, prednisone, vincristine sulfate, ...

10. mycancergenome.org mycancergenome.org/content/clinical_trials/NCT04139304/

Clinical Trial: NCT04139304 This feasibility trial studies how well daratumumab in combination with dose-adjusted etoposide, prednisone, vincristine sulfate, cyclophosphamide, and ...