Cellular Immunotherapy After Chemotherapy for Non-Hodgkin's Lymphoma and Chronic Lymphocytic Leukemia

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: City of Hope Medical Center

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

Compensation: Varies

Number of Visits: 1

37 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase I trial studies the side effects and best dose of cellular immunotherapy following chemotherapy in treating patients with non-Hodgkin lymphomas, chronic lymphocytic leukemia, or B-cell prolymphocytic leukemia that has come back. Placing a modified gene into white blood cells may help the body build an immune response to kill cancer cells.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications before participating. You must be at least two weeks from your last dose of immunosuppressant medications and certain chemotherapy drugs. Oral chemotherapy drugs like lenalidomide and ibrutinib are allowed if enough time has passed since your last dose.

What data supports the effectiveness of the treatment Cellular Immunotherapy After Chemotherapy for Non-Hodgkin's Lymphoma and Chronic Lymphocytic Leukemia?

The research indicates that chemoimmunotherapies, which include drugs like fludarabine and cyclophosphamide, are effective in treating chronic lymphocytic leukemia, with higher survival rates compared to treatments without antibodies. Additionally, fludarabine is noted for its effectiveness in inducing remission in chronic lymphocytic leukemia, suggesting potential benefits when used in combination with other therapies. ^{1 2 3 4 5}

Is cellular immunotherapy after chemotherapy for Non-Hodgkin's Lymphoma and Chronic Lymphocytic Leukemia safe?

Bendamustine, a drug used in this treatment, has been studied for safety in various regimens. Common side effects include mucositis (mouth sores), gastroenteritis (stomach issues), and skin reactions. Serious side effects like kidney problems and heart rhythm issues are less common, but they can occur, especially in patients with pre-existing conditions. ^{6 7 8 9 10}

What makes this treatment for Non-Hodgkin's Lymphoma and Chronic Lymphocytic Leukemia unique?

This treatment is unique because it combines chemotherapy with a novel cellular immunotherapy using genetically modified T-lymphocytes (a type of white blood cell) that are designed to specifically target cancer cells, potentially offering a more targeted approach compared to traditional chemotherapy alone. ^{1 11 12 13 14}

Research Team

Tanya Siddiqi

Principal Investigator

City of Hope Medical Center

Eligibility Criteria

This trial is for patients with certain types of blood cancers that have returned, including various non-Hodgkin lymphomas and chronic leukemias. Participants should have a life expectancy of at least 16 weeks, be able to use contraception, understand the study and consent to it, have adequate organ function (kidney, liver, heart), not be on immunosuppressants or other disqualifying treatments recently, and not need oxygen or intensive care support.

Inclusion Criteria

I have a specific type of lymphoma or leukemia and may not have qualified for certain other treatments.

I have CLL, PLL, or SLL.

I am able to care for myself but may not be able to do active work.

Exclusion Criteria

Participants who have previously received a specific type of experimental treatment.

I do not have any uncontrolled illnesses that would affect my study participation.

I do not have active hepatitis B or C, HIV, or any signs of active infection.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Lymphodepleting Chemotherapy

Patients receive a chemotherapy regimen based on disease type and extent of disease comprising of cyclophosphamide, bendamustine hydrochloride, fludarabine phosphate, etoposide.

1 week

Cellular Immunotherapy

Patients receive autologous CD19CAR-CD28-CD3zeta-EGFRt-expressing Tn/mem-enriched T-lymphocytes IV over 10-15 minutes on day 0. Patients with relapsed, residual or progressive disease may receive an optional second infusion.

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment. Follow-up includes every 2 days for 14 days, weekly for 1 month, monthly for 1 year, and then yearly for at least 15 years.

15 years

Treatment Details

Interventions

• Autologous CD19CAR-CD28-CD3zeta-EGFRt-expressing Tn/mem-enriched T-lymphocytes
• Bendamustine Hydrochloride
• Cyclophosphamide
• Etoposide
• Fludarabine Phosphate

Trial Overview The trial tests a cellular immunotherapy where white blood cells are genetically modified to attack cancer following chemotherapy. It aims to determine the best dose and side effects of this treatment in patients whose disease has recurred after previous therapies.

Participant Groups

Group I: Group II (lymphodepletion, cellular immunotherapy) Experimental Treatment 5 Interventions

LYMPHODEPLETING REGIMEN: Patients receive a chemotherapy regimen based on disease type and extent of disease comprising of cyclophosphamide, bendamustine hydrochloride, fludarabine phosphate, etoposide. CELLULAR IMMUNOTHERAPY: Beginning 3-10 days later after lymphodepletion, patients receive autologous CD19CAR-CD28-CD3zeta-EGFRt-expressing Tn/mem-enriched T-lymphocytes IV over 10-15 minutes on day 0. Patients with relapsed, residual or progressive disease may receive an optional second infusion of autologous CD19CAR-CD28-CD3zeta-EGFRt-expressing Tn/mem-enriched T-lymphocytes \>= 28 days post T cell infusion. Disease status: Patients with Chronic lymphocytic leukemia (CLL) and/or Prolymphocytic Leukemia (PLL).

Group II: Group I (lymphodepletion, cellular immunotherapy) Experimental Treatment 5 Interventions

LYMPHODEPLETING REGIMEN: Patients receive a chemotherapy regimen based on disease type and extent of disease comprising of cyclophosphamide, bendamustine hydrochloride, fludarabine phosphate, etoposide. CELLULAR IMMUNOTHERAPY: Beginning 3-10 days later after lymphodepletion, patients receive autologous CD19CAR-CD28-CD3zeta-EGFRt-expressing Tn/mem-enriched T-lymphocytes IV over 10-15 minutes on day 0. Patients with relapsed, residual or progressive disease may receive an optional second infusion of autologous CD19CAR-CD28-CD3zeta-EGFRt-expressing Tn/mem-enriched T-lymphocytes \>= 28 days post T cell infusion. Disease status: Patients with Non-Hodgkin lymphoma (NHL).

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 involving 561 patients with chronic lymphocytic leukaemia, the standard treatment of fludarabine, cyclophosphamide, and rituximab showed a longer median progression-free survival of 55.2 months compared to 41.7 months for the bendamustine and rituximab combination, indicating that the standard therapy is more effective.

However, the bendamustine and rituximab combination was associated with significantly fewer severe side effects, such as neutropenia and infections, making it a potentially safer alternative for patients, especially those over 65 years.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-line chemoimmunotherapy with bendamustine and rituximab versus fludarabine, cyclophosphamide, and rituximab in patients with advanced chronic lymphocytic leukaemia (CLL10): an international, open-label, randomised, phase 3, non-inferiority trial. Eichhorst, B., Fink, AM., Bahlo, J., et al.[2022]

The study evaluated an immunotherapy regimen combining rIL-2, rIFN-alpha, and histamine in a patient with relapsing aggressive non-Hodgkin's lymphoma, showing significant increases in T-cell responses and natural killer (NK) cell activity during chemotherapy-induced remission.

The treatment led to enhanced production of key cytokines (IFN-gamma, IL-4, and TNF-alpha) by T-cells, indicating a robust immune response, while also reducing potentially regulatory lymphocytes, suggesting a promising approach to boost immune function in lymphoma patients post-chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Stimulation of T-cell cytokine production and NK-cell function by IL-2, IFN-alpha and histamine treatment during remission of non-Hodgkin's lymphoma. Ahlberg, R., MacNamara, B., Andersson, M., et al.[2016]

Fludarabine is currently the most effective treatment for chronic lymphocytic leukemia, helping to activate apoptosis in abnormal lymphocytes, but it does not cure the disease.

For hairy-cell leukemia, treatments like pentostatin and 2-chlorodeoxyadenosine lead to durable complete remissions in 65% to 85% of patients, showing promising efficacy with similar toxicity levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chronic lymphocytic leukemia and hairy-cell leukemia. Cheson, BD.[2007]

The T(R)EC regimen, which replaces ifosfamide with bendamustine, demonstrated high response rates of 85% in classic Hodgkin lymphoma and 65% in diffuse large B cell lymphoma, indicating its efficacy as a treatment for relapsed or refractory cases.

This outpatient treatment was found to be safe, with no dose-limiting toxicities and successful stem cell collection in 30 out of 32 patients, making it a promising alternative to the traditional (R)ICE regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bendamustine with rituximab, etoposide and carboplatin (T(R)EC) in relapsed or refractory aggressive lymphoma: a prospective multicentre phase 1/2 clinical trial. Budde, LE., Wu, D., Martin, DB., et al.[2022]

In a study of 34 patients with multiple myeloma, the combination of bendamustine, etoposide, and dexamethasone (BED) successfully mobilized hematopoietic stem cells in all participants, with a median yield of 21.60 million cells per kg of body weight.

The treatment was effective and safe, with 88% of patients needing only one apheresis session, although six patients experienced serious nonhematologic adverse events, indicating a manageable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bendamustine, etoposide and dexamethasone to mobilize peripheral blood hematopoietic stem cells for autologous transplantation in patients with multiple myeloma. Green, DJ., Bensinger, WI., Holmberg, LA., et al.[2023]

The combination of fludarabine and cyclophosphamide effectively reduces tumor burden in chronic lymphocytic leukemia, but it also leads to a significant reduction in CD4(+) and CD8(+) T cells, indicating potential immunosuppressive effects.

Despite the depletion of T cells, the surviving T cells exhibit a more mature phenotype and increased responsiveness to stimulation, suggesting that fludarabine/cyclophosphamide therapy may create a favorable environment for subsequent T cell activation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fludarabine modulates composition and function of the T cell pool in patients with chronic lymphocytic leukaemia. Gassner, FJ., Weiss, L., Geisberger, R., et al.[2021]

References

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

First-line chemoimmunotherapy with bendamustine and rituximab versus fludarabine, cyclophosphamide, and rituximab in patients with advanced chronic lymphocytic leukaemia (CLL10): an international, open-label, randomised, phase 3, non-inferiority trial. [2022]

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

Cost-Effectiveness Analysis of Rituximab for Chronic Lymphocytic Leukemia Using a Semi-Markovian Model Approach in R. [2023]

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

Stimulation of T-cell cytokine production and NK-cell function by IL-2, IFN-alpha and histamine treatment during remission of non-Hodgkin's lymphoma. [2016]

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

Chronic lymphocytic leukemia and hairy-cell leukemia. [2007]

5. Italy pubmed.ncbi.nlm.nih.gov

Outcome of advanced chronic lymphocytic leukemia following different first-line and relapse therapies: a meta-analysis of five prospective trials by the German CLL Study Group (GCLLSG). [2018]

6. England pubmed.ncbi.nlm.nih.gov

Bendamustine with rituximab, etoposide and carboplatin (T(R)EC) in relapsed or refractory aggressive lymphoma: a prospective multicentre phase 1/2 clinical trial. [2022]

7. Korea (South) pubmed.ncbi.nlm.nih.gov

Safety and efficacy of bendamustine in the conditioning regimen for autologous stem cell transplantation in patients with relapsed/refractory lymphoma. [2022]

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

Bendamustine-based conditioning prior to autologous stem cell transplantation (ASCT): Results of a French multicenter study of 474 patients from LYmphoma Study Association (LYSA) centers. [2019]

9. England pubmed.ncbi.nlm.nih.gov

Bendamustine, etoposide and dexamethasone to mobilize peripheral blood hematopoietic stem cells for autologous transplantation in patients with multiple myeloma. [2023]

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

Bendamustine-induced nephrogenic diabetes insipidus - A case report. [2021]

11. Germany pubmed.ncbi.nlm.nih.gov

Systemic immune effects of adjuvant chemotherapy with 5-fluorouracil, epirubicin and cyclophosphamide and/or radiotherapy in breast cancer: a longitudinal study. [2013]

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

Therapy-related myeloid neoplasms following fludarabine, cyclophosphamide, and rituximab (FCR) treatment in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma. [2023]

13. Germany pubmed.ncbi.nlm.nih.gov

Fludarabine modulates composition and function of the T cell pool in patients with chronic lymphocytic leukaemia. [2021]

14. Germany pubmed.ncbi.nlm.nih.gov

Lymphocyte recovery is impaired in patients with chronic lymphocytic leukemia and indolent non-Hodgkin lymphomas treated with bendamustine plus rituximab. [2021]