CAR-T Cell Therapy for Lymphoma

Overseen By Benjamin Tomlinson, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Benjamin Tomlinson

Must not be taking: Immunosuppressants

Disqualifiers: CNS involvement, Second malignancy, HIV, others

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

Compensation: Varies

Number of Visits: Unknown

36 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this study is to determine if it is possible to treat relapsed or refractory lymphoid malignancies (Non-Hodgkin Lymphoma, Acute Lymphoblastic Leukemia, Chronic Lymphocytic Leukemia) with a new type of T cell-based immunotherapy (therapy that uses the immune system to treat the cancer).

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you need to stop your current medications. However, if you have had an allogeneic stem cell transplant, you must be off immunosuppressive agents. It's best to discuss your specific medications with the trial team.

What data supports the idea that CAR-T Cell Therapy for Lymphoma is an effective treatment?

The available research shows that CAR-T Cell Therapy, specifically using fludarabine before the treatment, can be effective for aggressive B-cell non-Hodgkin lymphoma. In a study with 199 patients, those who received an optimal amount of fludarabine had better outcomes. For example, 66% of these patients were alive without their disease getting worse after one year, compared to only 39% in the group with lower fludarabine exposure. This suggests that the right amount of fludarabine can make CAR-T Cell Therapy more effective. However, it's important to balance the dose to avoid side effects. ^{1 2 3 4 5}

What safety data is available for CAR-T cell therapy for lymphoma?

The safety data for CAR-T cell therapy, particularly involving fludarabine and cyclophosphamide, indicates several key points: 1) Fludarabine can cause myelosuppression, neurotoxicity, and other toxicities at higher doses, with a maximum tolerated dose of 40 mg/m2/day. 2) Optimal fludarabine exposure is crucial for balancing efficacy and safety, as higher exposure can increase the risk of neurotoxicity, including ICANS. 3) Cyclophosphamide, when used with fludarabine, may affect CAR-T cell efficacy due to its impact on regulatory T cells. 4) Alternatives like bendamustine may offer similar efficacy with potentially fewer side effects. Overall, careful dosing and monitoring are essential to minimize risks. ^{1 6 7 8 9}

Is the treatment with Cyclophosphamide, Fludarabine, and CAR-T Cell promising for lymphoma?

Yes, the combination of Cyclophosphamide, Fludarabine, and CAR-T Cell therapy is promising for treating lymphoma. Studies show that this combination improves the effectiveness of CAR-T cells, leading to higher response rates and better survival outcomes in patients with lymphoma. ^{10 11 12 13 14}

Research Team

Benjamin Tomlinson, MD

Principal Investigator

University Hospitals Cleveland Medical Center, Case Comprehensive Cancer Center

Eligibility Criteria

This trial is for adults with certain blood cancers (like different types of leukemia and lymphoma) that have come back or didn't respond to treatment. They should be relatively healthy otherwise, not pregnant or breastfeeding, able to understand the study, and willing to use effective birth control.

Inclusion Criteria

AST (SGOT) ≤ 3 times institutional upper limit of normal

I can take care of myself and am up and about more than half of my waking hours.

Total bilirubin ≤ 1.5 times the institutional upper limit of normal unless bilirubin rise is due to Gilbert's syndrome (maximum 2 time normal) or of non-hepatic origin

Exclusion Criteria

It has been at least 28 days since I last received experimental treatment.

I had a stem cell transplant 3 months ago and am not on immunosuppressants.

I am HIV positive.

Treatment Details

Interventions

• Cyclophosphamide
• Fludarabine
• Fully human anti CD19 CAR-T Cell Dose

Trial Overview Researchers are testing a new immunotherapy using T cells engineered to target CD19, a protein on cancer cells. Participants will also receive drugs Fludarabine and Cyclophosphamide to help these special T cells work better.

Participant Groups

Group I: Group B - ALL Experimental Treatment 3 Interventions

Upon enrollment, peripheral blood mononuclear cells will be collected, and T-cell selection and manufacture of CAR-T cells will be done. Participants will receive 60 mg/Kg/IV Cyclophosphamide on day -6 and 25 mg/m\^2 Fludarabine from day -5 to day -3. Participants with Acute Lymphoblastic Leukemia (and lymphoblastic lymphoma as a solid tumor equivalent) will be enrolled on this arm sequentially in a 3 + 3 design starting with infusion of CAR-T cells at DL1 on day 0 and 7. The maximum tolerated dose (MTD) will be determined and then 6 additional participants will be enrolled at the MTD.

Group II: Group A - NHL/CLL Experimental Treatment 3 Interventions

Upon enrollment, peripheral blood mononuclear cells will be collected, and T-cell selection and manufacture of CAR-T cells will be done. Participants will receive 60 mg/Kg/IV Cyclophosphamide on day -6 and 25 mg/m\^2 Fludarabine from day -5 to day -3. Participants with CD19+ lymphomas and chronic lymphocytic leukemia will be enrolled on this arm sequentially in a 3 + 3 design starting with infusion of CAR-T cells at dose level 1 (DL1) on day 0. The maximum tolerated dose (MTD) will be determined and then 6 additional participants will be enrolled at the MTD.

Cyclophosphamide is already approved in United States, European Union, Canada, Japan for the following indications:

Approved in United States as Cytoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in European Union as Endoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in Canada as Neosar for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in Japan as Endoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma

Who Is Running the Clinical Trial?

Benjamin Tomlinson

Lead Sponsor

Trials

4

Recruited

110+

Findings from Research

In a study of 199 adult patients with aggressive B-cell non-Hodgkin lymphomas, an optimal fludarabine exposure (18-20 mg×hour/L) was associated with the best progression-free survival (66%) and lowest risk of disease relapse compared to lower and higher exposure groups.

Higher fludarabine exposure (>20 mg×hour/L) increased the risk of immune effector cell-associated neurotoxicity syndrome (ICANS) and nonrelapse-related deaths, indicating that careful dosing is crucial for balancing efficacy and safety in patients receiving axicabtagene ciloleucel (Axi-cel).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Identifying an optimal fludarabine exposure for improved outcomes after axi-cel therapy for aggressive B-cell non-Hodgkin lymphoma. Scordo, M., Flynn, JR., Gonen, M., et al.[2023]

The combination of fludarabine and cyclophosphamide at the recommended dose of cyclophosphamide 1,000 mg/m² on day 1 and fludarabine 20 mg/m² from days 1 to 5 shows a high response rate of 100% in previously untreated patients with low-grade lymphoma, with 89% achieving complete remission.

Despite some hematologic toxicities, such as grade 4 neutropenia in 17% of cycles, the treatment demonstrated promising long-term outcomes, with estimated 5-year overall survival and disease-free survival rates of 66% and 53%, respectively.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I study of fludarabine plus cyclophosphamide in patients with previously untreated low-grade lymphoma: results and and long-term follow-up--a report from the Eastern Cooperative Oncology Group. Hochster, HS., Oken, MM., Winter, JN., et al.[2017]

In a study of 25 adults with advanced low-grade non-Hodgkin's lymphoma, the combination of fludarabine, cyclophosphamide, and dexamethasone (FluCyD) showed a significant response rate, with 72% of patients responding to treatment, including 32% achieving complete remission (CR).

The main side effect observed was myelosuppression, leading to treatment delays in 40% of courses, highlighting the need for further investigation into supportive treatments like granulocyte colony-stimulating factor to mitigate this toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fludarabine, cyclophosphamide, and dexamethasone (FluCyD) combination is effective in pretreated low-grade non-Hodgkin's lymphoma. Lazzarino, M., Orlandi, E., Montillo, M., et al.[2020]

The combination therapy of fludarabine, cyclophosphamide, and rituximab (FC-R) resulted in high objective response rates (83%) and complete response rates (42%) among 76 evaluable patients, demonstrating its efficacy in treating chronic lymphocytic leukemia (CLL) and follicular lymphoma.

Patients with CLL showed particularly impressive results, with 100% objective response and 67% complete response rates when treated as first-line therapy, indicating that FC-R is a potent option for both initial and salvage therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fludarabine, cyclophosphamide, and rituximab for the treatment of patients with chronic lymphocytic leukemia or indolent non-Hodgkin lymphoma. Tam, CS., Wolf, M., Prince, HM., et al.[2015]

In a study of 89 hematopoietic cell transplantation recipients, higher levels of the active metabolite of cyclophosphamide (PM AUC0-8 hr) were linked to worse nonrelapse mortality and overall survival, indicating that careful monitoring of this metabolite is crucial for patient outcomes.

Patients with low levels of the active metabolite of fludarabine (F-ara-ADay-4) and low PM AUC0-8 hr had significantly lower nonrelapse mortality, suggesting that optimizing drug exposure could improve safety and efficacy in reduced-intensity conditioning regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Higher Fludarabine and Cyclophosphamide Exposures Lead to Worse Outcomes in Reduced-Intensity Conditioning Hematopoietic Cell Transplantation for Adult Hematologic Malignancy. Takahashi, T., Scheibner, A., Cao, Q., et al.[2021]

F-Ara-AMP, an adenosine analogue, was administered to 27 adult patients with advanced cancer, showing it is a potent cytotoxic agent with myelosuppression as the primary side effect, particularly leukopenia.

The study found that a safe dose of 25 mg/m2/day can be given to patients with good renal function, but lower doses are recommended for those with a history of extensive chemotherapy or radiotherapy due to cumulative myelosuppressive effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I clinical trial of fludarabine phosphate (F-ara-AMP). Casper, ES., Mittelman, A., Kelson, D., et al.[2019]

Fludarabine phosphate, administered as a continuous infusion for 5 days, showed significant toxicity in patients with acute leukemia, including uniform myelosuppression and severe neurotoxicity at doses above 40 mg/m2/day.

The maximum tolerated dose for fludarabine phosphate was determined to be 40 mg/m2/day, as higher doses led to severe neurological complications, including blindness and encephalopathy, with some patients not recovering.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fludarabine phosphate (NSC 312878) infusions for the treatment of acute leukemia: phase I and neuropathological study. Spriggs, DR., Stopa, E., Mayer, RJ., et al.[2013]

In a study of 102 patients undergoing hematopoietic cell transplantation (HCT) with fludarabine and low-dose total body irradiation, significant variability was observed in pharmacological biomarkers related to fludarabine metabolism, indicating that individual responses to the drug can differ widely.

Despite the variability in biomarkers such as F-ara-A area under the curve and F-ara-ATP accumulation, no significant associations were found between these biomarkers and clinical outcomes like acute graft-versus-host disease or overall mortality, suggesting that these pharmacological measures may not predict treatment success.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Association of fludarabine pharmacokinetic/dynamic biomarkers with donor chimerism in nonmyeloablative HCT recipients. McCune, JS., Mager, DE., Bemer, MJ., et al.[2018]

The standard lymphodepletion regimen before CAR-T cell therapy, which combines cyclophosphamide and fludarabine, may preserve regulatory T cell activity and cause neurotoxicity, complicating treatment outcomes.

Recent studies suggest that using bendamustine as an alternative lymphodepleting agent before CAR-T cell infusion could provide similar efficacy with a potentially better safety profile, indicating a need for further randomized studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Has the shortage of fludarabine altered the current paradigm of lymphodepletion in favor of bendamustine? Filioglou, D., Husnain, M., Khurana, S., et al.[2023]

In a clinical trial involving 32 adults with relapsed B cell non-Hodgkin's lymphoma, CD19 CAR-T cells showed significantly improved efficacy when administered after cyclophosphamide and fludarabine (Cy/Flu) lymphodepletion, achieving a 50% complete remission rate and a 72% overall response rate.

The study identified that the Cy/Flu regimen enhanced CAR-T cell expansion and persistence while minimizing immune responses that could limit efficacy, although it also resulted in severe cytokine release syndrome and neurotoxicity in a notable percentage of patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunotherapy of non-Hodgkin's lymphoma with a defined ratio of CD8+ and CD4+ CD19-specific chimeric antigen receptor-modified T cells. Turtle, CJ., Hanafi, LA., Berger, C., et al.[2022]

In a phase II trial involving 60 patients with low-grade and select intermediate-grade lymphoid malignancies, the combination of fludarabine, cyclophosphamide, and filgrastim resulted in a high overall complete response rate of 51% and a partial response rate of 41%.

While the treatment was generally well-tolerated, with rapid engraftment observed in patients who underwent stem cell transplants, significant nonhematologic toxicities, including infections, were noted, highlighting the need for careful monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fludarabine and cyclophosphamide with filgrastim support in patients with previously untreated indolent lymphoid malignancies. Flinn, IW., Byrd, JC., Morrison, C., et al.[2021]

In a study of 26 patients with relapsed/refractory B-cell acute lymphoblastic leukemia receiving CD19 CAR T-cell therapy, higher cumulative exposure to fludarabine (≥14 mg*h/L) was linked to significantly better leukemia-free survival (12.9 months) compared to lower exposure (<14 mg*h/L, 1.8 months).

Patients with lower fludarabine exposure also experienced a higher rate of CD19-positive relapse (100% vs. 27.4%) and shorter duration of B-cell aplasia, indicating that optimizing fludarabine dosing could improve outcomes in CAR T-cell therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fludarabine exposure predicts outcome after CD19 CAR T-cell therapy in children and young adults with acute leukemia. Dekker, L., Calkoen, FG., Jiang, Y., et al.[2022]

The combination therapy of fludarabine, cyclophosphamide, and rituximab (FCR) achieved a high complete remission (CR) rate of 70% in 224 previously untreated patients with chronic lymphocytic leukemia (CLL), indicating its efficacy as an initial treatment.

Despite the high response rate, the treatment was associated with significant side effects, including grade 3 to 4 neutropenia in 52% of treatment courses and a notable incidence of infections, highlighting the need for careful monitoring during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Early results of a chemoimmunotherapy regimen of fludarabine, cyclophosphamide, and rituximab as initial therapy for chronic lymphocytic leukemia. Keating, MJ., O'Brien, S., Albitar, M., et al.[2021]

In a study of 17 patients with relapsed or refractory non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukaemia (CLL), the combination therapy of fludarabine and cyclophosphamide showed an overall response rate of 71% for CLL and 50% for NHL, indicating its efficacy in treating these conditions.

While the treatment was effective, it was associated with significant side effects, including nausea, vomiting, infections, and prolonged hematological suppression, highlighting the need for careful monitoring of patient tolerance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination therapy with fludarabine and cyclophosphamide as salvage treatment in lymphoproliferative disorders. Frewin, R., Turner, D., Tighe, M., et al.[2019]

References

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

Identifying an optimal fludarabine exposure for improved outcomes after axi-cel therapy for aggressive B-cell non-Hodgkin lymphoma. [2023]

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

Phase I study of fludarabine plus cyclophosphamide in patients with previously untreated low-grade lymphoma: results and and long-term follow-up--a report from the Eastern Cooperative Oncology Group. [2017]

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

Fludarabine, cyclophosphamide, and dexamethasone (FluCyD) combination is effective in pretreated low-grade non-Hodgkin's lymphoma. [2020]

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

Fludarabine, cyclophosphamide, and rituximab for the treatment of patients with chronic lymphocytic leukemia or indolent non-Hodgkin lymphoma. [2015]

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

Higher Fludarabine and Cyclophosphamide Exposures Lead to Worse Outcomes in Reduced-Intensity Conditioning Hematopoietic Cell Transplantation for Adult Hematologic Malignancy. [2021]

6. Germany pubmed.ncbi.nlm.nih.gov

Phase I clinical trial of fludarabine phosphate (F-ara-AMP). [2019]

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

Fludarabine phosphate (NSC 312878) infusions for the treatment of acute leukemia: phase I and neuropathological study. [2013]

8. Germany pubmed.ncbi.nlm.nih.gov

Association of fludarabine pharmacokinetic/dynamic biomarkers with donor chimerism in nonmyeloablative HCT recipients. [2018]

9. Switzerland pubmed.ncbi.nlm.nih.gov

Has the shortage of fludarabine altered the current paradigm of lymphodepletion in favor of bendamustine? [2023]

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

Immunotherapy of non-Hodgkin's lymphoma with a defined ratio of CD8+ and CD4+ CD19-specific chimeric antigen receptor-modified T cells. [2022]

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

Fludarabine and cyclophosphamide with filgrastim support in patients with previously untreated indolent lymphoid malignancies. [2021]

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

Fludarabine exposure predicts outcome after CD19 CAR T-cell therapy in children and young adults with acute leukemia. [2022]

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

Early results of a chemoimmunotherapy regimen of fludarabine, cyclophosphamide, and rituximab as initial therapy for chronic lymphocytic leukemia. [2021]

14. England pubmed.ncbi.nlm.nih.gov

Combination therapy with fludarabine and cyclophosphamide as salvage treatment in lymphoproliferative disorders. [2019]