Optimized Lymphodepletion + CAR T Therapy for Diffuse Large B-Cell Lymphoma

(ODIN Trial)

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: University Health Network, Toronto

Must not be taking: Corticosteroids, Immunosuppressives, others

Disqualifiers: Richter's transformation, CNS disease, others

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

Compensation: Varies

Number of Visits: Unknown

40 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to find the best way to prepare patients with Diffuse Large B-Cell Lymphoma (DLBCL) for CAR T cell therapy, a cancer treatment using modified immune cells. Researchers are testing different doses of two chemotherapy drugs, Fludarabine and Cyclophosphamide (also known as Cytoxan, Neosar, or Endoxan), with or without added radiation, to determine the most effective approach. People with DLBCL that recurs or hasn't responded to at least two previous treatments might be suitable candidates. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the chance to contribute to groundbreaking cancer research.

Will I have to stop taking my current medications?

The trial requires that certain medications be stopped before participation. Specifically, corticosteroids above a certain dose, some chemotherapeutic agents, experimental agents, and immunosuppressive therapies must be stopped for a specified period before starting the trial. Please consult with the trial team for guidance on your specific medications.

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

Previous studies have used the combination of fludarabine and cyclophosphamide to treat lymphoma. Common side effects include low white blood cell counts (neutropenia) in about 45% of patients, low platelet counts (thrombocytopenia) in about 42%, and infections in 57% of cases. These side effects are significant but expected with chemotherapy drugs.

Research has shown that low doses of cyclophosphamide can safely prepare patients for further treatment by reducing side effects. This suggests the treatment is generally well-tolerated, especially at lower doses.

Since this trial is in an early phase, it focuses on finding safe dosage levels and identifying any potential side effects. While past research provides extensive safety data, this trial will confirm the safe and effective use of this specific treatment setup. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for Diffuse Large B-Cell Lymphoma because they combine optimized lymphodepletion with CAR T-cell therapy, potentially enhancing the effectiveness of the treatment. Unlike traditional chemotherapy and immunotherapy, these experimental approaches use a combination of cyclophosphamide and fludarabine, with some arms also including radiation, to prepare the body for CAR T-cell therapy. This could boost the immune system's ability to fight cancer by creating a more favorable environment for the modified T-cells to work. By experimenting with different doses and combinations, these treatments aim to improve outcomes and offer new hope for patients with this aggressive form of lymphoma.

What evidence suggests that this trial's treatments could be effective for Diffuse Large B-Cell Lymphoma?

Research has shown that using Cyclophosphamide and Fludarabine together can effectively treat certain blood cancers, such as Diffuse Large B-Cell Lymphoma (DLBCL). In studies, up to 79% of patients responded to this treatment, with many achieving complete remission, meaning no signs of cancer were found. In this trial, some participants will receive Cyclophosphamide and Fludarabine at standard doses, while others will receive intermediate doses. Additionally, some treatment arms will include radiation therapy, which has been linked to even better results. Studies also highlight the importance of maintaining consistent drug doses, as lowering them can lead to a shorter time before the disease worsens. These findings suggest that the combination of Cyclophosphamide, Fludarabine, and radiation may be effective for patients with DLBCL. ^{1 2 3 6 7}

Are You a Good Fit for This Trial?

Adults with Diffuse Large B Cell Lymphoma who haven't had adoptive T-cell immunotherapy or allogeneic stem cell transplant, have good organ function and life expectancy of at least 12 weeks. They must not be HIV positive, pregnant, or breastfeeding and agree to use contraception. Participants need measurable disease per Lugano criteria and should be eligible for standard CAR T cell therapy after at least two systemic therapies.

Inclusion Criteria

I am stable enough for CAR T-cell therapy and do not need intensive care support.

Life expectancy ≥ 12 weeks

It's been over 2 weeks or 5 half-lives since my last cancer treatment.

Exclusion Criteria

My cancer is still large (at least 10 cm) after initial treatment.

I haven't taken Ibrutinib, lenalidomide, or PI3K inhibitors recently.

Women of childbearing potential who are pregnant or breastfeeding because of the potentially dangerous effects of chemotherapy on the fetus or infant

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Participants receive a modified lymphodepletion regimen to assess safety and tolerability

Approximately 4-6 weeks

Multiple visits for dose administration and monitoring

Cohort Expansion

Further characterization of toxicity and efficacy profile to determine the recommended phase 2 dose

Approximately 4-6 weeks

Multiple visits for treatment and assessment

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 months

Regular visits for monitoring progression-free survival and response rate

What Are the Treatments Tested in This Trial?

Interventions

• Cyclophosphamide
• TLI

Trial Overview The trial is testing different pre-treatment regimens (lymphodepletion) before CAR T cell therapy in DLBCL patients. It compares standard and intermediate doses of Fludarabine/Cyclophosphamide with/without total lymphoid irradiation (TLI) to find the best way to prepare patients for the subsequent CAR T treatment.

How Is the Trial Designed?

Group I: Cyclophosphamide and fludarabine, standard dose with radiation Experimental Treatment 2 Interventions

Fludarabine 30mg/m2 Cyclophosphamide 500mg/m2 Days -6, -5, -4, and 2 Gy in 2 Fractions Days -3, -2

Group II: Cyclophosphamide (intermediate dose) and fludarabine with radiation Experimental Treatment 2 Interventions

Fludarabine 30mg/m2 Cyclophosphamide 750mg/m2 Days -6, -5, -4, and 2 Gy in 2 Fractions Days -3, -2

Group III: Cyclophosphamide (intermediate dose) and fludarabine Experimental Treatment 1 Intervention

Fludarabine 30mg/m2 Cyclophosphamide 750mg/m2 Days -4, -3, -2

Group IV: Cyclophosphamide and fludarabine, standard dose Active Control 1 Intervention

Fludarabine 30mg/m2 Cyclophosphamide 500mg/m2 Days -4, -3, -2

Who Is Running the Clinical Trial?

University Health Network, Toronto

Lead Sponsor

Trials

1,555

Recruited

526,000+

Published Research Related to This Trial

Chimeric antigen receptor (CAR) T-cell therapy, specifically anti-CD19 CAR T-cell therapies like axicabtagene ciloleucel and tisagenlecleucel, have been approved for treating relapsed or refractory aggressive B-cell lymphoma, marking a significant advancement after decades of limited treatment options.

These therapies have shown promising efficacy in clinical trials, but they also come with potential toxicities, highlighting the need for ongoing research to enhance their safety and effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The promise of CAR T-cell therapy in aggressive B-cell lymphoma. Nair, R., Neelapu, SS.[2021]

In a study of 60 patients with relapsed/refractory diffuse large B-cell lymphoma, CD19-directed CAR T-cell therapies achieved complete metabolic responses in 40% and partial responses in 23% of patients, indicating significant efficacy.

Factors such as the age-adjusted international prognostic index, T-cell subset phenotypes, and lower levels of exhaustion markers (LAG3 and Tim3) were associated with better outcomes, suggesting that these could be important indicators for predicting the success of CAR T-cell therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical and Product Features Associated with Outcome of DLBCL Patients to CD19-Targeted CAR T-Cell Therapy. Lamure, S., Van Laethem, F., De Verbizier, D., et al.[2021]

Chimeric antigen receptor (CAR) T-cell therapy shows promising efficacy in treating relapsed or refractory diffuse large B-cell lymphoma (DLBCL), with an objective response rate of 68% and a complete remission rate of 46% based on a meta-analysis of 306 patients.

While CAR T-cell therapy is effective, it is associated with significant adverse effects, including grade ≥3 anemia (34%) and thrombocytopenia (30%), although serious complications like cytokine release syndrome and neurotoxicity can be effectively managed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of second-generation CAR T-cell therapy in diffuse large B-cell lymphoma: A meta-analysis. Al-Mansour, M., Al-Foheidi, M., Ibrahim, E.[2023]

In a phase II clinical trial involving 33 patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), CD19/CD22 dual-targeted CAR-T therapy showed a high overall response rate of 90.9% and a complete remission rate of 63.6% after a median follow-up of 10.9 months.

The therapy was found to be safe, with no severe grade 4 cytokine release syndrome (CRS) and only mild, transient toxicities observed, indicating that CAR-T therapy can be a potent and manageable treatment option for R/R DLBCL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Decitabine-primed tandem CD19/CD22 CAR-T therapy in relapsed/refractory diffuse large B-cell lymphoma patients. Qu, C., Zou, R., Wang, P., et al.[2022]

Adoptive therapy using CAR T-cells, specifically targeting CD19, represents a promising new treatment option for patients with high-risk B-cell non-Hodgkin's lymphomas, such as DLBCL and FL, who do not respond to standard therapies.

The review highlights the efficacy and toxicity profiles of CD19-directed CAR T-cell therapy, showing its potential as a viable alternative for patients with poor prognosis, supported by data from both early single-center studies and larger multicenter clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR T cell therapy for B-cell lymphomas. Chavez, JC., Locke, FL.[2020]

Approximately 65% of patients with diffuse large B-cell lymphoma are cured with first-line therapy, but 10-15% may have primary refractory disease, and 20-25% may relapse, highlighting the need for effective second-line treatments.

Chimeric antigen receptor (CAR) T-cell therapies targeting CD19 offer a promising alternative curative option for patients with relapsed or refractory disease, but optimal patient selection for this novel treatment is still being defined.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Modern management of relapsed and refractory aggressive B-cell lymphoma: A perspective on the current treatment landscape and patient selection for CAR T-cell therapy. Bachanova, V., Perales, MA., Abramson, JS.[2021]

Chimeric antigen receptor (CAR)-T cell therapy, specifically targeting CD19, has shown promising results in treating non-Hodgkin lymphomas (NHLs) resistant to standard therapies, leading to FDA and EMA approvals for tisagenlecleucel and axicabtagene ciloleucel.

While CAR-T cell therapy can cause significant adverse events like cytokine release syndrome and neurological toxicity, these effects are manageable with proper medical support, highlighting the importance of trained teams in administering this novel treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR-T Cell Therapy in Diffuse Large B Cell Lymphoma: Hype and Hope. Hopfinger, G., Jäger, U., Worel, N.[2020]

CAR T cell therapy has emerged as a promising third-line treatment for patients with refractory or relapsed diffuse large B-cell lymphoma (DLBCL), significantly improving prognosis compared to traditional therapies.

This innovative treatment has shown a substantial rate of long-lasting complete responses, but it requires prompt specialized care to manage its unique side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Diffuse large B-cell lymphoma: a revolutionary treatment based on genetically-modified immune cells called CAR T cells]. Maquet, C., Beguin, Y., De Prijck, B., et al.[2021]

In a study of 66 adult patients with relapsed/refractory large B-cell lymphoma (LBCL) treated with CAR T-cell therapy, 53% achieved a complete response, and the median overall survival was 28.4 months, indicating the therapy's efficacy in this patient population.

Despite a high incidence of side effects, including cytokine release syndrome (88%) and infections (48%), older patients (21% over 70 years) can safely receive CAR T-cell therapy, although they face a higher risk of complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Outcomes of Chimeric Antigen Receptor (CAR) T-Cell Therapy in Patients with Large B-Cell Lymphoma (LBCL): A Single-Institution Experience. Trando, A., Ter-Zakarian, A., Yeung, P., et al.[2023]

In a study of 60 patients with relapsed diffuse large B cell lymphoma receiving CAR T therapy (axi-cel), the overall response rate was 63.3%, indicating a promising efficacy of this treatment.

The study found that responsiveness to immediate pre-CAR T chemotherapy did not significantly affect the outcomes, but patients with bulky disease before treatment had worse results, suggesting that those with known risk factors should consider interim therapies before CAR T infusion.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Predictors of response to axicabtagene-ciloleucel CAR T cells in aggressive B cell lymphomas: A real-world study. Iovino, L., Wu, QV., Voutsinas, J., et al.[2022]

CAR-T cell therapies have been approved for treating patients with primary refractory or relapsed large B cell lymphoma (LBCL), providing new options for those who previously had limited treatments available.

The management of CAR-T cell therapies involves complex clinical decisions, including patient selection and follow-up care, highlighting the need for careful planning and monitoring in these cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical Perspective: Treatment of Aggressive B Cell Lymphomas with FDA-Approved CAR-T Cell Therapies. Leick, MB., Maus, MV., Frigault, MJ.[2022]

CD19-directed CAR-T cell therapy has shown promising results in treating aggressive B-cell non-Hodgkin lymphoma, leading to durable complete remissions in heavily pretreated patients, as demonstrated in three major studies.

Despite its effectiveness, CAR-T cell therapy carries risks such as cytokine release syndrome, neurotoxicity, and delayed infections due to B-cell aplasia, highlighting the need for ongoing research to improve its safety and efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The acceleration of CAR-T therapy in non-Hodgkin lymphoma. Munshi, PN., Ujjani, C.[2021]

Chimeric antigen receptor T-cell (CAR-T) therapy has shown promising efficacy in treating relapsed or refractory diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL), with complete response rates of 40-60% in pivotal trials, and some patients achieving long-term remission.

While CAR-T therapy can lead to significant toxicities such as cytokine release syndrome and neurologic issues, these are generally treatable and reversible, making CAR-T a viable option for patients with poor prognosis in these lymphoma subtypes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[CAR-T therapy for malignant lymphoma]. Shimoyama, T.[2023]

Citations

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The addition of rituximab to a combination of fludarabine ... R-FCM revealed an overall response rate of 79% (33% complete remission [CR], 45% partial remission [PR]) as compared with 58% for FCM alone (13% CR, 45% PR; P = ...

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Excess mortality after treatment with fludarabine and ... Overall response rates were 91% with FCR and 90% with FCCam (P = .79). Complete remission rates were 33.75% with FCR and 19.2% with FCCam (P = .04). Three-year ...

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Trial | NCT05950802 The purpose of this study is to identify an optimized lymphodenpletion (LD) regimen by evaluating standard and intermediate doses of Fludarabine (Flu) / ...