Duvelisib After CAR T-Cell Therapy for Lymphoma

Overseen By Armin Ghobadi, M.D.

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Washington University School of Medicine

Must not be taking: CYP3A inducers, CYP3A inhibitors, Steroids, Immunosuppressants

Disqualifiers: CNS involvement, Uncontrolled infection, HIV, others

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

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

43 Participants Needed

Trial Summary

What is the purpose of this trial?

While chimeric antigen receptor T-cell (CAR T-cell) therapy produces impressive response rates in heavily pre-treated patients, early loss of response remains a barrier. One potential mechanism of relapse is limited CAR T-cell persistence. Pre-clinical research shows that PI3K inhibition represents an intriguing mechanism for increasing CAR T-cell persistence that is easily reversible and CAR T-cell agnostic. The investigators hypothesize that PI3K inhibition with duvelisib would be safe, may provide effective prophylaxis against cytokine release syndrome (CRS), and may enhance the persistence and efficacy of CAR T-cells in the treatment of hematologic malignancies.

Will I have to stop taking my current medications?

The trial requires that you stop taking any strong CYP3A inducers or inhibitors before starting duvelisib. If you're on such medications, you'll need to discontinue them 7 days before starting duvelisib for inhibitors, 14 days for inducers, or wait for 4-5 half-lives of the drug.

Is Duvelisib safe for use in humans?

Duvelisib, also known as Copiktra, IPI-145, or INK-1197, has been studied for safety in humans. It is generally considered safe, but like many treatments, it can have side effects. Common side effects include diarrhea, low white blood cell counts, and liver enzyme changes, which are usually manageable with medical supervision. ^{1 2 3 4 5}

How does the drug Duvelisib differ from other treatments for lymphoma after CAR T-cell therapy?

Duvelisib is unique because it is a targeted therapy that inhibits specific enzymes (PI3K-delta and PI3K-gamma) involved in the growth and survival of cancer cells, offering a different mechanism of action compared to traditional chemotherapy or CAR T-cell therapy. This makes it a potential option for patients who have not responded to or have relapsed after CAR T-cell therapy. ^{4 5 6 7 8}

Research Team

Armin Ghobadi, M.D.

Principal Investigator

Washington University School of Medicine

Eligibility Criteria

This trial is for adults over 18 with certain types of non-Hodgkin lymphoma eligible for CAR T-cell therapy, not B-cell acute lymphoblastic leukemia. Participants must understand the study and consent to it, use effective contraception, and not be pregnant or breastfeeding. They can't have allergies to duvelisib or similar drugs, uncontrolled infections, significant heart/kidney/liver disease, other cancers (except some skin cancers), active CNS involvement by malignancy, or be on strong CYP3A inducers/inhibitors.

Inclusion Criteria

I am eligible for specific FDA-approved treatments for non-Hodgkin lymphoma.

I am 18 years old or older.

I agree to use birth control during and for 3 months after the study.

Exclusion Criteria

I have an autoimmune disease affecting my brain or spinal cord, not related to my blood cancer.

I have a serious heart condition.

I cannot take preventive medication for certain infections.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Participants receive duvelisib from Day -2 through Day 28 to determine the maximum tolerated dose

4 weeks

Daily dosing

Dose Expansion

Participants in Cohort A receive duvelisib from Day -2 to Day 28, and Cohort B from Day -2 to Day 180 with cycles of dosing and rest

6 months

Cycle-based visits

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 months

Treatment Details

Interventions

• Duvelisib

Trial Overview The trial tests if duvelisib enhances CAR T-cell persistence and efficacy in treating hematologic malignancies post-CAR T-cell therapy. It also examines whether duvelisib can prevent cytokine release syndrome safely. Patients receive this PI3K inhibitor following their standard CAR T-cell treatment.

Participant Groups

Group I: Dose Escalation Stage: Duvelisib Experimental Treatment 1 Intervention

* Duvelisib is an oral medication taken on a once or twice daily basis on all dosing days. Doses being explored in this study are 15 mg BID (starting dose), 25 mg BID, and 15 mg QD. In the dose escalation stage, patients will receive duvelisib from Day -2 through Day 28. * CAR T-cells will be given per standard of care.

Group II: Cohort B Dose Expansion Stage: Duvelisib Experimental Treatment 1 Intervention

* Patients in Cohort B will receive duvelisib from Day -2 to Day 180 as follows: * Cycle 1 dosing begins on Day -2 and continues through Day 28 followed by 2 weeks off therapy * Cycles 2-6 are 28 days long and consist of dosing on Days 1 through 14, with 2 weeks off therapy. * CAR T-cells will be given per standard of care.

Group III: Cohort A Dose Expansion Stage: Duvelisib Experimental Treatment 1 Intervention

* Patients in Cohort A will receive duvelisib from Day -2 to Day 28. The dose that will be given will be determined in the dose escalation stage (the maximum tolerated dose). * CAR T-cells will be given per standard of care.

Who Is Running the Clinical Trial?

Washington University School of Medicine

Lead Sponsor

Trials

2,027

Recruited

2,353,000+

SecuraBio

Industry Sponsor

Trials

29

Recruited

2,400+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

The Foundation for Barnes-Jewish Hospital

Collaborator

Trials

43

Recruited

6,600+

Findings from Research

In a study involving 11 patients with relapsed/refractory B-cell non-Hodgkin lymphoma, the combination of CD19 CAR-T cells and the anti-PD-1 antibody nivolumab was found to be safe, with no dose-limiting toxicities and manageable side effects like cytokine release syndrome in a minority of patients.

The treatment showed promising efficacy, achieving an objective response rate of 81.81% and a complete response rate of 45.45%, indicating strong anti-lymphoma activity that warrants further investigation in larger clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-CD19 Chimeric Antigen Receptor T Cells in Combination With Nivolumab Are Safe and Effective Against Relapsed/Refractory B-Cell Non-hodgkin Lymphoma. Cao, Y., Lu, W., Sun, R., et al.[2020]

In a study of 15 patients with relapsed or refractory diffuse large B-cell lymphoma, administering CD19-specific CAR T cells after high-dose chemotherapy and autologous stem cell transplantation resulted in a 2-year progression-free survival rate of 30%.

The treatment was associated with a high incidence of reversible neurotoxicity and cytokine release syndrome, but patients with lower levels of naive-like CD4+ and CD8+ CAR T cells showed better disease control, indicating that the immunophenotype of CAR T cells may influence treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CD19 CAR T cells following autologous transplantation in poor-risk relapsed and refractory B-cell non-Hodgkin lymphoma. Sauter, CS., Senechal, B., Rivière, I., et al.[2021]

The review of 9 studies involving patients with relapsed/refractory hematological malignancies suggests that combining CAR-T cell therapy with PD-1/PD-L1 inhibitors may be a promising option, particularly for B-cell acute lymphoblastic leukaemia (B-ALL), although the data is still modest.

The safety profile of the combination therapy appears to be comparable to that of CAR-T cell monotherapy, indicating that it may not introduce additional risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined or Sequential Treatment with Immune Checkpoint Inhibitors and Car-T Cell Therapies for the Management of Haematological Malignancies: A Systematic Review. Pérez-Moreno, MA., Ciudad-Gutiérrez, P., Jaramillo-Ruiz, D., et al.[2023]

Anti-CD19 CAR T cell therapies have shown promise in treating aggressive B-cell lymphomas that are resistant to conventional therapies, achieving durable remissions in 33%-40% of patients with relapsed or refractory disease.

While these therapies can lead to significant side effects like cytokine release syndrome and neurologic toxicities, these are generally manageable and reversible, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chimeric Antigen Receptor T-Cell Therapies for Aggressive B-Cell Lymphomas: Current and Future State of the Art. Abramson, JS., Lunning, M., Palomba, ML.[2021]

In a study of 42 patients with relapsed or refractory aggressive B cell lymphoma, the combination of high-dose chemotherapy followed by CD19/22 CAR T cell infusion showed a high overall response rate of 90.5%, indicating strong efficacy for this treatment approach.

The safety profile was favorable, with only 2 patients experiencing grade 3 cytokine release syndrome and 21% experiencing any grade of neurotoxicity, all of which were reversible, suggesting that this therapy is manageable for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CD19/CD22 Chimeric Antigen Receptor T Cell Cocktail Therapy following Autologous Transplantation in Patients with Relapsed/Refractory Aggressive B Cell Lymphomas. Cao, Y., Xiao, Y., Wang, N., et al.[2022]

In a study of 514 patients receiving CD19-directed CAR-T therapy for aggressive B-cell non-Hodgkin lymphoma, it was found that more lines of therapy before CAR-T and the use of bridging therapy were linked to worse progression-free survival (PFS) and overall survival (OS), with median PFS and OS of 7.6 and 25.6 months, respectively.

Allogeneic hematopoietic cell transplantation after CAR-T failure resulted in durable responses in over 50% of patients at one year, suggesting it may be a beneficial option for selected patients following CAR-T therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Peri-CAR-T practice patterns and survival predictors for all CAR-T patients and post-CAR-T failure in aggressive B-NHL. Zurko, J., Nizamuddin, I., Epperla, N., et al.[2023]

In a study of 57 patients with refractory/relapsed diffuse large B-cell lymphoma (DLBCL), pretreatment with intensive debulking chemotherapy significantly improved the objective response rate (ORR) and overall survival (OS) for patients with high tumor bulk undergoing anti-CD19 CAR-T therapy.

Patients who were sensitive to debulking chemotherapy had a higher ORR and longer OS compared to those who were refractory, with 1-year disease-free survival rates of 52.6% and OS rates of 57.9%, indicating that effective debulking can enhance CAR-T therapy outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intensive Debulking Chemotherapy Improves the Short-Term and Long-Term Efficacy of Anti-CD19-CAR-T in Refractory/Relapsed DLBCL With High Tumor Bulk. Lyu, C., Cui, R., Wang, J., et al.[2022]

Anti-CD19 CAR-T therapy has been approved for patients with relapsed/refractory diffuse large B cell lymphoma, showing promising clinical outcomes based on recent trials like ZUMA-1, JULIET, and TRANSCEND NHL-001.

Healthcare providers need to understand the indications, potential toxicities, and limitations of this therapy to effectively manage patient referrals and treatment plans.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-CD19 Chimeric Antigen Receptor T Cell Therapies: Harnessing the Power of the Immune System to Fight Diffuse Large B Cell Lymphoma. Havard, R., Stephens, DM.[2020]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

Anti-CD19 Chimeric Antigen Receptor T Cells in Combination With Nivolumab Are Safe and Effective Against Relapsed/Refractory B-Cell Non-hodgkin Lymphoma. [2020]

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

CD19 CAR T cells following autologous transplantation in poor-risk relapsed and refractory B-cell non-Hodgkin lymphoma. [2021]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Combined or Sequential Treatment with Immune Checkpoint Inhibitors and Car-T Cell Therapies for the Management of Haematological Malignancies: A Systematic Review. [2023]

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

Chimeric Antigen Receptor T-Cell Therapies for Aggressive B-Cell Lymphomas: Current and Future State of the Art. [2021]

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

CD19/CD22 Chimeric Antigen Receptor T Cell Cocktail Therapy following Autologous Transplantation in Patients with Relapsed/Refractory Aggressive B Cell Lymphomas. [2022]

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

Peri-CAR-T practice patterns and survival predictors for all CAR-T patients and post-CAR-T failure in aggressive B-NHL. [2023]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Intensive Debulking Chemotherapy Improves the Short-Term and Long-Term Efficacy of Anti-CD19-CAR-T in Refractory/Relapsed DLBCL With High Tumor Bulk. [2022]

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

Anti-CD19 Chimeric Antigen Receptor T Cell Therapies: Harnessing the Power of the Immune System to Fight Diffuse Large B Cell Lymphoma. [2020]