Duvelisib After CAR T-Cell Therapy for Lymphoma

Not currently recruiting at 1 trial location

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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the effectiveness of duvelisib, a cancer treatment drug, in prolonging the activity of CAR T-cells, a type of cancer-fighting immune cell, in individuals with non-Hodgkin lymphoma. While CAR T-cell therapy is effective at combating cancer, its effects can sometimes be short-lived. Duvelisib may help these cells persist and function more effectively. Individuals who have previously undergone CAR T-cell treatment for non-Hodgkin lymphoma and do not have certain health issues, such as active infections or heart problems, may be suitable candidates for this trial. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants a chance to be among the first to receive this potentially groundbreaking therapy.

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

Research has shown that duvelisib holds promise in earlier studies. For instance, the DYNAMO study found that duvelisib had a manageable safety profile in patients who had received multiple prior treatments. Most side effects were not severe and could be treated with medical care.

However, important safety concerns exist. The FDA has warned about a possible higher risk of death with duvelisib compared to other treatments. Therefore, careful consideration and close monitoring of this drug are crucial.

Overall, while duvelisib offers potential benefits, it also carries risks. Prospective trial participants should consult their healthcare provider to make an informed decision. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about duvelisib for lymphoma treatment because it offers a unique approach compared to traditional options. Unlike standard therapies that primarily target cancer cells directly, duvelisib works by inhibiting specific pathways (PI3K-δ and PI3K-γ) that are crucial for the growth and survival of lymphoma cells, potentially leading to more effective disruption of the disease. Additionally, duvelisib is an oral medication, which provides a more convenient and less invasive method of administration compared to intravenous therapies. This novel mechanism of action and ease of use could improve treatment outcomes and patient quality of life.

What evidence suggests that duvelisib might be an effective treatment for lymphoma?

Research shows that duvelisib, an oral medication, may help treat certain blood cancers. In earlier studies, nearly half of the patients who had tried many other treatments saw their cancer shrink or disappear. Specifically, 48% of these patients responded to the treatment, and 33% showed no signs of cancer. The duration during which the cancer did not worsen varied, lasting about 3.45 months in some studies and up to 14.7 months in others. Duvelisib blocks a protein called PI3K, which helps some cancer cells survive. In this trial, participants will receive duvelisib in different dosing schedules. It may also help CAR T-cells, specially modified immune cells, last longer in the body to fight cancer. This makes duvelisib a potentially effective option for enhancing CAR T-cell therapy in lymphoma. ^{3 6 7 8 9}

Who Is on the Research Team?

Armin Ghobadi, M.D.

Principal Investigator

Washington University School of Medicine

Are You a Good Fit for This Trial?

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

I can understand and am willing to sign the consent form.

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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 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 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 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]

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]

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]

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]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/30742566/

A Phase II Study of Duvelisib (IPI-145) in Patients With ... In the DYNAMO study, oral duvelisib monotherapy demonstrated clinically meaningful activity and a manageable safety profile in heavily pretreated, ...

2. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/nda/2018/211155Orig1Orig2s000MultidisciplineR.pdf

211155Orig1s000 211155Orig2s000 - accessdata.fda.gov The pivotal evidence of effectiveness comes from the efficacy results in Study-IPI-145-07 and Study IPI-145-06. Is the proposed dosing ...

3. ashpublications.org ashpublications.org/blood/article/144/Supplement%201/3061/533672/Duvelisib-in-Patients-with-Relapsed-Refractory

Duvelisib in Patients with Relapsed/Refractory Peripheral T ... Efficacy outcomes: ORR: 48%, complete response rate (CRR): 33%, median progression-free survival (mPFS): 3.45 mo, median duration of response ( ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6220789/

Duvelisib, an oral dual PI3K‐δ, γ inhibitor, shows clinical ... Median progression‐free survival was 14.7 months, and the probability of overall survival at 24 months was 71.7%. Severe (Grade ≥ 3) adverse events included ...

5. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0006497124058130

Duvelisib in Patients with Relapsed/Refractory Peripheral T ... Efficacy outcomes: ORR: 48%, complete response rate (CRR): 33%, median progression-free survival (mPFS): 3.45 mo, median duration of response ( ...

6. fda.gov fda.gov/drugs/drug-safety-and-availability/fda-warns-about-possible-increased-risk-death-and-serious-side-effects-cancer-drug-copiktra

FDA warns about possible increased risk of death and ... FDA is warning that results from a clinical trial showed a possible increased risk of death with Copiktra (duvelisib) compared to the monoclonal ...

7. fda.gov fda.gov/safety/medical-product-safety-information/copiktra-duvelisib-drug-safety-communication-fda-warns-about-possible-increased-risk-death-and

Copiktra (duvelisib): Drug Safety Communication The FDA is warning that results from a clinical trial show a possible increased risk of death with Copiktra (duvelisib) compared to another medicine to treat a ...

8. ons.org ons.org/publications-research/voice/news-views/07-2022/fda-warns-about-risk-death-and-serious-side-effects

FDA Warns About Risk of Death and Serious Side Effects ... The trial's results showed a possible increased risk of death with duvelisib compared to the monoclonal antibody ofatumumab. The rate of serious ...

9. ascopubs.org ascopubs.org/doi/10.1200/JCO.2021.39.15_suppl.e19532

A single-arm, open-label, multicenter, phase Ⅱ clinical trial. Conclusions: Duvelisib yielded impressive anti-tumor activity with manageable safety profiles in Chinese R/R FL pts and could be a compelling treatment option ...