Duvelisib for Diffuse Large B-Cell Lymphoma

No longer recruiting at 1 trial location

Overseen By Edmund Waller, MD, PhD

Age: 18+

Sex: Any

Trial Phase: Phase < 1

Sponsor: Emory University

Must not be taking: Immunosuppressants, Steroids

Disqualifiers: CNS lymphoma, Autoimmune diseases, HIV, others

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

Compensation: Varies

Number of Visits: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether duvelisib can enhance the effectiveness of CAR-T cell therapy in patients with diffuse large B-cell lymphoma that is difficult to treat or has recurred. Taken orally, duvelisib may enhance the immune cells needed for CAR-T therapy, potentially boosting their performance. Participants will take duvelisib for two weeks before the creation of personalized CAR-T cells, followed by an infusion of these cells. The trial seeks participants diagnosed with relapsed or resistant diffuse large B-cell lymphoma who completed previous treatments at least two weeks prior. As an Early Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants a chance to be among the first to receive this novel therapy.

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

The trial protocol does not specify if you need to stop all current medications. However, you cannot be on immunosuppressive therapy, including steroids, or any other investigational drugs. Also, you should not have had chemotherapy or radiotherapy within 2 weeks before starting the study. If you are taking medications that are strong inhibitors or inducers of CYP3A, you must stop them at least 2 weeks before the trial.

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

Research has shown that duvelisib has been tested for safety in patients with certain recurring or hard-to-treat lymphoid cancers, such as diffuse large B-cell lymphoma (DLBCL). Most findings suggest that duvelisib is generally well-tolerated. Some patients may experience side effects like diarrhea, tiredness, or low blood counts, but these are often manageable.

For tisagenlecleucel, safety data is also encouraging. Studies indicate it is generally safe for patients with aggressive B-cell cancers, including DLBCL. Common side effects include fever and chills, but these usually don't last long.

Both treatments have been used in other situations, providing some reassurance about their safety. However, since this is an early phase trial, the main goal is to learn more about their safety and effectiveness when used together. Participants will be closely monitored to manage any side effects. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about duvelisib for treating Diffuse Large B-Cell Lymphoma because it targets a specific pathway that's different from traditional chemotherapy. Most treatments for this condition, like R-CHOP, work by attacking rapidly dividing cells, but duvelisib works by inhibiting PI3K, an enzyme crucial for cancer cell survival and growth. Additionally, in this trial, the use of duvelisib is paired with tisagenlecleucel, a CAR-T cell therapy, which is designed to modify a patient's own immune cells to better fight cancer. This combination has the potential to offer a more tailored and robust approach to tackling this aggressive type of lymphoma.

What evidence suggests that duvelisib might be an effective treatment for diffuse large B-cell lymphoma?

Research has shown that duvelisib, a pill that blocks certain pathways in cancer cells, may help treat various types of relapsed or hard-to-treat lymphomas. It has proven effective in patients who have already tried many treatments and maintains a reasonable safety record. In this trial, participants will receive duvelisib before the collection of CAR-T cells. The CAR-T cell therapy, tisagenlecleucel (or Kymriah), is already approved for treating diffuse large B-cell lymphoma (DLBCL) and works by targeting and killing cancerous B cells. This therapy has consistently demonstrated success and safety in both clinical trials and real-world use for aggressive forms of this lymphoma. Both treatments are being studied in this trial for their potential to enhance immune responses in patients with DLBCL. ^{1 2 3 4 6}

Who Is on the Research Team?

Edmund Waller, MD

Principal Investigator

Emory University Hospital/Winship Cancer Institute

Are You a Good Fit for This Trial?

This trial is for adults with relapsed/refractory diffuse large B-cell lymphoma. Participants must be in good physical condition (ECOG < 2), have normal organ function, and not be pregnant or breastfeeding. They should agree to use effective contraception and not donate blood or organs during the study. People with CNS lymphoma involvement, autoimmune diseases, active infections, recent immunosuppressive therapy, or prior CD19 directed therapy are excluded.

Inclusion Criteria

I practice total abstinence as a form of contraception.

An absolute neutrophil count (ANC) > 1,000/mm^3

I finished all treatments for my DLBCL at least 2 weeks ago.

Exclusion Criteria

I am currently being treated for a serious infection.

I have had treatment targeting CD19 before.

I have a positive hepatitis B core antibody but my hepatitis B virus DNA is negative.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Duvelisib Treatment

Participants receive duvelisib orally twice daily for 2 weeks prior to collection of CAR-T cells

2 weeks

CAR-T Cell Infusion

Participants receive tisagenlecleucel via infusion

Follow-up

Participants are monitored for safety and effectiveness after CAR-T cell infusion

100 days

What Are the Treatments Tested in This Trial?

Interventions

• Duvelisib
• Tisagenlecleucel

Trial Overview The DEEP T CELLS Study is testing whether taking duvelisib before manufacturing CAR-T cells can improve the immune profiles of T cells in patients with difficult-to-treat diffuse large B-cell lymphoma. Duvelisib is an oral drug that may make T cells more efficient for later CAR-T cell treatment.

How Is the Trial Designed?

Group I: Treatment (duvelisib) Experimental Treatment 2 Interventions

Patients receive duvelisib PO BID for 2 weeks prior to collection of CAR-T cells in the absence of disease progression or unacceptable toxicity. Patients then receive tisagenlecleucel via infusion.

Duvelisib is already approved in United States for the following indications:

Approved in United States as Copiktra for:

• Relapsed or refractory chronic lymphocytic leukemia (CLL)
• Relapsed or refractory small lymphocytic lymphoma (SLL)

Who Is Running the Clinical Trial?

Emory University

Lead Sponsor

Trials

1,735

Recruited

2,605,000+

Novartis

Industry Sponsor

Trials

1,646

Recruited

2,778,000+

Vasant Narasimhan

Novartis

Chief Executive Officer since 2018

MD from Harvard Medical School, Bachelor's in Biological Sciences from University of Chicago, Master's in Public Policy from John F. Kennedy School of Government

Shreeram Aradhye

Novartis

Chief Medical Officer since 2022

MD from Yale University, MSc in Clinical Epidemiology from University of Pennsylvania

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Secura Bio, Inc.

Industry Sponsor

Trials

9

Recruited

200+

Published Research Related to This Trial

In the JULIET trial, tisagenlecleucel showed high efficacy in 7 patients with relapsed or refractory diffuse large B-cell lymphoma who achieved complete response after bridging therapy, with all patients remaining in complete response at 3 months and 5 out of 7 remaining progression-free for over 12 months.

The safety profile of tisagenlecleucel was consistent with the overall trial population, with manageable adverse events including cytokine release syndrome in 4 patients, none of whom required additional treatment for CRS, suggesting a favorable safety profile for this therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tisagenlecleucel in relapsed/refractory diffuse large B-cell lymphoma patients without measurable disease at infusion. Bishop, MR., Maziarz, RT., Waller, EK., et al.[2020]

Chimeric antigen receptor (CAR) T cell therapies, specifically axicabtagene ciloleucel and tisagenlecleucel, have been approved for treating large B-cell lymphomas after two prior therapies, showing durable remissions in 30% to 40% of patients.

While these therapies are effective, they can cause serious side effects like cytokine release syndrome and neurotoxicity, necessitating treatment in specialized medical centers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Translating anti-CD19 CAR T-cell therapy into clinical practice for relapsed/refractory diffuse large B-cell lymphoma. Chow, VA., Shadman, M., Gopal, AK.[2022]

Duvelisib is a dual inhibitor of PI3Kδ and PI3Kγ, approved by the FDA in 2018 for treating adult patients with relapsed or refractory chronic lymphocytic leukaemia (CLL) and small lymphocytic lymphoma (SLL) after at least two prior therapies.

It has also received accelerated approval for relapsed or refractory follicular lymphoma (FL) after at least two prior systemic therapies, highlighting its efficacy in difficult-to-treat blood cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Duvelisib: A 2018 Novel FDA-Approved Small Molecule Inhibiting Phosphoinositide 3-Kinases. Rodrigues, DA., Sagrillo, FS., Fraga, CAM.[2020]

CAR T cell therapy, specifically tisagenlecleucel, has significantly improved treatment outcomes for patients with relapsed or refractory diffuse large B cell lymphoma, showcasing its efficacy in this challenging condition.

The review also highlights the importance of understanding the biological mechanisms of tisagenlecleucel and its comparison to other CAR T therapies, as well as the financial considerations and ongoing clinical trials that may influence future treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluating tisagenlecleucel and its potential in the treatment of relapsed or refractory diffuse large B cell lymphoma: evidence to date. Zavras, PD., Wang, Y., Gandhi, A., et al.[2020]

In the phase II JULIET trial, the CAR T-cell therapy tisagenlecleucel targeting CD19 demonstrated durable responses in patients with relapsed and refractory diffuse large B-cell lymphoma, with 32% achieving complete responses at 3 months.

The efficacy remained stable at 6 months, with 30% of patients still showing complete responses, indicating the potential long-term effectiveness of this therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Value in Using CAR T Cells for DLBCL. [2019]

Duvelisib is an oral small-molecule inhibitor of phosphatidylinositol-3 kinase that received its first global approval in the USA in September 2018 for treating adult patients with relapsed or refractory chronic lymphocytic leukaemia (CLL) and small lymphocytic lymphoma (SLL) after at least two prior therapies.

It also received accelerated approval for treating adult patients with relapsed or refractory follicular lymphoma (FL) after at least two prior systemic therapies, indicating its efficacy in multiple hematological malignancies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Duvelisib: First Global Approval. Blair, HA.[2019]

In a study of 91 patients with relapsed/refractory large B-cell lymphoma (LBCL), treatment with the CAR T-cell therapy tisagenlecleucel (tisa-cel) resulted in a best overall response rate of 60% and a complete response rate of 32%, indicating its efficacy in a real-world setting.

The safety profile of tisa-cel was manageable, with only 5% of patients experiencing severe cytokine release syndrome and 1% experiencing neurotoxicity, suggesting that it can be safely administered in standard-of-care settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-world evidence of tisagenlecleucel for the treatment of relapsed or refractory large B-cell lymphoma. Iacoboni, G., Villacampa, G., Martinez-Cibrian, N., et al.[2021]

Recent phase 3 clinical trials have shown that CD19-directed CAR T cell therapies, specifically axicabtagene ciloleucel and lisocabtagene maraleucel, significantly improve outcomes in patients with relapsed/refractory aggressive diffuse large B cell lymphoma compared to standard treatments, while tisagenlecleucel did not demonstrate a similar benefit.

The FDA has approved axicabtagene ciloleucel and lisocabtagene maraleucel for use in patients whose lymphoma is refractory to first-line chemoimmunotherapy or who relapse within 12 months, marking a significant advancement in treatment options for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Role of CD19 Chimeric Antigen Receptor T Cells in Second-Line Large B Cell Lymphoma: Lessons from Phase 3 Trials. An Expert Panel Opinion from the American Society for Transplantation and Cellular Therapy. Perales, MA., Anderson, LD., Jain, T., et al.[2023]

In a study of 119 patients with relapsed/refractory diffuse large B-cell lymphoma, tisagenlecleucel (tisa-cel) was associated with a significantly shorter hospital stay compared to axicabtagene ciloleucel (axi-cel), with mean inpatient stays of 11.3 days versus 18.3 days.

Tisa-cel also resulted in lower healthcare costs during both the infusion and follow-up periods, with non-CAR-T costs of $27,594.8 compared to $51,378.3 for axi-cel during infusion, indicating a more cost-effective option without compromising safety, as adverse event rates were similar for both therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-world healthcare resource utilization and costs associated with tisagenlecleucel and axicabtagene ciloleucel among patients with diffuse large B-cell lymphoma: an analysis of hospital data in the United States. Maziarz, RT., Yang, H., Liu, Q., et al.[2022]

Duvelisib, an oral dual inhibitor targeting PI3K-δ and PI3K-γ, was found to have a maximum tolerated dose of 75 mg twice daily in a phase 1 study involving 210 patients with advanced hematologic malignancies, showing promising efficacy across various cancer types.

The treatment resulted in significant clinical responses, with overall response rates of 58% in indolent non-Hodgkin lymphoma and 56% in relapsed/refractory chronic lymphocytic leukemia, although severe adverse events were reported in 84% of patients, highlighting the need for careful monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Duvelisib, a novel oral dual inhibitor of PI3K-δ,γ, is clinically active in advanced hematologic malignancies. Flinn, IW., O'Brien, S., Kahl, B., et al.[2023]

Duvelisib, a dual inhibitor of PI3K-δ and -γ, was well tolerated in a phase I study involving 7 Japanese patients with relapsed or refractory lymphoma, with no dose-limiting toxicities reported.

The treatment showed promising preliminary efficacy, with an overall response rate of 71.4%, including one complete response and several partial responses among the patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I study of duvelisib in Japanese patients with relapsed or refractory lymphoma. Izutsu, K., Kato, K., Kiyoi, H., et al.[2022]

Tisagenlecleucel significantly improves overall survival (OS) in adults with relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL), with a median OS of 12.48 months compared to just 4.34 to 4.40 months for historical treatments.

The overall response rate (ORR) for tisagenlecleucel was also significantly higher, showing a 36% improvement compared to historical treatments, indicating its efficacy as a treatment option for r/r DLBCL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Indirect comparison of tisagenlecleucel and historical treatments for relapsed/refractory diffuse large B-cell lymphoma. Maziarz, RT., Zhang, J., Yang, H., et al.[2022]

Duvelisib, an oral dual inhibitor of PI3K-δ and -γ, showed promising efficacy in treating advanced hematologic malignancies, with an overall response rate of 56.4% in relapsed/refractory chronic lymphocytic leukemia (CLL) patients and 83.3% in treatment-naïve CLL patients.

The most common side effects included diarrhea (78% in treatment-naïve and 47% in relapsed/refractory patients) and transaminase elevations, indicating that while duvelisib is effective, it also has notable safety considerations that need monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Duvelisib, an oral dual PI3K-δ,γ inhibitor, shows clinical and pharmacodynamic activity in chronic lymphocytic leukemia and small lymphocytic lymphoma in a phase 1 study. O'Brien, S., Patel, M., Kahl, BS., et al.[2023]

Citations

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

Duvelisib, an oral dual PI3K‐δ, γ inhibitor, shows clinical ... Duvelisib demonstrated favorable clinical activity and an acceptable safety profile in these high‐risk, heavily pretreated, relapsed/refractory iNHL patients.

2. clinicaltrials.gov clinicaltrials.gov/study/NCT05923502?term=AREA%5BBasicSearch%5D(AREA%5BBasicSearch%5D(Copiktra))&rank=4

(CHANT)Real World Study of Duvelisib in the Treatment ... This is a multicenter, non-interventional and prospective real-world study to evaluate the efficacy and safety of Duvelisib administered to subjects who have ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9845779/

Safety and efficacy of dual PI3K-δ, γ inhibitor, duvelisib in ... This systematic review and meta-analysis aimed to evaluate the safety and efficacy of duvelisib in treating different relapsed or refractory (RR) lymphoid ...

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

211155Orig1s000 211155Orig2s000 - accessdata.fda.gov lines, including: diffused large B-cell lymphoma (DLBCL, both Activated B-cell type [ABC] and ... effectiveness comes from the efficacy results in ...

5. eocco.com eocco.com/-/media/EOCCO/PDFs/Formulary/duvelisib_Copiktra.pdf

duvelisib (Copiktra®) It is commonly treated with regimens used for clinically aggressive lymphomas, such as a Diffuse Large B-Cell Lymphoma. (DLBCL). v. Although, the primary ...

6. onlinelibrary.wiley.com onlinelibrary.wiley.com/doi/full/10.1002/ajh.25634

Combination trial of duvelisib (IPI‐145) with rituximab or ... Twenty-nine patients (63.0%) had a diagnosis of CD20+ B-Cell lymphoma of which 15 (32.6%) patients had follicular lymphoma, 9 (19.6%) had ...