Itacitinib + CAR T-Cell Therapy for Lymphoma

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: H. Lee Moffitt Cancer Center and Research Institute

Must not be taking: Chronic steroids, CYP3A4 inhibitors

Disqualifiers: Cardiac disease, HIV, Hepatitis, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

27 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination treatment for people with diffuse large B-cell lymphoma (DLBCL), a type of blood cancer. The study aims to determine if the oral drug itacitinib is safe and enhances the effects of CAR T-cell therapy, specifically axi-cel, which uses modified immune cells. It seeks participants with DLBCL who plan to undergo CAR T-cell therapy and are ineligible for a stem cell transplant due to active lymphoma. As a Phase 2 trial, this research focuses on assessing the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot take strong inhibitors of CYP3A4. You should discuss any medications you are taking with the study team to ensure they don't interfere with the trial.

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

Research shows that itacitinib, when combined with CAR T-cell therapy, is generally well-tolerated. Studies have found that itacitinib can help prevent cytokine release syndrome (CRS), a serious side effect of immune therapies. One study found that taking itacitinib twice daily effectively prevented CRS and another condition called ICANS in individuals receiving CD19-directed therapy. Another study showed that using itacitinib for 30 days did not interfere with the success of the cancer treatment. Overall, these findings suggest that itacitinib is safe to use with CAR T-cell therapy in lymphoma patients. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Itacitinib is unique because it targets the JAK-STAT signaling pathway, which plays a crucial role in the inflammatory processes associated with lymphoma. Unlike standard treatments that often focus on directly targeting cancer cells, itacitinib modulates the immune system, potentially enhancing the effectiveness of CAR T-cell therapy. Researchers are excited about this combination because it may improve the outcomes of CAR T-cell therapy, offering a more comprehensive approach to tackling lymphoma.

What evidence suggests that Itacitinib + CAR T-Cell Therapy could be effective for lymphoma?

Research shows that itacitinib, a type of medication, can lower levels of certain proteins that cause inflammation, which are linked to an overactive immune response. In this trial, participants will receive itacitinib as part of the pre-modulation treatment before CAR-T cell therapy. Studies have found that itacitinib helps prevent cytokine release syndrome (CRS) and some brain-related side effects in patients undergoing CAR-T cell therapy. Specifically, itacitinib reduced the occurrence of moderate to severe CRS to 17.4% in patients treated with axi-cel therapy. This suggests that itacitinib could make CAR-T cell therapy safer and more effective for treating diffuse large B-cell lymphoma (DLBCL). ^{2 3 4 6 7}

Who Is on the Research Team?

Michael Jain, MD, PhD

Principal Investigator

Moffitt Cancer Center

Are You a Good Fit for This Trial?

Adults with diffuse large B-cell lymphoma planning to receive CAR-T cell therapy at Moffitt Cancer Center, who can't have stem cell transplants due to active lymphoma. They must understand and consent to the study, meet certain blood test criteria, agree to use contraception, and not be pregnant or nursing. Excluded are those with prior CAR-T therapy, severe itacitinib reactions, strong CYP3A4 inhibitors usage, uncontrolled infections or cardiac disease, unstable arrhythmias on medication within 2 weeks of screening.

Inclusion Criteria

I agree to use birth control during the study.

I am eligible for a specific immune therapy for my lymphoma.

I am a woman who cannot become pregnant.

Exclusion Criteria

I am not taking strong CYP3A4 inhibitors.

I currently have an untreated infection.

I have active or chronic hepatitis B.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Pre-Modulation Treatment

Participants receive itacitinib 200 mg PO QD starting at time of apheresis approximately 4-6 weeks prior to CAR-T-cell therapy and continue until Day 30 post-CAR-T-cell therapy

4-6 weeks

CAR-T-cell Therapy

Participants receive a single infusion of axi-cel therapy on Day 0

1 day

Follow-up

Participants are monitored for safety and effectiveness after treatment, including incidence of severe CRS and ICANS

3 months

Long-term Follow-up

Participants are monitored for overall survival and progression-free survival

up to 27 months

What Are the Treatments Tested in This Trial?

Interventions

• Itacitinib

Trial Overview The trial is testing the safety and effectiveness of taking a daily oral dose of itacitinib before receiving axicabtagene ciloleucel (axi-cel) CAR-T cell therapy for treating diffuse large B-cell lymphoma. It aims to see if pre-modulating with itacitinib improves outcomes.

How Is the Trial Designed?

Group I: Pre-Modulation Treatment Experimental Treatment 2 Interventions

Participants will receive itacitinib 200 mg PO QD beginning at time of apheresis approximately 4-6 weeks prior to CAR-T-cell therapy and will continue until Day 30 (30 Days Post-CAR-T-cell therapy)

Who Is Running the Clinical Trial?

H. Lee Moffitt Cancer Center and Research Institute

Lead Sponsor

Trials

576

Recruited

145,000+

Incyte Corporation

Industry Sponsor

Trials

408

Recruited

66,800+

Steven Stein

Incyte Corporation

Chief Medical Officer since 2015

MD from University of Witwatersrand

Hervé Hoppenot

Incyte Corporation

Chief Executive Officer since 2014

MBA from ESSEC Business School

Published Research Related to This Trial

Anti-CD19-directed CAR T cell therapy has shown significant efficacy in treating relapsed or refractory B-cell malignancies, leading to the approval of tisagenlecleucel (Kymriah) for B-ALL in 2018 and for aggressive B-cell lymphoma shortly thereafter.

The review highlights ongoing research into resistance mechanisms and the exploration of new target antigens, indicating a continued effort to improve treatment outcomes for patients with CD19 positive B-cell lymphomas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[CAR T-cell therapy for malignant B-cell lymphoma : A new treatment paradigm]. Balke-Want, H., Borchmann, P.[2021]

The addition of the anti-CD20 monoclonal antibody rituximab to standard therapies has significantly improved overall survival rates in newly diagnosed diffuse large B-cell lymphoma (DLBCL).

Innovative T-cell redirecting therapies, such as bispecific antibodies targeting both T-cell and B-cell antigens, have shown impressive efficacy in heavily pre-treated patients with relapsed/refractory B-cell non-Hodgkin lymphoma, leading to ongoing clinical trials exploring their combinations with other treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

T-cell redirecting therapies for B-cell non-Hodgkin lymphoma: recent progress and future directions. Russler-Germain, DA., Ghobadi, A.[2023]

CAR T-cell therapy is becoming a groundbreaking treatment for aggressive non-Hodgkin B-cell lymphoma, showing promise in improving patient outcomes.

The review discusses not only the efficacy of CAR T-cell therapy but also highlights the potential short- and long-term toxicities associated with the treatment, emphasizing the need for careful monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chimeric Antigen Receptor T-Cell Therapy in Aggressive B-Cell Lymphoma. Hamilton, MP., Miklos, DB.[2023]

CAR T-cell therapy is an important treatment option for patients with refractory or relapsed diffuse large B-cell lymphoma, providing a targeted approach to combat this aggressive cancer.

The review discusses the criteria for selecting patients for CAR T-cell therapy and emphasizes the importance of bridging therapy and timing to improve treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR T-cell therapy for the management of refractory/relapsed high-grade B-cell lymphoma: a practical overview. Mohty, M., Dulery, R., Gauthier, J., et al.[2023]

CAR T-cell therapy targeting CD19 has transformed the treatment landscape for relapsed or refractory B-cell lymphomas, leading to rapid FDA approval for multiple lymphoma subtypes due to high response rates and durability.

Three second-generation anti-CD19 CAR T-cell products have been approved for use in aggressive non-Hodgkin's lymphoma, and ongoing research is focused on understanding treatment failures and improving outcomes for patients who do not respond to therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR T-cell therapy for B-cell lymphoma. Denlinger, N., Bond, D., Jaglowski, S.[2022]

CD19-directed CAR T-cell therapy has shown promising results in treating relapsed/refractory B-cell non-Hodgkin lymphoma, with 30-40% of patients achieving durable responses in pivotal phase I/II trials, leading to FDA and EMA approvals for specific therapies.

Despite its effectiveness, the therapy is associated with significant toxicities, such as cytokine release syndrome and neurotoxicity, which can limit its use and present challenges in patient management during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CD19-directed CAR T-cell therapy in B-cell NHL. Kersten, MJ., Spanjaart, AM., Thieblemont, C.[2021]

CD19CAR T cells have shown promising results in treating aggressive B-lineage cancers, but their effectiveness can be limited by the loss of the targeted CD19 antigen, leading to treatment failure.

The newly developed adapter CAR T cell technology (AdCAR) allows for multitargeting of different antigens, such as CD20 and CD22, which can enhance the anti-cancer activity and potentially overcome issues related to antigen loss in lymphoma treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adapter CAR T Cell Therapy for the Treatment of B-Lineage Lymphomas. Atar, D., Mast, AS., Scheuermann, S., et al.[2022]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7895329/

Itacitinib (INCB039110), a JAK1 inhibitor, Reduces ... We report that itacitinib, a potent, selective JAK1 inhibitor, was able to significantly and dose-dependently reduce levels of multiple cytokines implicated in ...

2. ashpublications.org ashpublications.org/blood/article-abstract/146/4/422/536095/Itacitinib-for-the-prevention-of-IEC-therapy

Itacitinib for the prevention of IEC therapy–associated CRS Prophylactic itacitinib (200 mg) twice daily was effective in preventing CRS and ICANS in patients who underwent CD19-directed IEC therapy.

3. sciencedirect.com sciencedirect.com/science/article/pii/S0006497125006160

Itacitinib for the prevention of IEC therapy–associated CRS Prophylactic itacitinib (200 mg) twice daily was effective in preventing CRS and ICANS in patients who underwent CD19-directed IEC therapy. •.

4. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2023-01299

Itacitinib or Ruxolitinib to Improve Efficacy in Patients with ... Patients with DLBCL who express high levels of systemic inflammation may have worse outcomes with axi-cel than patients with low systemic inflammation. Giving a ...

5. hematologyadvisor.com hematologyadvisor.com/news/itacitinib-crs-icans-and-cd19-cart-therapy/

Itacitinib May Prevent CRS and ICANS Associated With ... Itacitinib resulted in a substantial decrease in the incidence of grade 2 or higher CRS by day 14, with a rate of 17.4% in the axi-cel group and ...

6. ash.confex.com ash.confex.com/ash/2023/webprogram/Paper180205.html

Itacitinib for the Prevention of Immune Effector Cell Therapy ... Rates of severe infections were comparable in both arms. Longer follow-up data on lymphoma response will be available upon presentation.

7. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/32998963/

Itacitinib (INCB039110), a JAK1 Inhibitor, Reduces Cytokines ... Such targeted therapies have shown long-term relapse-free survival in patients with B-cell leukemia and lymphoma. However, cytokine release ...