Siltuximab for CRS and ICANS Related to CAR-T Therapy

Overseen By Mayur Narkhede

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Alabama at Birmingham

Must not be taking: Corticosteroids, Immunosuppressives

Disqualifiers: Pregnancy, Active infections, HIV, 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 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 14 days

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if siltuximab can reduce the severity of cytokine release syndrome (CRS) and immune effector cell-associated neurological syndrome (ICANS) in patients receiving CAR T-cell therapy. CAR T-cell therapy treats certain blood cancers, such as lymphoma and leukemia. The trial targets patients already planning to undergo CAR T-cell therapy for specific types of these cancers. Participants must manage any hepatitis infections and maintain normal liver, kidney, and blood function. If CRS or ICANS symptoms develop, participants will receive siltuximab treatment. As a Phase 2 trial, this research measures how well siltuximab works in an initial, smaller group, offering participants a chance to contribute to significant advancements in cancer treatment.

Will I have to stop taking my current medications?

The trial requires a washout period (time without taking certain medications) for some therapies before starting CAR T-cell infusion. Systemic therapy must be stopped 2 weeks before, radiation therapy 1 week before, and corticosteroids 5 days before the infusion. If you are on these treatments, you may need to stop them temporarily.

Is there any evidence suggesting that siltuximab is likely to be safe for humans?

Research has shown that siltuximab is generally safe for people with cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). One study found that siltuximab effectively treated CRS in 75% of cases and ICANS in 60% of cases. Another study reported that 79% of patients responded well to siltuximab, with symptoms improving quickly, often within an hour. These findings suggest that siltuximab is safe and works quickly to help manage these conditions. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), which often involve steroids and tocilizumab, siltuximab offers a different approach. Siltuximab is an antibody that specifically targets and binds to interleukin-6 (IL-6), a key player in the inflammation process associated with CRS and ICANS. This targeted action could mean more precise control over symptoms with potentially fewer side effects compared to broader immunosuppressive strategies. Researchers are excited about siltuximab because it may provide a more effective and safer option for patients experiencing these complications from CAR-T therapy.

What evidence suggests that siltuximab might be an effective treatment for CRS and ICANS?

Research has shown that siltuximab, a monoclonal antibody, effectively treats cytokine release syndrome (CRS) and immune effector cell-associated neurological syndrome (ICANS). Studies have found that it helps 79% of people with CRS, with symptoms often improving within an hour. Siltuximab also proves effective for ICANS, even in challenging cases. In this trial, patients experiencing CRS or ICANS related to CAR-T therapy will receive siltuximab to reduce the severity of these conditions. ^{1 3 6 7 8}

Who Is on the Research Team?

Amitkumar Mehta, MD

Principal Investigator

University of Alabama at Birmingham

Are You a Good Fit for This Trial?

This trial is for patients with certain blood cancers who are getting CAR-T cell therapy and can handle a washout period before treatment. They must have good liver, kidney, and blood function, not be pregnant or HIV positive, and agree to use effective contraception.

Inclusion Criteria

I have Hepatitis B but am on treatment with no detectable virus.

I am a man who can father children and will use contraception.

I have hepatitis C but have completed treatment and now have an undetectable viral load.

Exclusion Criteria

I do not have an active autoimmune disease that needs immunosuppressive therapy, or I have discussed it with the PI.

I take more than 10 mg of prednisone daily, not just in short bursts.

I have HIV.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive CAR T-cell therapy and are monitored for CRS and ICANS. Siltuximab is administered upon development of these syndromes.

14 days

Frequent monitoring visits

Follow-up

Participants are monitored for resolution of CRS and ICANS, and for adverse events from Siltuximab.

28 days

Regular follow-up visits

Long-term follow-up

Participants are monitored for response to CAR T-cell therapy and overall outcomes.

90 days

What Are the Treatments Tested in This Trial?

Interventions

• Siltuximab

Trial Overview The study tests if siltuximab can reduce the severity of CRS and ICANS in patients undergoing CAR-T cell therapy for hematological malignancies like lymphoma or leukemia.

How Is the Trial Designed?

Group I: Siltuximab Experimental Treatment 1 Intervention

Patients who experience CRS/ICANS will receive this treatment

Who Is Running the Clinical Trial?

University of Alabama at Birmingham

Lead Sponsor

Trials

1,677

Recruited

2,458,000+

Published Research Related to This Trial

A 77-year-old male with relapsed/refractory multiple myeloma experienced cytokine release syndrome (CRS) and neurotoxicity after bispecific antibody therapy, but recovered rapidly after receiving siltuximab, an IL-6 inhibitor.

Siltuximab effectively managed CRS symptoms within 1 hour and neurotoxicity within 7 hours, allowing the patient to tolerate further treatment without recurrence of CRS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Siltuximab as a primary treatment for cytokine release syndrome in a patient receiving a bispecific antibody in a clinical trial setting. Lipe, BC., Renaud, T.[2023]

A patient with severe cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) related to CAR T-cell therapy was successfully treated with dasatinib, a tyrosine kinase inhibitor, after failing standard treatments like IL-6 blockade and steroids.

This case suggests that dasatinib may be a promising alternative treatment for severe complications from CAR T-cell therapy, highlighting the need for further research into its efficacy and safety in this context.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dasatinib for treatment of CAR T-cell therapy-related complications. Baur, K., Heim, D., Beerlage, A., et al.[2023]

In a study of 40 patients undergoing CAR T-cell therapy, those who received early management with tocilizumab and corticosteroids experienced significantly lower rates of severe cytokine release syndrome (CRS) and neurologic syndrome (ICANS), with only 5% and 9% developing grade 3+ toxicities, respectively.

Patients managed with the early protocol had a higher overall response rate (ORR) of 89% compared to 50% for those under standard management, indicating that early intervention does not compromise treatment efficacy while effectively reducing toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Early versus standard management of chimeric antigen receptor therapy toxicities and management's impact on safety and efficacy. Gaffney, KJ., Davis, JA., McGann, M., et al.[2023]

In a study of 15 patients with relapsed/refractory diffuse large B cell lymphoma treated with CAR T cells, 27% experienced immune effector cell-associated neurotoxicity syndrome (ICANS), but most cases were low grade and manageable.

Close monitoring and a thorough neurological assessment before treatment helped identify neurotoxicity early, allowing for effective intervention with dexamethasone, which resolved symptoms in affected patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neurological management and work-up of neurotoxicity associated with CAR T cell therapy. Möhn, N., Bonda, V., Grote-Levi, L., et al.[2022]

In a study of 31 adult patients receiving commercial anti-CD19 CAR T cell therapy, cytokine release syndrome (CRS) occurred in 26 patients, but the treatment was generally administered with minimal toxicity, indicating a manageable safety profile.

With a median follow-up of 13.4 months, the treatment showed promising efficacy, with a one-year overall survival rate of 88.1% and a progression-free survival rate of 41.2%, although certain factors like MCL diagnosis and elevated CRP levels were linked to poorer outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Molecular and Clinical Characteristics of Different Toxicity Rates in Anti-CD19 Chimeric Antigen Receptor T Cells: Real-World Experience. Gavriilaki, E., Mallouri, D., Bousiou, Z., et al.[2023]

Chimeric antigen receptor (CAR) T-cell therapy is becoming more widely used due to improved safety measures, including the establishment of diagnostic criteria for cytokine release syndrome (CRS) and neurotoxicity, as well as the use of treatments like tocilizumab and corticosteroids.

Despite these advancements, some patients still experience severe and persistent CRS and neurotoxicity, which can negatively affect outcomes; new strategies, including the use of anakinra, are being explored to manage these refractory cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

How I treat refractory CRS and ICANS after CAR T-cell therapy. Jain, MD., Smith, M., Shah, NN.[2023]

A 65-year-old male with Mantle Cell Lymphoma achieved complete remission after receiving CAR T-cell therapy, despite undergoing a prolonged treatment with high-dose corticosteroids for severe ICANS.

This case suggests that corticosteroids can be effectively used to manage severe neurotoxicity associated with CAR T-cell therapy without compromising the overall treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of long-term corticosteroids in patients treated with CAR T-cell therapy. Hashmi, H., McGann, M., Greenwell, BI.[2023]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39437770/

Siltuximab for chimeric antigen receptor T-cell therapy-related ... Siltuximab appeared to be effective for both CRS and ICANS, including previously treated toxicities. These data support the use of siltuximab in CRS and ICANS.

2. clinicaltrials.gov clinicaltrials.gov/study/NCT04975555

NCT04975555 | Study to Evaluate the Role of Siltuximab in ... This study will evaluate the use of siltuximab to decrease the severity of cytokine release syndrome (CRS) and immune effector cell-associated neurological ...

3. ashpublications.org ashpublications.org/blood/article/144/Supplement%201/3449/529605/Phase-2-Trial-of-Siltuximab-for-the-Treatment-of

Phase 2 Trial of Siltuximab for the Treatment of Cytokine ... In this phase 2 study, we utilized siltuximab, an IL-6 binding monoclonal antibody, to assess its efficacy for the treatment of CRS and/or ICANS in patients ...

4. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0006497124062013

Phase 2 Trial of Siltuximab for the Treatment of Cytokine ... In this prospective phase 2 trial, siltuximab demonstrated a high response rate (79%) and rapid time to resolution (median 1 hour) of CRS following CAR T-cell ...

5. astctjournal.org astctjournal.org/article/S2666-6367(23)01996-6/fulltext

Efficacy of Siltuximab for Chimeric Antigen Receptor T-Cell ... Siltuximab appeared to be effective for both CRS and ICANS, including refractory toxicities. These data support the use of siltuximab for refractory CRS and ...

6. ashpublications.org ashpublications.org/bloodadvances/article/9/1/170/518288/Siltuximab-for-chimeric-antigen-receptor-T-cell

Siltuximab for chimeric antigen receptor T-cell therapy–related ... Key PointsIn this retrospective analysis, siltuximab effectively treated CRS and ICANS with an objective response rate of 75% and 60%, respectively.Siltuxi.

7. hematologyadvisor.com hematologyadvisor.com/news/siltuximab-promising-efficacy-crs-icans-cart-therapy-risk/

Siltuximab Shows Promising Efficacy Against CRS and ... Siltuximab demonstrated promising safety and efficacy for the treatment of cytokine release syndrome (CRS) and immune effector cell-associated ...

8. ncbi.nlm.nih.gov ncbi.nlm.nih.gov/books/NBK604827/

Anticytokine Therapy and Corticosteroids for Cytokine ... - NCBI Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are the most common toxicities secondary to T-cell ...