CAR T-Cell Therapy for Chronic Lymphocytic Leukemia

Overseen By Micaela A Ganaden, R.N.

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: Anticoagulants, Checkpoint inhibitors

Disqualifiers: HIV, Second malignancies, Uncontrolled infections, others

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

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 6

132 Participants Needed

Trial Summary

What is the purpose of this trial?

Background: Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are blood cancers that affect certain white blood cells. Advanced forms of these diseases are difficult to treat. CD19 is a protein often found on the surfaces of these cancer cells. Researchers can modify a person's own immune cells (T cells) to target CD19. When these modified T cells are returned to the body-a treatment called anti-CD19 chimeric antigen receptor (CAR) T cell therapy-they may help kill cancer cells. Objective: To test anti-CD19 CAR T cell therapy in people with CLL or SLL. Eligibility: People aged 18 years and older with CLL or SLL that has not been controlled with standard drugs. Design: Participants will be screened. They will have imaging scans and tests of their heart function. If a sample of tissue from their tumor is not available, a new one may be taken; the sample will be tested for CD19. Participants will receive a drug to reduce the leukemia cells in their blood. Then they will undergo apheresis: Blood will be taken from the body through a needle. The blood will pass through a machine that separates out the T cells. The remaining blood will be returned to the body through a different needle. The collected T cells will be gene edited to make them attack cells with CD19. Participants will take drugs to prepare them for treatment for 3 days. These drugs will start 5 days before the treatment. Then their own modified CAR T cells will be returned to their bloodstream. Participants will stay in the hospital for at least 9 days after the treatment. Follow-up visits will continue for 5 years.

Will I have to stop taking my current medications?

The trial requires that participants stop taking systemic corticosteroids greater than 5 mg/day of prednisone or equivalent at least 14 days before starting rituximab. Additionally, participants on systemic anticoagulant therapy, except aspirin, are not allowed.

What data supports the effectiveness of the treatment for Chronic Lymphocytic Leukemia?

The treatment, which involves CAR T cells targeting CD19, has shown effectiveness in treating other B-cell cancers like acute lymphoblastic leukemia and diffuse large B-cell lymphoma. These successes suggest potential benefits for similar B-cell malignancies, such as Chronic Lymphocytic Leukemia. ^{1 2 3 4 5}

Is CAR T-cell therapy safe for humans?

CAR T-cell therapy, including treatments like tisagenlecleucel (Kymriah), has been associated with serious but mostly reversible side effects, such as cytokine release syndrome (a severe immune reaction) and neurotoxicity (effects on the nervous system). Medium-term complications can include low blood cell counts and B-cell aplasia (a lack of B cells, which are part of the immune system). ^{1 2 4 5 6}

How is CAR T-cell therapy for chronic lymphocytic leukemia different from other treatments?

CAR T-cell therapy for chronic lymphocytic leukemia is unique because it uses the patient's own T cells, which are modified to target and destroy cancer cells expressing the CD19 protein. This personalized approach is different from standard treatments like chemotherapy or kinase inhibitors, which are not specifically tailored to target cancer cells in this way. ^{5 7 8 9 10}

Research Team

Jennifer N Brudno, M.D.

Principal Investigator

National Cancer Institute (NCI)

Eligibility Criteria

This trial is for adults over 18 with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) that hasn't responded to standard treatments. Participants must have a tumor sample available for CD19 testing, and their heart and overall health should be stable enough to undergo the procedures involved in the trial.

Inclusion Criteria

I've had at least two treatments for my condition, including one with a BTK inhibitor.

I am fully active or can carry out light work.

My heart pumps blood effectively.

Exclusion Criteria

I have an active condition where my red blood cells are being destroyed faster than they can be made.

I have had a stem cell transplant from a donor.

I need urgent treatment because my tumor is pressing on my spine or other organs.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Pre-treatment

Participants receive a drug to reduce leukemia cells and undergo apheresis to collect T cells

1 week

1 visit (in-person)

Conditioning Chemotherapy

Participants receive rituximab and a lymphocyte-depleting chemotherapy regimen

3 days

3 visits (in-person)

CAR T-cell Infusion

Participants receive an infusion of genetically modified CAR T cells

1 day

1 visit (in-person)

Inpatient Monitoring

Participants are monitored for toxicity in the hospital

9 days

Inpatient stay

Follow-up

Participants are monitored for safety and effectiveness after treatment

5 years

Regular visits (in-person and virtual)

Treatment Details

Interventions

• Autologous HuCD19 (Anti-CD19) CAR T cells

Trial Overview The study tests anti-CD19 CAR T cell therapy, where patients' own immune cells are modified to target cancer cells. It involves taking medication to reduce leukemia cells, extracting T cells from blood, genetically modifying them in a lab, and then infusing them back into the patient's bloodstream.

Participant Groups

Group I: 2/Rituximab, conditioning chemotherapy plus CAR T-cells- Dose expansion Experimental Treatment 4 Interventions

MTD dose or Optimal dose of Anti-CD19 CAR T- cells/kg + rituximab and conditioning chemotherapy

Group II: 1/Rituximab, conditioning chemotherapy plus CAR T-cells- Dose escalation Experimental Treatment 4 Interventions

Escalating dose of anti-CD19 CAR T- cells/kg + rituximab and conditioning chemotherapy

Autologous HuCD19 (Anti-CD19) CAR T cells is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Kymriah for:

• B-cell precursor acute lymphoblastic leukemia (ALL)
• Relapsed or refractory large B-cell lymphoma
• Relapsed or refractory follicular lymphoma

Approved in European Union as Kymriah for:

• B-cell precursor acute lymphoblastic leukemia (ALL)
• Relapsed or refractory large B-cell lymphoma
• Relapsed or refractory follicular lymphoma

Approved in Canada as Kymriah for:

• B-cell precursor acute lymphoblastic leukemia (ALL)
• Relapsed or refractory large B-cell lymphoma
• Relapsed or refractory follicular lymphoma

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

CAR T cell therapy, specifically with tisagenlecleucel and axicabtagene ciloleucel, has been authorized in Europe for treating certain types of blood cancers, showing efficacy in relapsed/refractory acute lymphoblastic leukemia and diffuse large B-cell lymphoma.

The recommendations provided focus on managing medium-term complications like cytopenias and B-cell aplasia, emphasizing the importance of supportive care for patients undergoing this innovative treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Medium-term follow-up of patients treated with chimeric antigen receptor T cells (CAR T cells): Recommendations of the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC)]. Alsuliman, T., Drieu La Rochelle, L., Campidelli, A., et al.[2022]

Two CAR T cell therapies, Tisagenlecleucel and Axicabtagene ciloleucel, have been approved for treating specific types of blood cancers, including B-cell acute lymphoblastic leukemia and large B-cell lymphoma, in patients who have not responded to other treatments.

This review emphasizes the importance of recognizing and managing the toxicities associated with CAR T cell therapies, while also suggesting future strategies to reduce these side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR T Cell Toxicity: Current Management and Future Directions. Yáñez, L., Sánchez-Escamilla, M., Perales, MA.[2020]

CAR T-cell therapies, such as tisagenlecleucel (Kymriah™) and axicabtagene ciloleucel (Yescarta™), are effective treatments for relapsed/refractory B-cell acute lymphoblastic leukemia and diffuse large B-cell lymphoma, utilizing genetically modified T cells that target the CD19 antigen.

These therapies are classified as 'living drugs' because they involve the genetic engineering of a patient's own T cells, highlighting the importance of proper collection and manufacturing processes for effective treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[How to perform leukapheresis for procurement of the staring material used for commercial CAR T-cell manufacturing: A consensus from experts convened by the SFGM-TC]. Carnoy, S., Beaumont, JL., Kanouni, T., et al.[2021]

CAR T cell therapies, such as tisagenlecleucel and axicabtagene ciloleucel, are effective treatments for certain types of blood cancers, specifically targeting the CD19 antigen in patients with relapsed or refractory conditions.

The recommendations provided by the European Society of Blood and Marrow Transplantation cover comprehensive patient care aspects, including eligibility, treatment procedures, and management of potential complications, ensuring a structured approach to administering these innovative therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Management of adults and children undergoing chimeric antigen receptor T-cell therapy: best practice recommendations of the European Society for Blood and Marrow Transplantation (EBMT) and the Joint Accreditation Committee of ISCT and EBMT (JACIE). Yakoub-Agha, I., Chabannon, C., Bader, P., et al.[2022]

Chimeric antigen receptor (CAR) T-cell therapy targeting the CD19 antigen has shown high effectiveness in treating patients with relapsed or refractory B-cell malignancies, with several therapies like tisagenlecleucel already approved in Japan.

Research is ongoing for CAR T-cell therapies targeting other cancers, such as acute myeloid leukemia (AML) and multiple myeloma, indicating a broadening scope of CAR T-cell applications beyond just B-cell malignancies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Chimeric antigen receptor T-cell therapy for hematological malignancies]. Nakazawa, Y.[2019]

In a global study involving 75 pediatric and young adult patients with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL), the CAR T-cell therapy tisagenlecleucel achieved an impressive overall remission rate of 81% within 3 months, with all responders showing no minimal residual disease.

While 73% of patients experienced serious adverse events, including cytokine release syndrome in 77% and neurologic events in 40%, these effects were mostly manageable and reversible, indicating that tisagenlecleucel can provide durable remission despite the risk of significant side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia. Maude, SL., Laetsch, TW., Buechner, J., et al.[2022]

The FDA has approved tisagenlecleucel, the first anti-CD19 CAR T-cell therapy, specifically for treating pediatric and young adult patients with relapsed or refractory acute lymphocytic leukemia (ALL).

CAR T-cell therapy, particularly with tisagenlecleucel, shows promise as a standard treatment option for patients with B-cell malignancies, although it has primarily been developed through small clinical studies and poses unique management challenges.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tisagenlecleucel-T for the treatment of acute lymphocytic leukemia. Thomas, X., Paubelle, E.[2019]

In a study of 47 patients with relapsed/refractory large B cell lymphomas receiving CAR T-cell therapy, changes in PET scan results at 30 days post-infusion were found to be predictive of patient outcomes, with a significant correlation between SUVmean variation and progression-free survival.

Patients with a Deauville score of 4-5 and a decrease in SUVmean had a similar 1-year progression-free survival rate (61-62%) as those with a better score (1-3), while those with an increase in SUVmean had a much poorer survival rate of 33%, highlighting the importance of these metrics in assessing treatment response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination of Deauville score and quantitative positron emission tomography parameters as a predictive tool of anti-CD19 chimeric antigen receptor T-cell efficacy. Guidetti, A., Dodero, A., Lorenzoni, A., et al.[2023]

In a phase 1 clinical trial involving 20 patients with relapsed or refractory chronic lymphocytic leukemia (CLL) and indolent B-cell non-Hodgkin lymphoma (B-NHL), CAR T-cell therapy combined with conditioning chemotherapy was found to be well-tolerated, with serious side effects like cytokine release syndrome occurring in only 10% of patients.

Among the CLL patients who received conditioning chemotherapy, 25% achieved complete remission, and all patients who reached this remission remained progression-free for a median follow-up of 53 months, indicating the potential for long-lasting treatment effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and tolerability of conditioning chemotherapy followed by CD19-targeted CAR T cells for relapsed/refractory CLL. Geyer, MB., Rivière, I., Sénéchal, B., et al.[2021]

In a study of 42 patients with relapsed or refractory chronic lymphocytic leukemia (CLL), those treated with anti-CD19 CAR T cells showed a complete response (CR) rate of 28% and an overall response rate of 44% after 4 weeks, with a median overall survival of 64 months.

Achieving a complete response was linked to significantly longer overall survival and progression-free survival, indicating that the effectiveness of CAR T cell therapy is enhanced in patients who reach CR, regardless of whether they received a low or high dose.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-Term Outcomes From a Randomized Dose Optimization Study of Chimeric Antigen Receptor Modified T Cells in Relapsed Chronic Lymphocytic Leukemia. Frey, NV., Gill, S., Hexner, EO., et al.[2021]

References

1. France pubmed.ncbi.nlm.nih.gov

[Medium-term follow-up of patients treated with chimeric antigen receptor T cells (CAR T cells): Recommendations of the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC)]. [2022]

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

CAR T Cell Toxicity: Current Management and Future Directions. [2020]

3. France pubmed.ncbi.nlm.nih.gov

[How to perform leukapheresis for procurement of the staring material used for commercial CAR T-cell manufacturing: A consensus from experts convened by the SFGM-TC]. [2021]

4. Italy pubmed.ncbi.nlm.nih.gov

Management of adults and children undergoing chimeric antigen receptor T-cell therapy: best practice recommendations of the European Society for Blood and Marrow Transplantation (EBMT) and the Joint Accreditation Committee of ISCT and EBMT (JACIE). [2022]

5. Japan pubmed.ncbi.nlm.nih.gov

[Chimeric antigen receptor T-cell therapy for hematological malignancies]. [2019]

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

Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia. [2022]

7. England pubmed.ncbi.nlm.nih.gov

Tisagenlecleucel-T for the treatment of acute lymphocytic leukemia. [2019]

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

Combination of Deauville score and quantitative positron emission tomography parameters as a predictive tool of anti-CD19 chimeric antigen receptor T-cell efficacy. [2023]

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

Safety and tolerability of conditioning chemotherapy followed by CD19-targeted CAR T cells for relapsed/refractory CLL. [2021]

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

Long-Term Outcomes From a Randomized Dose Optimization Study of Chimeric Antigen Receptor Modified T Cells in Relapsed Chronic Lymphocytic Leukemia. [2021]