CLIC-2201 for B-Cell Lymphoma

Recruiting at 7 trial locations

Overseen By Narsis Afghari, MSc

Age: Any Age

Sex: Any

Trial Phase: Phase 1

Sponsor: British Columbia Cancer Agency

Must not be taking: Corticosteroids, Immunosuppressives, Chemotherapy, others

Disqualifiers: Infections, Autoimmune disease, GVHD, others

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

Compensation: Varies

Number of Visits: 17

Duration: 1 day

24 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a phase I dose-finding trial of an autologous CD22 targeting chimeric antigen receptor (CAR)-T cell product, called CLIC-2201, for participants with relapsed/refractory B cell malignancies. In the proposed trial, eligible enrolled participants will undergo leukapheresis for autologous T cell collection to enable CLIC-2201 manufacturing, followed by lymphodepletion with cyclophosphamide and fludarabine, then intravenous infusion of the autologous CLIC-2201 product. The trial will use the 3+3 design to escalate or de-escalate the dose level of CLIC-2201 administered. Participants will be monitored for safety and tolerability up to day 365 following CLIC-2201 infusion. The primary objective is to evaluate the safety and tolerability of CLIC-2201 and estimate the maximum tolerated dose (MTD) of CLIC-2201 in B-cell malignancies. The secondary objectives are to evaluate the (i) feasibility; (ii) anti-tumour activity of CLIC-2201; (iii) and characterize the pharmacokinetic (PK) profile of CLIC-2201. Exploratory objectives will include: i) characterizing the cellular and humoral immune responses against CLIC-2201 up to 1 year following infusion of CLIC-2201; (ii) characterizing the phenotype and gene expression profile of CLIC-2201 cells; (iii) evaluating immune and tumour cells at baseline and relapse for biomarkers of response or toxicity; (iv) evaluating serum cytokines, circulating tumour DNA (ctDNA) and B cell aplasia as biomarkers of clinical outcomes; and (v) assessing the quality of life.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop all current medications, but certain treatments must be stopped before joining. For example, you cannot have had certain therapies like bendamustine in the last 6 months or systemic corticosteroids within 7 days before starting the trial. However, if you are taking BTK inhibitors like ibrutinib for mantle cell lymphoma, you can continue them during the trial.

What data supports the effectiveness of the drug CLIC-2201 for B-Cell Lymphoma?

The research highlights the effectiveness of drugs targeting similar pathways, such as idelalisib, which inhibits a specific protein involved in B-cell signaling and has shown high anti-tumor activity in B-cell lymphomas. Additionally, the combination of Akt inhibitors with other treatments has shown promising results in related conditions like chronic lymphocytic leukemia, suggesting potential effectiveness for CLIC-2201. ^{1 2 3 4 5}

What safety data is available for CLIC-2201 or similar treatments in humans?

The safety data for treatments similar to CLIC-2201, such as Bruton tyrosine kinase inhibitors (BTKis) like ibrutinib and acalabrutinib, show that they can cause side effects like heart rhythm problems, bleeding, infections, diarrhea, joint pain, and high blood pressure. Newer BTKis have improved safety profiles, but still have common side effects like infections and headaches. Venetoclax combined with obinutuzumab has an acceptable safety profile, with common side effects including low white blood cell counts and infections. ^{4 6 7 8 9}

How does the drug CLIC-2201 differ from other treatments for B-cell lymphoma?

The drug CLIC-2201 is unique because it may target the Bcl-2 family of proteins, which are involved in preventing the death of cancerous B-cells, a mechanism not directly addressed by many standard treatments. This approach could potentially overcome resistance to traditional chemotherapy by promoting the natural death of these malignant cells. ^{4 10 11 12 13}

Research Team

Kevin Hay, MD

Principal Investigator

BC Cancer

Eligibility Criteria

This trial is for people with certain types of B-cell blood cancers that have come back or haven't responded to treatment. Participants must be able to undergo a procedure to collect their T cells, receive high-dose chemotherapy, and then get an infusion of the CAR-T cell therapy CLIC-2201.

Inclusion Criteria

My disease came back or didn't respond after 2 treatments, a stem cell transplant, or CAR-T therapy.

I can take care of myself but might not be able to do heavy physical work.

My heart, kidneys, and liver are functioning well enough for the trial.

Exclusion Criteria

I have no other cancers or have been cancer-free for 2 years, except for treated skin or cervical cancer.

Active (confirmed by PCR) hepatitis B or hepatitis C at time of enrolment

My cancer has not started in the brain or spinal cord.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Leukapheresis and Manufacturing

Participants undergo leukapheresis for autologous T cell collection, followed by CLIC-2201 manufacturing

Up to 4 weeks

Lymphodepletion

Participants receive lymphodepleting chemotherapy with fludarabine and cyclophosphamide

5 days

Treatment

Participants receive an intravenous infusion of the CLIC-2201 product

1 day

In-patient stay for a minimum of 7 days post-infusion

Follow-up

Participants are monitored for safety and effectiveness after treatment

365 days

Visits on days 10, 14, 21, 28, 60, 90, 180, and 365

Long-term Follow-up

Annual follow-up visits to monitor long-term safety and effectiveness

Up to 15 years

Treatment Details

Interventions

• CLIC-2201

Trial Overview The study tests different doses of CLIC-2201, a new type of personalized immune cell therapy targeting CD22 on cancer cells. It involves collecting patients' own T cells, modifying them in the lab into CAR-T cells, and infusing them back after chemotherapy.

Participant Groups

Group I: CLIC-2201 Experimental Treatment 1 Intervention

A single Intravenous infusion of CLIC-2201 will be given.

Who Is Running the Clinical Trial?

British Columbia Cancer Agency

Lead Sponsor

Trials

181

Recruited

95,900+

Findings from Research

Idelalisib, a PI3K delta inhibitor, has shown significant anti-tumor activity in patients with chronic lymphocytic leukemia (CLL) and indolent B-cell non-Hodgkin lymphomas, marking it as the first approved treatment in this category for refractory cases.

Despite its effectiveness, idelalisib has notable side effects that limit its widespread use, highlighting the need for the development of new PI3K inhibitors that maintain high efficacy while improving safety profiles.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of idelalisib for the treatment of indolent B-cell malignancies. Smolewski, P., Rydygier, D.[2022]

In a phase I/II study involving 13 patients with relapsed or refractory chronic lymphocytic leukemia (CLL), the Akt inhibitor MK-2206 was safely combined with bendamustine and rituximab, achieving a maximum tolerated dose of 90 mg weekly.

The treatment combination resulted in a high overall response rate of 92%, with a median progression-free survival of 16 months and 38% of patients achieving complete remission, suggesting that this approach is a promising option for CLL therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Akt inhibitor MK-2206 in combination with bendamustine and rituximab in relapsed or refractory chronic lymphocytic leukemia: Results from the N1087 alliance study. Larsen, JT., Shanafelt, TD., Leis, JF., et al.[2023]

Recent advancements in the management of chronic lymphocytic leukemia (CLL) have shown that clinical interventions can significantly change the disease's natural progression, marking a major shift in treatment approaches.

Ongoing research, including the analysis of 200 CLL genomes, aims to improve patient selection and response prediction, which is crucial for optimizing treatment strategies, especially for patients with additional health issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

State-of-the-Art Management of Patients Suffering from Chronic Lymphocytic Leukemia. Clifford, R., Schuh, A.[2021]

The combination therapy of obinutuzumab and ibrutinib, following a debulking phase with bendamustine, resulted in a 100% overall response rate in 61 patients with chronic lymphocytic leukemia (CLL), demonstrating its high efficacy.

The treatment was generally safe, with the most common severe side effects being neutropenia (14.8%) and thrombocytopenia (13.1%), and only one reported fatality, indicating a manageable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CLL2-BIG: sequential treatment with bendamustine, ibrutinib and obinutuzumab (GA101) in chronic lymphocytic leukemia. von Tresckow, J., Cramer, P., Bahlo, J., et al.[2022]

The standard treatment for chronic lymphocytic leukemia (CLL) varies by patient age and health, with younger patients typically receiving FCR (fludarabine, cyclophosphamide, and rituximab) and older patients benefiting from BR (bendamustine and rituximab) due to its lower toxicity.

Novel oral kinase inhibitors like ibrutinib and idelalisib have shown long-term effectiveness in treating relapsed/refractory CLL and are being explored for use as initial treatments, especially for patients with specific genetic markers like del(17p).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evolving Strategies for the Treatment of Chronic Lymphocytic Leukemia in the Upfront Setting. Bachow, SH., Lamanna, N.[2018]

BTK inhibitors (BTKis) have significantly improved treatment for chronic lymphocytic leukemia (CLL) by targeting Bruton's tyrosine kinase, which is crucial for B-cell receptor signaling, leading to reduced cell proliferation and activation of harmful pathways.

While BTKis like ibrutinib and acalabrutinib are effective, they come with notable long-term adverse effects, including cardiac issues and infections, highlighting the need for careful management of these side effects during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Managing toxicities of Bruton tyrosine kinase inhibitors. Lipsky, A., Lamanna, N.[2023]

The combination of venetoclax and obinutuzumab was found to be safe and well-tolerated in patients with relapsed/refractory or previously untreated chronic lymphocytic leukemia, with no dose-limiting toxicities observed during the study.

The treatment resulted in a high overall response rate of 95% in relapsed/refractory patients and 100% in previously untreated patients, with significant rates of undetectable minimal residual disease, indicating effective disease control.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1b study of venetoclax-obinutuzumab in previously untreated and relapsed/refractory chronic lymphocytic leukemia. Flinn, IW., Gribben, JG., Dyer, MJS., et al.[2021]

New-generation Bruton tyrosine kinase inhibitors (BTKi) show a high overall response rate of 92% in treating chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), particularly benefiting younger patients and those receiving combination therapy.

While BTKi-based therapies are generally well-tolerated, they can lead to significant adverse events like cytopenia and hypertension, and zanubrutinib may offer better efficacy than acalabrutinib as a monotherapy for CLL/SLL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of new-generation Bruton tyrosine kinase inhibitors in chronic lymphocytic leukemia/small lymphocytic lymphoma: a systematic review and meta-analysis. Yin, S., Zheng, X., Zhang, W., et al.[2023]

Recent advancements in chronic lymphocytic leukemia (CLL) treatment, particularly with small molecule inhibitors, have shown significant clinical efficacy in both untreated and relapsed patients, but they also come with increased risks of specific adverse events.

An individualized treatment approach is now possible with targeted therapies like B-cell receptor inhibitors and venetoclax, emphasizing the need for a thorough understanding of their mechanisms, efficacy, and side effects to optimize patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Minimizing and managing treatment-associated complications in patients with chronic lymphocytic leukemia. Iskierka-Jażdżewska, E., Robak, T.[2021]

Novel targeted therapies like ibrutinib, venetoclax, and idelalisib are changing how chronic lymphocytic leukemia (CLL) is treated, making it crucial to explore combinations of these agents with different mechanisms and side effects.

Current trials are investigating various combinations of these novel agents with anti-CD20 monoclonal antibodies and traditional chemo-immunotherapy, aiming for effective and well-tolerated treatment strategies that could potentially cure CLL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The future of chronic lymphocytic leukemia: potential directions from ASH 2017. Molica, S.[2019]

B-cell chronic lymphocytic leukaemia (B-CLL) is characterized by the accumulation of malignant B-cells that resist apoptosis, primarily due to an imbalance in the Bcl-2 family of proteins, which affects treatment response.

Recent advancements in therapy for B-CLL include humanized monoclonal antibodies and kinase inhibitors that specifically target the apoptotic pathways of malignant B-cells, showing promise in improving clinical efficacy and potentially overcoming chemotherapy resistance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Bcl-2 family as a rational target for the treatment of B-cell chronic lymphocytic leukaemia. Capitani, N., Baldari, CT.[2019]

Rituximab, a monoclonal antibody, has become the standard treatment for B-cell lymphoid malignancies, particularly in chronic lymphocytic leukemia (CLL), where it shows improved clinical benefits when combined with chemotherapy, such as purine nucleoside analogs.

In the Phase III REACH trial, the combination of rituximab with fludarabine and cyclophosphamide (R-FC regimen) resulted in significantly longer progression-free survival and higher response rates compared to the standard FC regimen, highlighting its efficacy in previously treated CLL patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rituximab plus fludarabine and cyclophosphamide or other agents in chronic lymphocytic leukemia. Robak, T., Lech-Maranda, E., Robak, P.[2015]

Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the Western world, and recent research is focusing on new therapies that show promise in treating this condition.

A variety of novel agents, including purine nucleoside analogs, Bcl-2 inhibitors, and monoclonal antibodies, are currently being evaluated in preclinical and early clinical trials, highlighting the need for more effective and targeted treatments for CLL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Novel drugs for chronic lymphoid leukemias: mechanism of action and therapeutic activity. Robak, T.[2019]

References

1. England pubmed.ncbi.nlm.nih.gov

Efficacy and safety of idelalisib for the treatment of indolent B-cell malignancies. [2022]

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

Akt inhibitor MK-2206 in combination with bendamustine and rituximab in relapsed or refractory chronic lymphocytic leukemia: Results from the N1087 alliance study. [2023]

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

State-of-the-Art Management of Patients Suffering from Chronic Lymphocytic Leukemia. [2021]

4. England pubmed.ncbi.nlm.nih.gov

CLL2-BIG: sequential treatment with bendamustine, ibrutinib and obinutuzumab (GA101) in chronic lymphocytic leukemia. [2022]

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

Evolving Strategies for the Treatment of Chronic Lymphocytic Leukemia in the Upfront Setting. [2018]

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

Managing toxicities of Bruton tyrosine kinase inhibitors. [2023]

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

Phase 1b study of venetoclax-obinutuzumab in previously untreated and relapsed/refractory chronic lymphocytic leukemia. [2021]

8. Germany pubmed.ncbi.nlm.nih.gov

Efficacy and safety of new-generation Bruton tyrosine kinase inhibitors in chronic lymphocytic leukemia/small lymphocytic lymphoma: a systematic review and meta-analysis. [2023]

9. England pubmed.ncbi.nlm.nih.gov

Minimizing and managing treatment-associated complications in patients with chronic lymphocytic leukemia. [2021]

10. England pubmed.ncbi.nlm.nih.gov

The future of chronic lymphocytic leukemia: potential directions from ASH 2017. [2019]

11. United Arab Emirates pubmed.ncbi.nlm.nih.gov

The Bcl-2 family as a rational target for the treatment of B-cell chronic lymphocytic leukaemia. [2019]

12. England pubmed.ncbi.nlm.nih.gov

Rituximab plus fludarabine and cyclophosphamide or other agents in chronic lymphocytic leukemia. [2015]

13. United Arab Emirates pubmed.ncbi.nlm.nih.gov

Novel drugs for chronic lymphoid leukemias: mechanism of action and therapeutic activity. [2019]