CLIC-2201 for B-Cell Lymphoma
Recruiting in Palo Alto (17 mi)
+6 other locations
Overseen ByKevin Hay, MD
Age: Any Age
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: British Columbia Cancer Agency
Must not be taking: Corticosteroids, Immunosuppressives, Chemotherapy, others
Disqualifiers: Infections, Autoimmune disease, GVHD, others
No Placebo Group
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.
12345What 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.
46789How 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.
410111213Eligibility 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.
+6 more
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.
+9 more
Trial 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
Participant Groups
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.
1Treatment groups
Experimental Treatment
Group I: CLIC-2201Experimental Treatment1 Intervention
A single Intravenous infusion of CLIC-2201 will be given.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Alberta Children's HospitalCalgary, Canada
The Ottawa Hospital - General CampusOttawa, Canada
BC Children's HospitalVancouver, Canada
Calgary Cancer CentreCalgary, Canada
More Trial Locations
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Who Is Running the Clinical Trial?
British Columbia Cancer AgencyLead Sponsor
References
Efficacy and safety of idelalisib for the treatment of indolent B-cell malignancies. [2022]Label="INTRODUCTION" NlmCategory="BACKGROUND">The outcome of patients with lymphoid malignancies has markedly improved in recent years due to the implementation of new therapeutic options. Chronic lymphocytic leukemia (CLL) and indolent B-cell non-Hodgkin lymphomas (NHL) are characterized by the activation of the phosphatidylinositol 3-kinase (PI3 K) pathway via B-cell receptor signaling. The PI3 K delta (PI3 Kδ) p110δ isoform inhibitor, idelalisib, showed high anti-tumor activity in this group of tumors. It was the first agent from a new class of isoform-specific inhibitors to receive regulatory approvals for the treatment of refractory/relapsed CLL, as well as small lymphocytic lymphoma and follicular lymphoma.
Akt inhibitor MK-2206 in combination with bendamustine and rituximab in relapsed or refractory chronic lymphocytic leukemia: Results from the N1087 alliance study. [2023]Akt is a downstream target of B cell receptor signaling and is a central regulator of CLL cell survival. We aim to investigate the safety and efficacy of the Akt inhibitor MK-2206 in combination with bendamustine and rituximab (BR) in relapsed and/or refractory CLL in a phase I/II study. A standard phase I design was used with cohorts of three plus three patients to determine the maximum tolerated dose (MTD) of MK-2206 in combination with BR in relapsed CLL. Single-agent MK-2206 (weekly dosed) was administered one-week in advance before BR on cycle 1 and subsequently was given with BR at the same time for cycle 2-6. Phase II employed the MTD of MK-2206 with BR to evaluate safety and efficacy of this study combination. Thirteen relapsed/refractory CLL were treated for maximal 6-cycle of therapy. The maximum tolerated dose of MK-2206 was 90 mg by mouth once weekly. The most common grade 3/4 adverse events were neutropenia (46%), febrile neutropenia (23%), rash (15%), diarrhea (15%), and thrombocytopenia (15%). Overall response rate was 92% with a median progression free survival and treatment free survival of 16 and 24 months, respectively. Five patients (38%) achieved complete remission or complete remission with incomplete count recovery, two of whom were MRD negative. The efficacy and tolerability of this combination indicates that Akt inhibition combined with chemoimmunotherapy is a promising novel treatment combination in CLL and deserves further prospective clinical trial.
State-of-the-Art Management of Patients Suffering from Chronic Lymphocytic Leukemia. [2021]The management of chronic lymphocytic leukemia (CLL) has evolved dramatically in the last decade. For the first time, clinical intervention has been shown to alter the natural history of the disease. Considerable efforts are focussing on better patient selection and response prediction, and it is expected that the publication of the first 200 CLL genomes will spark new insights into risk stratification of CLL patients. Besides, many new agents are being evaluated on their own and in combination therapy in early and late Phase clinical studies. Here, we provide a general clinical introduction into CLL including diagnosis and prognostic markers followed by a summary of the current state-of-the-art treatment. We point to areas of continued clinical research in particular for patients with co-morbidities and highlight the challenges in managing refractory disease.
CLL2-BIG: sequential treatment with bendamustine, ibrutinib and obinutuzumab (GA101) in chronic lymphocytic leukemia. [2022]Obinutuzumab (GA101) and ibrutinib show excellent efficacy for treatment of chronic lymphocytic leukemia (CLL). Preclinical investigations and a complementary safety profile were in support of testing their combined use. The exploratory CLL2-BIG-trial evaluated a sequential combination therapy following a recently proposed strategy. Two courses of bendamustine were used for debulking in patients with a high tumor load, followed by six courses of induction therapy with ibrutinib and GA101, followed by an MRD-triggered maintenance phase. The results of a pre-planned analysis at the end of the induction phase are presented. 61 patients were included, 30 previously untreated and 31 with relapsed/refractory CLL. 44 patients received bendamustine. During induction, neutropenia (14.8%) and thrombocytopenia (13.1%) were the most common CTC grade 3 and 4 events. One fatality (duodenitis) occurred. The overall response rate was 100%. 54.1% of patients achieved a partial remission, 41% a clinical complete remission (cCR) without confirmation by CT scan or bone marrow (BM) biopsy according to protocol and 4.9% a cCR with incomplete recovery of the BM. 29 patients (47.5%) had no detectable (<10-4) minimal residual disease assessed by flow cytometry in peripheral blood. In conclusion, the BIG regimen is a safe and highly effective therapy for CLL.
Evolving Strategies for the Treatment of Chronic Lymphocytic Leukemia in the Upfront Setting. [2018]Chronic lymphocytic leukemia (CLL) is a disease of marked clinical heterogeneity, and while some patients have a normal life expectancy, others develop rapidly progressive disease shortly after diagnosis. The current standard for upfront treatment of CLL is chemoimmunotherapy for younger fit patients, FCR (fludarabine, cyclophosphamide, and rituximab) being the prototype. For older patients, BR (bendamustine and rituximab) exhibits excellent activity with decreased toxicity. For the frailest patients, CD20 monoclonal antibodies with or without chlorambucil have proven to be efficacious. The novel oral kinase inhibitors ibrutinib and idelalisib are FDA-approved in the relapsed/refractory setting, and ibrutinib is approved upfront for those with del(17p). These drugs have produced long-term durable responses in the relapsed/refractory setting, and studies are underway using these as single agent upfront or in combination with both chemotherapy and monoclonal antibodies. Here, we review standard upfront therapies and new agents and combinations that are on the horizon for CLL.
Managing toxicities of Bruton tyrosine kinase inhibitors. [2023]Inhibition of Bruton's tyrosine kinase (BTK) has revolutionized the treatment landscape for patients with chronic lymphocytic leukemia (CLL). By targeting this critical kinase in proximal B-cell receptor signaling, BTK inhibitors (BTKis) impair cell proliferation, migration, and activation of NF-κB. Clinically, because indefinite inhibition is a mainstay of therapy, there is an extended period of exposure in which adverse effects can develop. Given the impressive efficacy and activity of BTKis in the treatment of patients with CLL, appropriate management of treatment-emergent adverse events (AEs) is of paramount importance. Here we review the BTKi landscape and present the available toxicity and safety data for each agent. The long-term toxicity profile of ibrutinib, a first-in-class inhibitor, is well characterized and includes a clinically significant incidence of cardiac arrhythmias, bleeding, infection, diarrhea, arthralgias, and hypertension. Acalabrutinib, the initial second-generation BTKi to earn approval from the US Food and Drug Administration, demonstrates improved kinase selectivity for BTK, with commonly observed adverse reactions including infection, headache, and diarrhea. Mediated by both on-target inhibition of BTK and variable off-target inhibition of other kinases including interleukin-2-inducible T-cell kinase (ITK), tyrosine-protein kinase (TEC), and endothelial growth factor receptor (EGFR), the toxicity profile of BTKis is closely linked to their pattern of kinase binding. Other emerging BTKis include second-generation agents with variable degrees of kinase selectivity and third-generation agents that exhibit reversible noncovalent binding to BTK. We also highlight critical considerations for the prevention and monitoring of AEs and offer practical management strategies for treatment-emergent toxicities.
Phase 1b study of venetoclax-obinutuzumab in previously untreated and relapsed/refractory chronic lymphocytic leukemia. [2021]This single-arm, open-label, phase 1b study evaluated the maximum tolerated dose (MTD) of venetoclax when given with obinutuzumab and its safety and tolerability in patients with relapsed/refractory (R/R) or previously untreated (first line [1L]) chronic lymphocytic leukemia (CLL). Venetoclax dose initially was escalated (100-400 mg) in a 3 + 3 design to define MTD combined with standard-dose obinutuzumab. Patients received venetoclax (schedule A) or obinutuzumab (schedule B) first to compare safety and determine dose/schedule for expansion. Venetoclax-obinutuzumab was administered for 6 cycles, followed by venetoclax monotherapy until disease progression (R/R) or fixed duration 1-year treatment (1L). Fifty R/R and 32 1L patients were enrolled. No dose-limiting toxicities were observed. Safety, including incidence of tumor lysis syndrome (TLS), did not differ between schedules (2 laboratory TLSs per schedule). Schedule B and a 400-mg dose of venetoclax were chosen for expansion. The most common grade 3-4 adverse event was neutropenia (R/R, 58% of patients; 1L, 53%). Rates of grade 3-4 infections were 29% (R/R) and 13% (1L); no fatal infections occurred in 1L. All infusion-related reactions were grade 1-2, except for 2 grade 3 events. No clinical TLS was observed. Overall best response rate was 95% in R/R (complete response [CR]/CR with incomplete marrow recovery [CRi], 37%) and 100% in 1L (CR/CRi, 78%) patients. Rate of undetectable (<10-4) minimal residual disease (uMRD) in peripheral blood for R/R and 1L patients, respectively, was 64% and 91% ≥3 months after last obinutuzumab dose. Venetoclax and obinutuzumab therapy had an acceptable safety profile and elicited durable responses and high rates of uMRD. This trial was registered at www.clinicaltrials.gov as #NCT01685892.
Efficacy and safety of new-generation Bruton tyrosine kinase inhibitors in chronic lymphocytic leukemia/small lymphocytic lymphoma: a systematic review and meta-analysis. [2023]Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is a type of mature B lymphocyte clonal proliferative tumor with a specific immunophenotype. Bruton tyrosine kinase inhibitors (BTKi) have been approved for the treatment of CLL/SLL. However, the efficacy and safety of new-generation BTKi-based regimens have not been systematically studied. In this systematic review, we evaluated the efficacy and safety of new-generation BTKi-based regimens for the treatment of patients with CLL/SLL. A comprehensive search on PubMed, Embase, Cochrane Library, and ClinicalTrials.gov. up to January 31, 2023, was conducted by us. Studies reporting data on CLL/SLL patients treated with new-generation BTKi were included. We assessed the overall response rate (ORR), complete response (CR) rate, and 24-month OS/PFS rates for efficacy analysis. For safety analysis, we evaluated the incidence of grade ≥ 3 adverse events (AEs). The meta-analysis included twenty studies. The pooled ORR for new-generation BTKi was 92% (95% CI, 89-95%, I2 = 80.68%, P = 0.00), while the pooled CR rate was 10% (95% CI, 6-14%, I2 = 88.11%, P = 0.00). Research has found that the new-generation BTKi-based therapy had higher efficacy under the following treatment conditions: < 65 years old, treatment-naive (TN)-CLL, and BTKi combination therapy. The ORR/CR rates and 24-month OS/PFS rates of BTKi combination therapy were higher than that of BTKi monotherapy. Compared to acalabrutinib monotherapy, zanubrutinib monotherapy demonstrated higher ORR/CR rates and 24-month OS/PFS rates. Common grade ≥ 3 AEs included cytopenia and hypertension. The new-generation BTKi-based therapy has good tolerance and provides incremental benefits for CLL/SLL patients. Despite the superior efficacy of BTKi combination therapy compared to monotherapy, its AEs rates are relatively high. Compared to acalabrutinib, Zanubrutinib may be the preferred monotherapy for CLL. However, randomized-controlled studies are still needed.
Minimizing and managing treatment-associated complications in patients with chronic lymphocytic leukemia. [2021]Introduction: During recent years, therapy in chronic lymphocytic leukemia (CLL) has changed dramatically. The introduction of small molecule inhibitors has shown remarkable clinical efficacy in both previously untreated and relapsed CLL patients. However, these therapies are associated with an increased risk of specific adverse events. Selection of the best therapeutic approach for patients with CLL should be based on an assessment of general condition, comorbidities, and most importantly, the individual risk of serious side effects.Areas covered: The review presents available data about the occurrence, prophylaxis and management of the most common and clinically most relevant adverse events associated with novel therapy in CLL.Expert opinion: The incorporation of novel drugs, such as B-cell receptor inhibitors and venetoclax, a selective inhibitor of B-cell lymphoma, influences the CLL management paradigm. An individualized approach to CLL is now possible with targeted therapies. The appropriate and optimal use of current therapies requires a precise understanding of their mechanisms of action, efficacy and adverse effect profiles. A fuller understanding of the prophylaxis and management of specific adverse events stemming from CLL therapy could minimize its associated morbidity and mortality. Next-generation agents with improved efficacy and better safety profiles will further advance outcomes for patients with CLL.
The future of chronic lymphocytic leukemia: potential directions from ASH 2017. [2019]Novel targeted therapies - including ibrutinib, venetoclax, and idelalisib - have revolutionized the treatment landscape of chronic lymphocytic leukemia (CLL). Therefore, studying combinations of novel agents (NAs) with a distinct mechanism of action and nonoverlapping toxicities is challenging. Area covered: The 2017 American Society Hematology Annual Meeting has represented a showcase for several trials combining NAs. These studies are currently evaluating the efficacy NA plus anti-CD20 monoclonal antibody, NA plus NA (with or without anti-CD20 monoclonal antibody), and NA plus chemo-immunotherapy. Expert commentary: The development of well-tolerated, highly effective combination strategies with curative potential for patients with CLL is becoming a realistic goal in CLL. From a practical standpoint, it is hard to determine which regimen will be most beneficial. Until studies of association will provide more mature results, the sequencing of NA remains a reasonable approach.
The Bcl-2 family as a rational target for the treatment of B-cell chronic lymphocytic leukaemia. [2019]B-cell chronic lymphocytic leukaemia (B-CLL) is the most common lymphoid malignancy in the Western world, characterized by clonal growth and accumulation of monoclonal CD5+ B-cells in peripheral blood, bone marrow and peripheral lymphoid organs. Although the clinical course in B-CLL patients is highly variable, the most conserved feature is the prolonged survival of malignant B-cells, which has been associated to defects in the apoptotic machinery. The apoptosis defects are mainly determined by a defective balance among pro- and anti-apoptotic members of the Bcl-2 family, often related to resistance of CLL B-cells to chemotherapy. Purine nucleoside analogs or alkylating agents, alone or in combination, are the first-line treatment for B-CLL patients. Alternative, more specifically tailored therapeutics have been developed in recent years, including humanized monoclonal antibodies and kinase inhibitors. Here we shall review the drugs which are commonly used or are currently being assessed in clinical trials on B-CLL patients, their chemical structure, mechanisms of action, pharmacological properties, molecular targets, clinical efficacy and side effects, with a focus on drugs designed to promote apoptosis of malignant B-cells by targeting the Bcl-2 family.
Rituximab plus fludarabine and cyclophosphamide or other agents in chronic lymphocytic leukemia. [2015]Over the last few years, several monoclonal antibodies have been investigated in patients with B-cell lymphoid malignancies. Rituximab is the most important monoclonal antibody of clinical value in these disorders. Rituximab is an IgG1 chimeric antibody containing murine light- and heavy-chain variable region sequences and human constant region sequences. Since approval in 1997, rituximab has become the standard of care in follicular B-cell lymphoma, chronic lymphocytic leukemia (CLL) and aggressive lymphoma when combined with chemotherapy. Higher clinical benefits of rituximab can be seen in patients with CLL when it is added to other chemotherapeutic agents. Several recent reports have suggested that in patients with CLL, rituximab combined with purine nucleoside analogs (PNAs) or PNAs and cyclophosphamide may improve the results with acceptable toxicity, both in previously untreated and refractory/relapsed patients. The randomized, multinational Phase III study (REACH trial) has shown that rituximab combined with fludarabine and cyclophosphamide (R-FC regimen) results in 10 months longer progression-free survival, and higher overall response and complete response rates than fludarabine and cyclophosphamide (FC regimen) in previously treated patients. The German CLL study group initiated a multicenter, multinational Phase III trial, CLL8, to evaluate the efficacy and tolerability of R-FC versus FC for the first-line treatment of patients with advanced CLL. The overall response rate was significantly higher in the R-FC arm (95%) compared with FC (88%). The complete response rate in the R-FC arm was 44% compared with 27% in the FC arm. The recently updated analysis has demonstrated longer overall survival in the R-FC group. Recent clinical observations have revealed that combinations of rituximab with pentostatin and cyclophosphamide, or cladribine and cyclophosphamide are also highly active regimens in previously untreated CLL. In addition, the results of treatment with high-dose methylprednisolone in combination with rituximab in advanced CLL resistant to fludarabine have been reported recently by several groups. However, available therapies are only partially effective in CLL, exposing an obvious need to develop new, more specific and active drugs. Recently, several new anti-CD20 monoclonal antibodies have been developed and are now being evaluated in clinical trials.
Novel drugs for chronic lymphoid leukemias: mechanism of action and therapeutic activity. [2019]Chronic lymphoid leukemias include well defined mature B-cell and T-cell neoplasms with diverse natural history and specific morphological, immunophenotypic and molecular characteristics. The most common adult leukemia in the Western world is chronic lymphocytic leukemia (CLL). Rarer indolent lymphoid leukemias include prolymphocytic leukemia, hairy cell leukemia, large granular lymphocyte leukemia and T-cell leukemia/lymphoma. Recently, several new agents have been explored and have shown promise in CLL treatment. Novel therapies are being evaluated both in pre-clinical studies and in early clinical trials. These treatments include new purine nucleoside analogs, antisense oligonucleotides, agents targeting the antiapoptotic Bcl-2 family of proteins, receptors involved in mediation of survival signals from the microenvironment, cyclin-dependent kinase inhibitors, protein kinase C inhibitors, tyrosine kinase inhibitors, immunomodulating drugs, new monoclonal antibodies and other agents. At present, available therapies are only partially efficient and there is an obvious need to develop better strategies and new, more specific and active drugs. This review will focus on agents currently being explored in preclinical studies and in early clinical trials.