IKS03 for B-Cell Lymphoma

Recruiting at 16 trial locations

Overseen By David Browning

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Iksuda Therapeutics Ltd.

Must not be taking: NSAIDs, Aminoglycosides, Bisphosphonates, others

Disqualifiers: Pregnancy, CNS lymphoma, Cardiovascular disease, others

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

Compensation: Varies

Number of Visits: 2

140 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called IKS03 for individuals with advanced B-cell non-Hodgkin lymphoma (NHL), a type of blood cancer. The goal is to determine a safe dose and assess the treatment's effects on the cancer and the immune system. Participants will receive IKS03 through an IV every 21 days until the cancer progresses or side effects become too severe. The trial seeks individuals with B-cell NHL that hasn't responded to at least two prior treatments and who are not in immediate need of intense therapy. As a Phase 1 trial, this research aims to understand how the treatment works in people, offering participants the opportunity to be among the first to receive this new therapy.

Will I have to stop taking my current medications?

The trial requires stopping certain medications before participating. You must not have taken any CD19-targeted therapy within 3 months, tumor vaccines within 6 weeks, or other investigational treatments within 4 weeks. Additionally, certain drugs that impair renal function, immunosuppressive therapies, and herbal supplements must be stopped within specified timeframes before joining the trial.

Is there any evidence suggesting that IKS03 is likely to be safe for humans?

Research shows that IKS03 is generally well-tolerated. In earlier studies, most side effects were mild. The most common serious side effect was a decrease in white blood cells, known as neutropenia, occurring in about 26% of participants. This condition can increase the risk of infections. Other side effects were less severe and manageable.

Additionally, IKS03 caused less reduction in B-cells compared to similar treatments, even at higher doses. This suggests it might lead to fewer issues related to the loss of healthy B-cells, which are crucial for the immune system. Overall, the safety data for IKS03 indicates it is mostly manageable for patients. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for lymphoma?

Researchers are excited about IKS03 for B-cell lymphoma because it offers a potential new approach by targeting the cancer cells directly. Most current treatments, like chemotherapy and targeted therapies such as rituximab, work by killing or marking cancer cells for the immune system to attack. IKS03, on the other hand, is believed to target specific pathways within the cancer cells, potentially leading to more effective results with fewer side effects. Additionally, it's administered intravenously in a cyclical manner, which might allow for better control of the treatment process and monitoring of its effects on patients over time. This novel mechanism of action is what makes IKS03 stand out and fuels researchers' optimism about its potential benefits.

What evidence suggests that IKS03 might be an effective treatment for B-cell lymphoma?

Research has shown that IKS03 may help treat B-cell lymphoma, including types like follicular, mantle cell, and diffuse large B-cell lymphoma. In early lab studies, IKS03 completely shrank or eliminated tumors in a type of B-cell lymphoma with the CD19 protein. IKS03 targets this CD19 protein to attack cancer cells and has demonstrated strong effects in aggressive B-cell lymphoma models. This trial includes various treatment arms where participants with different types of B-cell lymphoma will receive IKS03. While these early results are promising, further research is needed to confirm its safety and effectiveness in people. ^{1 4 6 7 8}

Who Is on the Research Team?

Paul I Nadler, MD

Principal Investigator

Iksuda Therapeutics

Are You a Good Fit for This Trial?

Adults over 18 with advanced B cell non-Hodgkin lymphoma, excluding certain types like Burkitt lymphoma. They must have tried at least two other treatments without success and need further therapy but not immediate cytoreduction. Participants should be in a stable condition (ECOG status 0 or 1) and willing to use effective contraception.

Inclusion Criteria

I agree to a bone marrow biopsy if my B cell NHL shows a complete response.

My lymphoma is B cell type and CD19-positive.

My lymphoma is B cell type but not Burkitt, Waldenström, or CLL, and it's CD19-positive.

Exclusion Criteria

I haven't had cancer in the past 2 years, except for certain treated or controlled types.

Any of the following laboratory abnormalities at baseline: Total bilirubin > 1.5 × upper limit of normal (ULN); > 3 × ULN if with Gilbert's Syndrome, AST or ALT > 3 × ULN; > 5 × ULN if due to hepatic involvement by tumor, Estimated GFR ≤ 60 mL/min corrected for BSA, Albuminuria defined as urine albumin to creatinine ratio < 30 mg/g or < 3 mg/mmol) by spot urine albumin

Patients with: Active thrombosis, or a history of deep vein thrombosis or pulmonary embolism, within 4 weeks unless adequately treated and stable, Active uncontrolled bleeding or a known bleeding diathesis, Significant cardiovascular disease or condition, including: Congestive heart failure or angina pectoris requiring therapy, Ventricular arrhythmia requiring therapy or other uncontrolled arrhythmia, Severe conduction disturbance (e.g., 3rd degree heart block), QTc interval ≥ 480 milliseconds, Left ventricular ejection fraction below the lower limit of normal or < 50% by MUGA scan or echocardiogram, Class III or IV cardiovascular disease according to the New York Heart Association Functional Classification, History of acute coronary syndromes (e.g., MI, unstable angina), coronary angioplasty, stenting, or bypass within 6 months, Significant liver disease, including: Non-infectious hepatitis, Hepatic cirrhosis (Child-Pugh Class C), Significant pulmonary disease or condition, including: Significant symptomatic COPD, as assessed by the Investigator, History or any current evidence on imaging studies of interstitial lung disease, pulmonary fibrosis, History of pulmonary inflammatory disease, pneumonitis, ARDS, History of pneumonia within 6 months, Significant corneal disease or condition, including history of or current evidence of keratitis, Known HIV infection or AIDS, Active hepatitis B virus or hepatitis C virus infection, Any other serious/active/uncontrolled infection, any infection requiring parenteral antibiotics, or unexplained fever > 38ºC within 2 weeks, Unresolved Grade > 1 AE associated with any prior antineoplastic therapy (except persistent Grade 2 alopecia, peripheral neuropathy, decreased hemoglobin, neutropenia, lymphopenia, hypomagnesemia, and/or endocrine end-organ failure being adequately managed by HRT), Known or suspected hypersensitivity to any of the excipients of formulated study drug, Inadequate recovery from a surgical procedure, or a major surgical procedure within 4 weeks, Any other serious, life-threatening, or unstable preexisting medical condition, including significant organ system dysfunction, or clinically significant laboratory abnormality(ies), A psychiatric disorder or altered mental status that would preclude understanding of the informed consent process

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Evaluate the safety and tolerability of increasing dose levels of IKS03 to establish a recommended dose for expansion (RDE)

21-day cycles, up to 20 months

Visits on Day 1 of each cycle

Dose Expansion

Further evaluate the safety, pharmacokinetics/pharmacodynamics, and efficacy of IKS03 at the RDE

21-day cycles, up to 42 months

Visits on Day 1 of each cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• IKS03

Trial Overview IKS03, an experimental drug targeting CD19 on cancer cells, is being tested for safety, tolerability, dosage levels, effectiveness against the cancer, immune response it may cause, and how the body processes it.

How Is the Trial Designed?

Group I: Dose Expansion: Other B cell lymphoma (B-NHL not otherwise specified [NOS]) Experimental Treatment 1 Intervention

Each patient will receive IKS03 at the recommended dose for expansion (RDE) defined in Part 1 on Day 1 of each 21-day cycle. Participants may continue on study until disease progression, unacceptable toxicity, or other withdrawal criteria is met.

Group II: Dose Expansion: Mantle Cell Lymphoma Participants Experimental Treatment 1 Intervention

Each patient will receive IKS03 at the recommended dose for expansion (RDE) defined in Part 1 on Day 1 of each 21-day cycle. Participants may continue on study until disease progression, unacceptable toxicity, or other withdrawal criteria is met.

Group III: Dose Expansion: Follicular Cell Lymphoma Participants Experimental Treatment 1 Intervention

Each patient will receive IKS03 at the recommended dose for expansion (RDE) defined in Part 1 on Day 1 of each 21-day cycle. Participants may continue on study until disease progression, unacceptable toxicity, or other withdrawal criteria is met.

Group IV: Dose Expansion: Diffuse-Large B-Cell Lymphoma Participants Experimental Treatment 1 Intervention

Each patient will receive IKS03 at the recommended dose for expansion (RDE) defined in Part 1 on Day 1 of each 21-day cycle. Participants may continue on study until disease progression, unacceptable toxicity, or other withdrawal criteria is met.

Group V: Dose Escalation Cohort (Part 1) Experimental Treatment 1 Intervention

Each patient will receive repeat doses (by intravenous (IV) infusions) on Day 1 of each 21-day cycle. Participants may continue on study until disease progression, unacceptable toxicity, or other withdrawal criteria is met.

Who Is Running the Clinical Trial?

Iksuda Therapeutics Ltd.

Lead Sponsor

Trials

2

Recruited

310+

Published Research Related to This Trial

KA2237, a dual inhibitor of p110β and p110δ, showed promising efficacy in treating various types of B cell lymphomas, achieving an overall response rate of 37% in a phase I study with 21 patients.

While KA2237 demonstrated the ability to induce objective responses, it also had a high incidence of treatment-related adverse events, with 86% of patients experiencing side effects, leading to a 33% discontinuation rate due to these adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preclinical and phase I studies of KA2237, a selective and potent inhibitor of PI3K β/δ in relapsed refractory B cell lymphoma. Nastoupil, LJ., Neelapu, SS., Davis, RE., et al.[2022]

NK cells expressing high levels of KIR2DS2 show enhanced activation against various cancer cells, suggesting that KIR2DS2 is a marker for more effective anticancer activity.

The study indicates that KIR2DS2+ NK cells have increased cytotoxic capabilities and may be a promising target for developing NK cell-based therapies against hematological and solid tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

KIR2DS2 Expression Identifies NK Cells With Enhanced Anticancer Activity. Blunt, MD., Vallejo Pulido, A., Fisher, JG., et al.[2023]

In a study of 353 lymphoma cases, BCL-3 expression was found in 6% of B-cell lymphomas and 23% of T/NK-cell lymphomas, suggesting its potential role in the development of these cancers.

Notably, 41% of Hodgkin lymphomas tested positive for BCL-3, indicating that targeting BCL-3 could be a promising strategy for new therapies in certain lymphoma types.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunohistochemical detection of BCL-3 in lymphoid neoplasms: a survey of 353 cases. Canoz, O., Rassidakis, GZ., Admirand, JH., et al.[2023]

BCL3 is frequently targeted by growth-promoting cytokines in myeloma cells, and its increased expression is linked to enhanced cell proliferation.

In a study of 351 newly diagnosed myeloma patients, high levels of BCL3 expression were associated with a poorer 5-year survival rate, suggesting its potential role as an oncogene and a prognostic marker in multiple myeloma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High expression of BCL3 in human myeloma cells is associated with increased proliferation and inferior prognosis. Brenne, AT., Fagerli, UM., Shaughnessy, JD., et al.[2021]

BCL3 rearrangement (BCL3-R) in lymphoid neoplasms is associated with two distinct clinical entities based on the location of the breakpoints, with upstream breakpoints leading to overexpression of BCL3 and linked to atypical chronic lymphocytic leukemia (CLL) features.

Downstream breakpoints of BCL3-R are associated with marginal zone lymphomas (MZL) and exhibit different genomic and clinical characteristics, including mutated IGHV and complex karyotypes, highlighting the importance of breakpoint location in determining the type and behavior of the neoplasm.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

BCL3-rearrangements in B-cell lymphoid neoplasms occur in two breakpoint clusters associated with different diseases. Carbo-Meix, A., Guijarro, F., Wang, L., et al.[2023]

Transgenic mice overexpressing the BCL3 gene showed normal development but exhibited splenomegaly and an accumulation of mature B cells, indicating that BCL3 may play a role in B cell proliferation and immune response.

Despite the observed immune system hyperactivity and changes in antibody levels, no lymphoid neoplasms were found in these transgenic mice, suggesting that while BCL3 overexpression contributes to B cell expansion, it may not directly lead to cancer in this model.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lymphadenopathy, splenomegaly, and altered immunoglobulin production in BCL3 transgenic mice. Ong, ST., Hackbarth, ML., Degenstein, LC., et al.[2019]

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 study investigated the role of KIR3DL1 and KIR3DS1 genotypes in the pathogenesis of endemic Burkitt lymphoma (eBL) among 108 eBL patients and 99 healthy controls in Kenya, finding no significant differences in genotype frequencies between the two groups.

The results suggest that variations in KIR3DL1 and KIR3DS1 genotypes are not major contributors to eBL development, although the complexity of the KIR3DL1 locus means that other genetic factors, such as copy number variations, could still play a role.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of KIR3DL1/KIR3DS1 allelic polymorphisms in Kenyan children with endemic Burkitt lymphoma. Muriuki, BM., Forconi, CS., Kirwa, EK., et al.[2023]

IMP-3 is primarily expressed in germinal center B cells of normal lymphoid tissue, but is overexpressed in various lymphoid neoplasms, particularly in Hodgkin lymphoma where 100% of cases showed positive staining.

The presence of IMP-3 in lymphoid neoplasms, especially in Hodgkin and Burkitt lymphomas, suggests a potential diagnostic or therapeutic role, although its expression is less pronounced in other lymphoma types.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

IMP-3 is differentially expressed in normal and neoplastic lymphoid tissue. King, RL., Pasha, T., Roullet, MR., et al.[2019]

The combination of umbralisib (a PI3K-δ inhibitor) and ublituximab (an anti-CD20 monoclonal antibody) was well tolerated in patients with chronic lymphocytic lymphoma (CLL) and non-Hodgkin lymphoma (NHL), with only one dose-limiting toxicity observed and low rates of severe side effects.

The overall response rate to the U2 combination therapy was 46%, with a median duration of response of 20 months, indicating promising preliminary efficacy that supports further research.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ublituximab and umbralisib in relapsed/refractory B-cell non-Hodgkin lymphoma and chronic lymphocytic leukemia. Lunning, M., Vose, J., Nastoupil, L., et al.[2021]

In a study of 23 leukemia patients undergoing cord blood transplantation (CBT), those with a mismatch between killer cell immunoglobulin receptor (KIR) and HLA-C showed higher engraftment (65%) and overall survival rates (70%) compared to matched groups (50% for both).

The presence of homo-expression of HLA-Cw1 or Cw2 also correlated with better outcomes, while co-expression of KIR2DL2 and KIR2DS2 was associated with disease-free survival, highlighting the importance of KIR in predicting CBT success.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Killer cell immunoglobulin receptor plays an important role in cord blood transplantation for leukemia]. Zhang, X., Liu, KY., Lu, DP.[2007]

INCB040093 is a novel small-molecule inhibitor of PI3Kδ that shows strong selectivity and efficacy in inhibiting B cell functions, making it a promising candidate for treating B cell malignancies like Hodgkin's lymphoma.

In preclinical studies, INCB040093 not only inhibited tumor growth in models of non-Hodgkin's lymphoma but also enhanced the effectiveness of the chemotherapy drug bendamustine, indicating its potential as a valuable addition to cancer treatment regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

INCB040093 Is a Novel PI3K&#948; Inhibitor for the Treatment of B Cell Lymphoid Malignancies. Shin, N., Li, YL., Mei, S., et al.[2019]

The phase 1 trial of IPH2101, an anti-KIR antibody, demonstrated safety and tolerability in 32 patients with relapsed/refractory multiple myeloma, achieving full KIR2D occupancy without dose-limiting toxicity.

Although no objective responses were observed, IPH2101 enhanced the cytotoxicity of patient-derived NK cells against multiple myeloma cells, indicating potential for further development in treating this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase 1 trial of the anti-KIR antibody IPH2101 in patients with relapsed/refractory multiple myeloma. Benson, DM., Hofmeister, CC., Padmanabhan, S., et al.[2021]

The novel IKK2 inhibitor LY2409881 effectively inhibits tumor growth and induces apoptosis in lymphoma cells by targeting the NF-κB pathway, demonstrating significant activity in preclinical models, including a xenograft mouse model.

LY2409881 shows a safe profile in mice at various doses (50, 100, and 200 mg/kg) and exhibits marked synergy when combined with the HDAC inhibitor romidepsin, suggesting a promising new treatment strategy for B- and T-cell lymphoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The novel IKK2 inhibitor LY2409881 potently synergizes with histone deacetylase inhibitors in preclinical models of lymphoma through the downregulation of NF-κB. Deng, C., Lipstein, M., Rodriguez, R., et al.[2021]

Treatment with IPH2101, aimed at enhancing natural killer (NK) cell function in smoldering multiple myeloma, unexpectedly led to a reduction in NK cell function due to a process called monocyte trogocytosis.

This finding suggests that while IPH2101 was designed to block inhibitory KIRs to boost NK cell activity, it may have the opposite effect, highlighting the complexity of immune responses in cancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting KIR Blockade in Multiple Myeloma: Trouble in Checkpoint Paradise? Felices, M., Miller, JS.[2021]

Citations

1. ashpublications.org ashpublications.org/blood/article/140/Supplement%201/3134/487274/IKS03-a-Next-Generation-CD19-Targeted-Antibody

IKS03, a Next Generation CD19-Targeted Antibody Drug ... IKS03 was highly active yielding complete tumor regressions following a single dose of 0.3 mg/kg in a refractory lymphoma Bcl2+ PDX model ...

2. iksuda.com iksuda.com/media/df1d3cws/2022-aacr-iks03-poster-1755.pdf

IKS03, a CD19-targeted antibody drug conjugate with ... No neutropenia or lymphocytopenia was noted. Reduced B-cell depletion was noted for IKS03 as compared to data from comparator agents5, even at doses much ...

3. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0006497123096970

A Phase 1 Cohort Dose Escalation and Expansion Trial to ... In preclinical studies, IKS03 demonstrated significant in vivo efficacy with complete tumor regressions in CD19-positive diffuse large B-cell ...

4. pharmaceutical-technology.com pharmaceutical-technology.com/data-insights/iks-03-iksuda-therapeutics-b-cell-non-hodgkin-lymphoma-likelihood-of-approval/

IKS-03 by Iksuda Therapeutics for B-Cell Non-Hodgkin ... According to GlobalData, Phase I drugs for B-Cell Non-Hodgkin Lymphoma have a 72% phase transition success rate (PTSR) indication benchmark for ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10887180/

Innovations in Antibody-Drug Conjugate (ADC) ... A phase I trial showed higher efficacy when used as monotherapy compared to its use in combination with rituximab, where the DLBCL group had an ...

6. ashpublications.org ashpublications.org/blood/article/142/Supplement%201/3095/499509/A-Phase-1-Cohort-Dose-Escalation-and-Expansion

A Phase 1 Cohort Dose Escalation and Expansion Trial to ... In preclinical studies, IKS03 demonstrated significant in vivo efficacy with complete tumor regressions in CD19-positive diffuse large B-cell ...

7. sciencedirect.com sciencedirect.com/science/article/pii/S0006497123096970

A Phase 1 Cohort Dose Escalation and Expansion Trial to ... In preclinical studies, IKS03 demonstrated significant in vivo efficacy with complete tumor regressions in CD19-positive diffuse large B-cell lymphoma (DLBCL), ...

8. withpower.com withpower.com/trial/phase-1-lymphoma-non-hodgkin-6-2022-fd80c

IKS03 for B-Cell Lymphoma What safety data exists for IKS03 in humans? The safety data for IKS03, also known as umbralisib, shows that it was generally well tolerated in combination ...