IKS03 for B-Cell Lymphoma

Recruiting at 12 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

Trial Summary

What is the purpose of this trial?

This first-in-human study will evaluate the recommended dose for further clinical development, safety, tolerability, antineoplastic activity, immunogenicity, pharmacokinetics and pharmacodynamics of IKS03, a CD19 targeting antibody-drug conjugate, in patients with advanced B cell non-Hodgkin lymphoma (NHL).

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.

What data supports the effectiveness of the treatment IKS03 for B-Cell Lymphoma?

Research shows that NK cells with high KIR2DS2 expression, which are involved in the immune response, have enhanced activity against B cell lymphoma. This suggests that targeting similar pathways could be effective in treating B-Cell Lymphoma. ^{1 2 3 4 5}

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 with ublituximab for B-cell lymphomas, with low instances of severe diarrhea, pneumonia, or liver toxicity. In another study, a similar compound, KA2237, showed that 86% of patients experienced treatment-related side effects, with 43% experiencing severe side effects like rash and pneumonia. ^{6 7 8 9 10}

What makes the drug IKS03 unique for treating B-cell lymphoma?

IKS03 is unique because it involves the BCL3 gene, which is part of the IkappaB family that regulates the NF-kappaB pathway, a key player in immune response and cell proliferation. This drug may target BCL3 overexpression, which is linked to the development of certain B-cell lymphomas, offering a novel approach compared to traditional treatments. ^{11 12 13 14 15}

Research Team

Paul I Nadler, MD

Principal Investigator

Iksuda Therapeutics

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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]

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]

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 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]

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]

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]

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]

References

1. China pubmed.ncbi.nlm.nih.gov

[Killer cell immunoglobulin receptor plays an important role in cord blood transplantation for leukemia]. [2007]

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

A phase 1 trial of the anti-KIR antibody IPH2101 in patients with relapsed/refractory multiple myeloma. [2021]

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

Targeting KIR Blockade in Multiple Myeloma: Trouble in Checkpoint Paradise? [2021]

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

Evaluation of KIR3DL1/KIR3DS1 allelic polymorphisms in Kenyan children with endemic Burkitt lymphoma. [2023]

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

KIR2DS2 Expression Identifies NK Cells With Enhanced Anticancer Activity. [2023]

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

Ublituximab and umbralisib in relapsed/refractory B-cell non-Hodgkin lymphoma and chronic lymphocytic leukemia. [2021]

7. United States 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. [2022]

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

INCB040093 Is a Novel PI3K&#948; Inhibitor for the Treatment of B Cell Lymphoid Malignancies. [2019]

9. United States 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. [2021]

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

Managing toxicities of Bruton tyrosine kinase inhibitors. [2023]

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

IMP-3 is differentially expressed in normal and neoplastic lymphoid tissue. [2019]

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

Immunohistochemical detection of BCL-3 in lymphoid neoplasms: a survey of 353 cases. [2023]

13. England pubmed.ncbi.nlm.nih.gov

High expression of BCL3 in human myeloma cells is associated with increased proliferation and inferior prognosis. [2021]

14. Italy pubmed.ncbi.nlm.nih.gov

BCL3-rearrangements in B-cell lymphoid neoplasms occur in two breakpoint clusters associated with different diseases. [2023]

15. England pubmed.ncbi.nlm.nih.gov

Lymphadenopathy, splenomegaly, and altered immunoglobulin production in BCL3 transgenic mice. [2019]