IKS03 in Patients With Advanced B Cell Non-Hodgkin Lymphomas

Study Overview
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Brief Summary
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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).

Detailed Description
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The study will consist of 2 parts: dose-escalation (Part 1) and dose-expansion (Part 2). The dose-escalation part (Part 1) of the study is to evaluate the safety and tolerability of increasing dose levels of IKS03 to establish a recommended dose for expansion (RDE); and the dose-expansion part (Part 2) of the study is to further evaluate the safety, pharmacokinetics/pharmacodynamics, and efficacy of IKS03 at the RDE.

Official Title
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A Phase 1 Cohort Dose Escalation and Expansion Trial to Determine the Safety, Tolerance, Maximum Tolerated Dose, and Preliminary Antineoplastic Activity of IKS03 in Patients With Advanced B Cell Non-Hodgkin Lymphomas (NHL)

Conditions
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B-cell Non-Hodgkin Lymphoma, Diffuse Large B Cell Lymphoma, Follicular Lymphoma, Mantle Cell Lymphoma, B-cell Lymphoma

Intervention / Treatment
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* Drug: IKS03


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males or females, ≥ 18 years of age Part 1: documented B cell NHL (any subtype except Burkitt lymphoma, Waldenström macroglobulinemia, chronic lymphocytic leukemia); previously confirmed CD19-positive if feasible Part 2: documented B cell NHL (subtypes to be determined); confirmed CD19-positive; possible expansion cohorts may include: Diffuse large B cell lymphoma (including germinal center B cell type, activated B cell type) Follicular lymphoma (including duodenal-type follicular lymphoma) Mantle cell lymphoma B cell lymphomas not specified If B cell NHL subtype likely to have bone marrow involvement must be willing to undergo bone marrow biopsy in the event of an on-study complete response to confirm response NHL that is relapsed, refractory to, or intolerant of existing therapy(ies) with known curative potential, or for which no standard therapy is available; must have received at least 2 prior lines of systemic therapy Must be in need of systemic treatment and not require immediate cytoreductive therapy Part 1: measurable or non-measurable disease Part 2: measurable disease according to The Revised Criteria/Lugano Classification Part 1: screening tumor biopsy requested, but optional; Part 2: patient must agree to screening tumor biopsy ECOG performance status 0 or 1; anticipated life expectancy ≥ 10 weeks Women of childbearing potential and fertile men agreeing to use two effective methods of contraception (including a highly effective method of contraception); women beginning 2 weeks prior to the first dose, men beginning prior to the first dose, and both continuing until 6 months after the last dose of study drug; male patients must also agree to refrain from sperm donation during this period. Ability to understand and give written informed consent Exclusion Criteria: Women who are pregnant or intending to become pregnant before, during, or within 6 months after the last dose of study drug; women who are breastfeeding. Central nervous system (CNS) lymphoma, leptomeningeal infiltration, or spinal cord compression not controlled by prior surgery or radiotherapy; symptoms suggesting CNS involvement Part 2: History of another malignancy within 2 years, with the exception of: Treated, non-melanoma skin cancers Treated carcinoma in situ (e.g., breast, cervix) Controlled, superficial carcinoma of the urinary bladder T1a or b prostate carcinoma treated according to standard of care, with PSA within normal limits Papillary thyroid carcinoma Stage I treated surgically for cure Any of the following hematologic abnormalities at baseline (transfusion allowed > 5 days previous): Hemoglobin < 8.0 g/dL Absolute neutrophil count < 1,000 per mm3 Platelet count < 75,000 per mm3 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 Any of the following coagulation parameter abnormalities at baseline unless on a stable dose of anticoagulant therapy for a prior thrombotic event: PT or INR > 1.5 × ULN; > 3× ULN if anticoagulated) PTT > 1.5 × ULN; > 3× ULN if anticoagulated 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 Drugs and Other Treatments to be Excluded: Receipt of: Any CD19-targeted therapy within 3 months Any tumor vaccine within 6 weeks (must have progressed if previously received) Prior autologous/allogeneic CAR-T therapy if known to be CD19-negative after Any other antineoplastic agent for the primary malignancy without delayed toxicity within 4 weeks or 5 plasma half-lives, whichever is shortest (except nitrosoureas and mitomycin C within 6 weeks) Any other investigational treatments within 4 weeks Drugs known to impair renal function, including: NSAIDS within 3 days Aminoglycoside antibiotics, amphotericin B, etc. within 1 week Bisphosphonates within 1 month Autologous hematopoietic stem cell transplantation (HSCT) within 3 months Allogeneic HSCT within 6 months, or: If receiving immunosuppression If with active evidence of GVHD Radiotherapy: To target lesions within 4 weeks unless progression of the lesion has been documented To non-target lesions within 1 week Live/live-attenuated vaccines against infectious diseases within 4 weeks Immunosuppressive or systemic glucocorticoid therapy (> 10 mg prednisone daily or equivalent) within 2 weeks Prophylactic use of hematopoietic growth factors within 1 week

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Escalation Cohort (Part 1)<br>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. | Drug: IKS03<br>* IKS03 is a human monoclonal antibody (Ab) targeting CD19 linked to a pyrrolobenzodiazepine (PBD) pro-drug as the cytotoxic agent.<br>|
| Experimental: Dose Expansion: Diffuse-Large B-Cell Lymphoma Participants<br>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. | Drug: IKS03<br>* IKS03 is a human monoclonal antibody (Ab) targeting CD19 linked to a pyrrolobenzodiazepine (PBD) pro-drug as the cytotoxic agent.<br>|
| Experimental: Dose Expansion: Follicular Cell Lymphoma Participants<br>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. | Drug: IKS03<br>* IKS03 is a human monoclonal antibody (Ab) targeting CD19 linked to a pyrrolobenzodiazepine (PBD) pro-drug as the cytotoxic agent.<br>|
| Experimental: Dose Expansion: Mantle Cell Lymphoma Participants<br>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. | Drug: IKS03<br>* IKS03 is a human monoclonal antibody (Ab) targeting CD19 linked to a pyrrolobenzodiazepine (PBD) pro-drug as the cytotoxic agent.<br>|
| Experimental: Dose Expansion: Other B cell lymphoma (B-NHL not otherwise specified [NOS])<br>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. | Drug: IKS03<br>* IKS03 is a human monoclonal antibody (Ab) targeting CD19 linked to a pyrrolobenzodiazepine (PBD) pro-drug as the cytotoxic agent.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recommended Dose for Expansion (Part 1) | RDE will be determined using dose limiting toxicities (DLTs) and all other available study data | Up to 20 months | 
| Objective Response Rate (Part 2) | Antineoplastic effects will be assessed by Criteria for Response Assessment: The Lugano Classification (Cheson 2014) | up to 42 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluation of the immunogenicity of IKS03 (Part 1 and 2) | Occurrence of ADA measured in serum at selected timepoints during the study | Up to 42 months | 
| Plasma Concentrations of IKS03 (Part 1 and 2) | Pharmacokinetic profile will be characterized by concentrations of IKS03 | Up to 42 months | 
| Determine recommended Phase 2 dose (RP2D) (Part 2) | Based on evidence of antitumor activity, acceptable tolerability, evidence of achieving target plasma concentration | Up to 42 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CD19, non-Hodgkin lymphoma, NHL, DLBCL, MCL, advance lymphoma, IKS03, lymphoma