IKS03 in Patients With Advanced B Cell Non-Hodgkin Lymphomas

Sponsor

Iksuda Therapeutics Ltd. (Industry)

Overall Status

Not yet recruiting

CT.gov ID

NCT05365659

Collaborator

(none)

140

Enrollment

Arms

Anticipated Duration (Months)

Study Details

Study Description

Brief Summary

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).

Condition or Disease	Intervention/Treatment	Phase
B-cell Non-Hodgkin Lymphoma Diffuse Large B Cell Lymphoma Follicular Lymphoma Mantle Cell Lymphoma B-cell Lymphoma	Drug: IKS03	Phase 1

Detailed Description

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

140 participants

Allocation:

Non-Randomized

Intervention Model:

Sequential Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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)

Anticipated Study Start Date :

Jul 1, 2022

Anticipated Primary Completion Date :

Jul 1, 2024

Anticipated Study Completion Date :

Jul 1, 2026

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

Recommended Dose for Expansion (Part 1) [Up to 20 months]
RDE will be determined using dose limiting toxicities (DLTs) and all other available study data
Antineoplastic effect of IKS03 (Part 2) [up to 42 months]
Antineoplastic effects will be assessed by Criteria for Response Assessment: The Lugano Classification (Cheson 2014)

Secondary Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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 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
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/1.73 m2
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