IKS03 in Patients With Advanced B Cell Non-Hodgkin Lymphomas

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)

Overview

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

The study will consist of 2 parts: dose-escalation (Part I) and dose-expansion (Part II). The dose-escalation part (Part I) of the study is to evaluate the safety and tolerability of increasing dose levels of IKS03 to establish a recommended Phase 2 dose (RP2D); and the dose-expansion part (Part II) of the study is to further evaluate the safety, pharmacokinetics/pharmacodynamics, and efficacy of IKS03 at the RP2D.

Interventions

• Drug IKS03
  IKS03 is a human monoclonal antibody (Ab) targeting CD19 linked to a pyrrolobenzodiazepine (PBD) pro-drug as the cytotoxic agent.

Primary outcome measures

• Recommended Phase 2 Dose (Part I) [Time frame: Up to 20 months]
• Objective Response Rate (Part II) [Time frame: up to 42 months]

Secondary outcome measures (3)

• Evaluation of the immunogenicity of IKS03 (Part I and II) [Time frame: Up to 42 months]
• Plasma Concentrations of IKS03 (Part I and II) [Time frame: Up to 42 months]
• Determine recommended Phase 2 dose (RP2D) (Part II) [Time frame: Up to 42 months]

Eligibility criteria

Inclusion criteria

• Males or females, ≥ 18 years of age
• Part I: documented B cell NHL (any subtype except Burkitt lymphoma, Waldenström macroglobulinemia, chronic lymphocytic leukemia); previously confirmed CD19-positive if feasible
• Part II: 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 I: measurable or non-measurable disease
• Part II: measurable disease according to The Revised Criteria/Lugano Classification
• Part I: screening tumor biopsy requested, but optional; Part 2: patient must agree to screening tumor biopsy
• ECOG performance status 0 or 1
• 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 8 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 8 months after the last dose of study drug; women who are breastfeeding
• Patients documented to be CD19-negative
• 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
• Any of the following laboratory abnormalities at baseline aimed at assessing renal function:

• Estimated glomerular filtration rate (eGFR) ≤ 60 mL/min, corrected for BSA.
• Albuminuria defined as urine albumin to creatinine ratio (UACR) ≥ 45 mg/g or ≥ 4.5 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 B and 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 1 month
• Significant corneal disease or condition, including history of or current evidence of keratitis
• Clinically significant CNS disease or condition including PML, epilepsy, vasculitis, or neurodegenerative disease. Also including TIA or stroke within 6 months
• 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
• Autoimmune disease or condition requiring systemic steroids or other immunosuppressive medications
• 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 4 weeks
• 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 3 weeks or 5 plasma half-lives, whichever is shortest (except nitrosoureas and mitomycin C within 6 weeks)
• Any other investigational treatments within 3 weeks
• Drugs known to impair renal function, including:

• NSAIDS within 3 days
• Aminoglycoside antibiotics, amphotericin B, etc. within 1 week
• Bisphosphonates within 1 month
• Prior solid organ transplant
• Allogeneic HSCT within 6 months, or:

• If receiving immunosuppression
• If with active evidence of GVHD
• Autologous hematopoietic stem cell transplantation (HSCT) within 3 months
• 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
• Herbal therapies and supplements within 2 weeks
• Strong inhibitors of cytochrome P450 within 2 weeks

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Sequential

Masking

Open label

Primary purpose

Treatment

Study locations

Australia · 4 centers

• Westmead Hospital — Westmead
• Royal Adelaide Hospital — Adelaide
• Royal Hobart Hospital — Hobart
• Linear Clinical Research — Perth

Italy · 4 centers

• Istituto Nazionale Oncologico Candiolo — Candiolo
• Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ospedale San Raffaele — Milan
• Istituto Europeo Clinico Humanitas — Milan
• Istituto Europeo di Oncologia — Milan

Spain · 3 centers

• Institut Catala D&#39;Oncologia — Badalona
• Hospital Universitario Quironsalud Madrid — Madrid
• Hospital Clinico Universitario de Salamanca — Salamanca

United States · 1 center

• University of Maryland Baltimore — Baltimore

Canada · 1 center

• Jewish General Hospital — Montreal

Identifiers

NCT: NCT05365659 · IKS03-01

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗