Clinical trial NCT05365659: 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)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: B-cell Non-Hodgkin Lymphoma
Diffuse Large B Cell Lymphoma
Follicular Lymphoma
Mantle Cell Lymphoma
B-cell Lymphoma
Keywords: CD19
non-Hodgkin lymphoma
NHL
DLBCL
MCL
advance lymphoma
IKS03
lymphoma
Lead sponsor: Iksuda Therapeutics Ltd.
Sponsor class: INDUSTRY
First posted: 2022-05-09
Enrollment: 140
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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).

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.

Eligibility criteria: Inclusion Criteria:

1. Males or females, ≥ 18 years of age
2. Part 1: documented B cell NHL (any subtype except Burkitt lymphoma, Waldenström macroglobulinemia, chronic lymphocytic leukemia); previously confirmed CD19-positive if feasible
3. Part 2: documented B cell NHL (subtypes to be determined); confirmed CD19-positive; possible expansion cohorts may include:

   1. Diffuse large B cell lymphoma (including germinal center B cell type, activated B cell type)
   2. Follicular lymphoma (including duodenal-type follicular lymphoma)
   3. Mantle cell lymphoma
   4. B cell lymphomas not specified
4. 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
5. 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
6. Must be in need of systemic treatment and not require immediate cytoreductive therapy
7. Part 1: measurable or non-measurable disease
8. Part 2: measurable disease according to The Revised Criteria/Lugano Classification
9. Part 1: screening tumor biopsy requested, but optional; Part 2: patient must agree to screening tumor biopsy
10. ECOG performance status 0 or 1; anticipated life expectancy ≥ 10 weeks
11. 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.
12. Ability to understand and give written informed consent

Exclusion Criteria:

1. 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
2. Patients documented to be CD19-negative
3. Central nervous system (CNS) lymphoma, leptomeningeal infiltration, or spinal cord compression not controlled by prior surgery or radiotherapy; symptoms suggesting CNS involvement
4. Part 2: History of another malignancy within 2 years, with the exception of:

   1. Treated, non-melanoma skin cancers
   2. Treated carcinoma in situ (e.g., breast, cervix)
   3. Controlled, superficial carcinoma of the urinary bladder
   4. T1a or b prostate carcinoma treated according to standard of care, with PSA within normal limits
   5. Papillary thyroid carcinoma Stage I treated surgically for cure
5. Any of the following hematologic abnormalities at baseline (transfusion allowed \> 5 days previous):

   1. Hemoglobin \< 8.0 g/dL
   2. Absolute neutrophil count \< 1,000 per mm3
   3. Platelet count \< 75,000 per mm3
6. Any of the following laboratory abnormalities at baseline:

   1. Total bilirubin \> 1.5 × upper limit of normal (ULN); \> 3 × ULN if with Gilbert's Syndrome
   2. AST or ALT \> 3 × ULN; \> 5 × ULN if due to hepatic involvement by tumor
   3. Estimated GFR ≤ 60 mL/min corrected for BSA
   4. Albuminuria defined as urine albumin to creatinine ratio \< 30 mg/g or \< 3 mg/mmol) by spot urine albumin
7. Any of the following coagulation parameter abnormalities at baseline unless on a stable dose of anticoagulant therapy for a prior thrombotic event:

   1. PT or INR \> 1.5 × ULN; \> 3× ULN if anticoagulated)
   2. PTT \> 1.5 × ULN; \> 3× ULN if anticoagulated
8. Any of the following laboratory abnormalities at baseline aimed at assessing renal function:

   1. Estimated glomerular filtration rate (eGFR) ≤ 60 mL/min, corrected for BSA.
   2. Albuminuria defined as urine albumin to creatinine ratio (UACR) ≥ 30 mg/g or ≥ 3 mg/mmol by spot urine albumin
9. Patients with:

   1. Active thrombosis, or a history of deep vein thrombosis or pulmonary embolism, within 4 weeks unless adequately treated and stable
   2. Active uncontrolled bleeding or a known bleeding diathesis
10. Significant cardiovascular disease or condition, including:

    1. Congestive heart failure or angina pectoris requiring therapy
    2. Ventricular arrhythmia requiring therapy or other uncontrolled arrhythmia
    3. Severe conduction disturbance (e.g., 3rd degree heart block)
    4. QTc interval ≥ 480 milliseconds
    5. Left ventricular ejection fraction below the lower limit of normal or \< 50% by MUGA scan or echocardiogram
    6. Class III or IV cardiovascular disease according to the New York Heart Association Functional Classification
    7. History of acute coronary syndromes (e.g., MI, unstable angina), coronary angioplasty, stenting, or bypass within 6 months
11. Significant liver disease, including:

    1. Non-infectious hepatitis
    2. Hepatic cirrhosis (Child-Pugh Class B and Class C)
12. Significant pulmonary disease or condition, including:

    1. Significant symptomatic COPD, as assessed by the Investigator
    2. History or any current evidence on imaging studies of interstitial lung disease, pulmonary fibrosis
    3. History of pulmonary inflammatory disease, pneumonitis, ARDS
    4. History of pneumonia within 6 months
13. Significant corneal disease or condition, including history of or current evidence of keratitis
14. Clinically significant CNS disease or condition including PML, epilepsy, vasculitis, or neurodegenerative disease. Also including TIA or stroke within 6 months
15. Known HIV infection or AIDS
16. Active hepatitis B virus or hepatitis C virus infection
17. Any other serious/active/uncontrolled infection, any infection requiring parenteral antibiotics, or unexplained fever \> 38ºC within 2 weeks
18. Autoimmune disease or condition requiring systemic steroids or other immunosuppressive medications
19. 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)
20. Known or suspected hypersensitivity to any of the excipients of formulated study drug
21. Inadequate recovery from a surgical procedure, or a major surgical procedure within 4 weeks
22. Any other serious, life-threatening, or unstable preexisting medical condition, including significant organ system dysfunction, or clinically significant laboratory abnormality(ies)
23. A psychiatric disorder or altered mental status that would preclude understanding of the informed consent process

Drugs and Other Treatments to be Excluded:

1. Receipt of:

   1. Any CD19-targeted therapy within 3 months
   2. Any tumor vaccine within 6 weeks (must have progressed if previously received)
2. Prior autologous/allogeneic CAR-T therapy if known to be CD19-negative after
3. 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)
4. Any other investigational treatments within 4 weeks
5. Drugs known to impair renal function, including:

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

   1. If receiving immunosuppression
   2. If with active evidence of GVHD
8. Autologous hematopoietic stem cell transplantation (HSCT) within 3 months
9. Radiotherapy:

   1. To target lesions within 4 weeks unless progression of the lesion has been documented
   2. To non-target lesions within 1 week
10. Live/live-attenuated vaccines against infectious diseases within 4 weeks
11. Immunosuppressive or systemic glucocorticoid therapy (\> 10 mg prednisone daily or equivalent) within 2 weeks
12. Prophylactic use of hematopoietic growth factors within 1 week
13. Herbal therapies and supplements within 2 weeks
14. Strong inhibitors of cytochrome P450 within 2 weeks

Primary outcomes:
measure: Recommended Dose for Expansion (Part 1)
timeFrame: Up to 20 months
measure: Objective Response Rate (Part 2)
timeFrame: up to 42 months
Secondary outcomes:
measure: Evaluation of the immunogenicity of IKS03 (Part 1 and 2)
timeFrame: Up to 42 months
measure: Plasma Concentrations of IKS03 (Part 1 and 2)
timeFrame: Up to 42 months
measure: Determine recommended Phase 2 dose (RP2D) (Part 2)
timeFrame: Up to 42 months
Other outcomes:
Locations:
city: Baltimore
country: United States
facility: University of Maryland Baltimore
state: Maryland
city: Westmead
country: Australia
facility: Westmead Hospital
state: New South Wales
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital
state: South Australia
city: Perth
country: Australia
facility: Linear Clinical Research
state: Western Australia
city: Montréal
country: Canada
facility: Jewish General Hospital
state: Quebec
city: Candiolo
country: Italy
facility: La Fondazione e l'Istituto di Candiolo
city: Milano
country: Italy
facility: Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ospedale San Raffaele
city: Milano
country: Italy
facility: Istituto Europeo Clinico Humanitas
city: Milano
country: Italy
facility: Istituto Europeo di Oncologia
city: Badalona
country: Spain
facility: Institut Catala D&#39;Oncologia
city: Madrid
country: Spain
facility: Hospital Universitario Quironsalud Madrid
city: Salamanca
country: Spain
facility: Hospital Clinico Universitario de Salamanca
city: Valencia
country: Spain
facility: Hospital Universitari i Politecnic La Fe
Study officials:
affiliation: Iksuda Therapeutics
name: Paul I Nadler, MD
role: STUDY_DIRECTOR
References: