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)
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 140
- 试验地点
- 15
- 主要终点
- Recommended Dose for Expansion (Part 1)
研究概览
简要总结
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).
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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)
- 另有 28 项未显示
研究组 & 干预措施
Dose Expansion: Other B cell lymphoma (B-NHL not otherwise specified [NOS])
Each patient will receive IKS03 at the RP2D defined in Part I on Day 1 of each 21-day cycle. Participants may continue on study until disease progression, unacceptable toxicity, or other withdrawal criterion is met.
干预措施: IKS03 (Drug)
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 criterion is met.
干预措施: IKS03 (Drug)
Dose Expansion: Follicular Cell Lymphoma Participants
Each patient will receive IKS03 at the RP2D defined in Part I on Day 1 of each 21-day cycle. Participants may continue on study until disease progression, unacceptable toxicity, or other withdrawal criterion is met.
干预措施: IKS03 (Drug)
Dose Expansion: Mantle Cell Lymphoma Participants
Each patient will receive IKS03 at the RP2D defined in Part I on Day 1 of each 21-day cycle. Participants may continue on study until disease progression, unacceptable toxicity, or other withdrawal criterion is met.
干预措施: IKS03 (Drug)
Dose Expansion: Diffuse-Large B-Cell Lymphoma Participants
Each patient will receive IKS03 at the RP2D defined in Part I on Day 1 of each 21-day cycle. Participants may continue on study until disease progression, unacceptable toxicity, or other withdrawal criterion is met.
干预措施: IKS03 (Drug)
结局指标
主要结局
Recommended Dose for Expansion (Part 1)
时间窗: Up to 20 months
RDE will be determined using dose limiting toxicities (DLTs) and all other available study data
Objective Response Rate (Part 2)
时间窗: up to 42 months
Antineoplastic effects will be assessed by Criteria for Response Assessment: The Lugano Classification (Cheson 2014)
Recommended Phase 2 Dose (Part I)
时间窗: Up to 20 months
RP2D will be determined using dose limiting toxicities (DLTs) and all other available study data
Objective Response Rate (Part II)
时间窗: up to 42 months
Antineoplastic effects will be assessed by Criteria for Response Assessment: The Lugano Classification (Cheson 2014)
次要结局
- Evaluation of the immunogenicity of IKS03 (Part 1 and 2)(Up to 42 months)
- Plasma Concentrations of IKS03 (Part 1 and 2)(Up to 42 months)
- Determine recommended Phase 2 dose (RP2D) (Part 2)(Up to 42 months)
- Evaluation of the immunogenicity of IKS03 (Part I and II)(Up to 42 months)
- Plasma Concentrations of IKS03 (Part I and II)(Up to 42 months)
- Determine recommended Phase 2 dose (RP2D) (Part II)(Up to 42 months)