An Open-label, Multi-centre, Phase I/II Study to Investigate the Safety, Tolerability, and Preliminary Efficacy of CN1 in Combination With CN401 in Adult Patients With Relapsed/Refractory Lymphoid Malignancies
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 7
- 试验地点
- 1
- 主要终点
- To evaluate the safety and tolerability of CN1 in combination with CN401 in patients with relapsed/refractory lymphoid malignancies through Incidence of Treatment-Emergent Adverse Events as assessed by CTCAE v5.0
研究概览
简要总结
The study is designed to investigate the safety, tolerability and preliminary efficacy in combination with CN1 and CN401 in adult patients with relapsed/refractory lymphoid malignancies.
详细描述
This is an open-label, multi-center, phase I/II study. The study includes two study drugs CN1 and CN401 and will be conducted in two parts: phase 1 and phase 2.
Phase I: Dose-finding study for the assessment of dose limiting toxicities (DLTs) at 3 or more dose levels in patients with advanced lymphoid malignancies.
Phase II: Expansion study to evaluate the preliminary efficacy of CN1 in combination with CN401 at the RP2D in parallel patient cohorts grouped by non-Hodgkin's Lymphoma (NHL) subtype.
There will 9-18 patients enrolled in the Phase 1 portion of the study and 15- 60 patients will be enrolled in Phase 2 - dosing determined by Phase 1.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 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
- •Age ≥ 18 years on the day of signing informed consent.
- •Based on pathology review at the local institution, using the most recent edition of the World Health Organization (WHO) Classification of Tumors of Hematopoietic and Lymphoid Tissues as guidance, leading to the diagnosis of one of the following diseases and their histological subtypes: PTCL, CTCL, and B-cell NHL.
- •Patients must have relapsed or refractory disease after at least one prior systemic anti-tumor treatment.
- •The patients enrolled in Phase II of the study should have received NOT more than five lines of prior systemic therapies.
- •Patients must have at least one evaluable lesion per Lugano 2014 Criteria. Measurable lesions are defined as those that can be accurately measured in at least two dimensions with conventional techniques (positron emission tomography/Computed tomography [PET/CT], magnetic resonance imaging [MRI]) or as > 1.5 cm with spiral CT scan. Patients with non-measurable lesions but assessable diseases (e.g., marrow disease without other radiographically measurable diseases) may be enrolled on a case-by-case basis in discussion with the Sponsor.
- •ECOG performance status 0 to
- •At least 3 months of expected survival.
- •Adequate organ functions, further defined as:
- •Hemoglobin ≥ 9 g/dL.
- •Absolute neutrophil count (ANC) ≥ 1 × 10E+09/L.
- •Platelets ≥ 50 × 10E+09/L (patient without bone marrow [BM] involvement) and ≥ 30 × 10E+09/L (patient with BM involvement).
- •Total bilirubin ≤ 1.5 times the upper limit of normal (ULN).
- •Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN if known liver involvement. The ALT and AST should be ≤ 1.5 × ULN in absence of liver involvement/metastasis.
- •Serum creatinine ≤ 2.0 mg/dL or calculated creatinine clearance ≥ 50 mL/min (as calculated by the Cockcroft-Gault method).
- •Activated partial thromboplastin time (APTT) or international normalized ratio (INR) ≤ 1.5 × ULN (unless patient is receiving anticoagulants).
排除标准
- •Received any anti-tumour treatment (i.e., chemotherapy, radiotherapy, immunotherapy, biologic therapy, endocrine therapy, etc.,) within four weeks (or five half-lives of the agent, whichever is shorter) prior to the first dose of study drugs, with the following exceptions:
- •Palliative radiation therapy within 2 weeks.
- •Oral small molecule targeted therapies within 2 weeks prior to the first dose of study drugs or within 5 half-lives of the drug, whichever is shorter.
- •Herbal medications within 7 days prior to the first dose.
- •Received other investigational agents (not yet approved by any regulatory agency) within four weeks prior to the first dose of any study drugs.
- •Immunosuppressive medication > 10 mg prednisolone per day or equivalent within 14 days prior to the first dose of the study drug. Note: Use of immunosuppressive medications as prophylaxis in subjects with contrast allergies are acceptable. In addition, temporary uses of corticosteroids considered non-clinically significant may be approved on a case-by-case basis in discussion with the Sponsor.
- •Known clinically active central nervous system (CNS) or meningeal involvement. In the absence of symptoms, investigation into CNS involvement is not required. Patients are eligible if metastases have been treated, patients are neurologically returned to baseline or neurologically stable for at least four weeks and not requiring steroid therapy for at least one week prior to Cycle 1 Day
- •Active infection and in current need of, or likely to need, intravenous (IV) anti-infective therapy.
- •History of immunodeficiency, including history of any positive test result for human immunodeficiency virus (HIV) antibody.
- •Patients who are known to be hepatitis B or C positive (positive HBsAg and/or detectable level of HBV DNA or positive HCV antibody).
- •Active Epstein Barr virus (EBV) unrelated to underlying lymphoma (positive serology for anti-EBV VCA IgM antibody and negative for anti-EBV EBNA IgG antibody, or clinical manifestations and positive EBV polymerase chain reaction [PCR] consistent with active EBV infection).
- •Active CMV (positive serology for anti-CMV IgM antibody, negative for anti-CMV IgG antibody, and positive CMV PCR with clinical manifestations consistent with active CMV infection) and requiring therapy.
- •Current history of a serious uncontrolled medical disorder, metabolic dysfunction, physical examination findings, or clinical laboratory findings giving reasonable suspicion of a disease or condition that contraindicates use of an investigational drug or render the patient at high risk from treatment complications.
研究组 & 干预措施
D (CN1 3mg/kg and CN401 800mg)
Patients were administered with CN1, 3mg/kg, once every three week in combination with 800mg CN401 twice a day, fasted.
Dosage/Route of admin: CN1- Intravenous Infusion(IV); CN401- Tablet, Oral
Three to six patients are expected to be enrolled in each arm
干预措施: CN1, 3mg/kg and CN401, 800mg (Drug)
A (CN1 0.5mg/kg and CN401 400mg)
Patients were administered with CN1, 0.5mg/kg, once every three week in combination with 400mg CN401 twice a day, fasted.
Dosage/Route of admin: CN1- Intravenous Infusion(IV); CN401- Tablet, Oral
Three to six patients are expected to be enrolled in each arm.
干预措施: CN1, 0.5mg/kg and CN401, 400mg (Drug)
B (CN1 1mg/kg and CN401 600mg)
Patients were administered with CN1, 1mg/kg, once every three week in combination with 600mg CN401 twice a day, fasted.
Dosage/Route of admin: CN1- Intravenous Infusion(IV); CN401- Tablet, Oral
Three to six patients are expected to be enrolled in each arm
干预措施: CN1, 1mg/kg and CN401, 600mg (Drug)
C (CN1 1mg/kg and CN401 800mg)
Patients were administered with CN1, 1mg/kg, once every three week in combination with 800mg CN401 twice a day, fasted.
Dosage/Route of admin: CN1- Intravenous Infusion(IV); CN401- Tablet, Oral
Three to six patients are expected to be enrolled in each arm
干预措施: CN1, 1mg/kg and CN401, 800mg (Drug)
E (CN1 10mg/kg and CN401 800mg)
Patients were administered with CN1, 10mg/kg, once every three week in combination with 800mg CN401 twice a day, fasted.
Dosage/Route of admin: CN1- Intravenous Infusion(IV); CN401- Tablet, Oral
Three to six patients are expected to be enrolled in each arm
干预措施: CN1, 10mg/kg and CN401, 800mg (Drug)
结局指标
主要结局
To evaluate the safety and tolerability of CN1 in combination with CN401 in patients with relapsed/refractory lymphoid malignancies through Incidence of Treatment-Emergent Adverse Events as assessed by CTCAE v5.0
时间窗: Measurements at Baseline till completion of last safety visit (270 days)
Number of participants with treatment-related adverse events as assessed by CTCAE v5.0
To determine maximum tolerated dose and/or Recommended Phase II Dose (RP2D) of CN1 in combination with CN401
时间窗: DLT assessed within 21 days after the first dose
Measured by Incidence of dose limiting toxicities (DLT) during the first cycle of treatment with CN1 in combination with CN401.
To assess the change in anti-tumor activity of CN1 in combination with CN401 through Objective Response Rate analysis
时间窗: Baseline to End of the Treatment assessed up to an average of 1 year
Measured/determined by Objective Response Rate
次要结局
- To further evaluate the safety and tolerability of CN1 in combination with CN401 in patients with relapsed/refractory lymphoid malignancies through Incidence of Treatment-Emergent Adverse Events as assessed by CTCAE v5.0(Measurements at Baseline till completion of last safety visit (270 days))
- To characterize the pharmacokinetics of CN1 and CN401 when administered in combination through Area under the under the drug concentration-time curve.(Baseline to End of the Treatment assessed up to an average of 1 year)
- To evaluate safety and tolerability of CN1 and CN401 in patients with relapsed/refractory lymphoid malignancies through vital signs as assessed by body temperature(Baseline to End of the Treatment assessed up to an average of 1 year)
- To evaluate safety and tolerability of CN1 and CN401 in patients with relapsed/refractory lymphoid malignancies through vital signs as assessed by pulse, systolic blood pressure, and diastolic blood pressure(Baseline to End of the Treatment assessed up to an average of 1 year)
- To further assess change in anti-tumor activity of CN1 in combination with CN401 through ORR(Baseline to End of the treatment visit assessed up to an average of 1 year)
- To evaluate safety and tolerability of CN1 and CN401 in patients with relapsed/refractory lymphoid malignancies through vital signs as assessed by heart rate(Baseline to End of the Treatment assessed up to an average of 1 year)
- To evaluate safety and tolerability of CN1 and CN401 in patients with relapsed/refractory lymphoid malignancies through vital signs as assessed by respiratory rate(Baseline to End of the Treatment assessed up to an average of 1 year)
- To characterize the pharmacokinetics of CN1 and CN401 when administered in combination through Cmax and Tmax.(Baseline to End of the Treatment assessed up to an average of 1 year)
- To characterize the pharmacokinetics of CN1 and CN401 when administered in combination through Apparent terminal half-life (t½).(Baseline to End of the Treatment assessed up to an average of 1 year)
- To characterize the pharmacokinetics of CN1 and CN401 when administered in combination through Apparent terminal elimination rate constant (Kel).(Baseline to End of the Treatment assessed up to an average of 1 year)
- To characterize the pharmacokinetics of CN1 and CN401 when administered in combination through Apparent clearance.(Baseline to End of the Treatment assessed up to an average of 1 year)
- To characterize the pharmacokinetics of CN1 and CN401 when administered in combination through Accumulation ration.(Baseline to End of the Treatment assessed up to an average of 1 year)
- To characterize the pharmacokinetics of CN1 and CN401 when administered in combination through Apparent terminal volume of distribution.(Baseline to End of the Treatment assessed up to an average of 1 year)