A Phase 1, Multicenter, Open-Label, Dose-Escalation and Expansion Study to Evaluate Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Clinical Activity of Intravenously Administered KT-333 in Adult Patients with Relapsed or Refractory Lymphomas, Large Granular Lymphocytic Leukemia, and Solid Tumors
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 56
- 试验地点
- 13
- 主要终点
- Dose Limiting Toxicities (DLTs)
研究概览
简要总结
This Phase 1a/1b study will evaluate the safety, tolerability and the pharmacokinetics/pharmacodynamics (PK/PD) of KT-333 in Adult patients with Relapsed or Refractory (R/R) Lymphomas, Large Granular Lymphocytic Leukemia (LGL-L), T-cell prolymphocytic leukemia (T-PLL), and Solid Tumors. The Phase 1a stage of the study will explore escalating doses of single-agent KT-333. The Phase Ib stage will consist of 4 expansion cohorts to further characterize the safety, tolerability and the pharmacokinetics/pharmacodynamics (PK/PD) of KT-333 in Peripheral T-cell Lymphoma (PTCL), Cutaneous T-Cell Lymphoma (CTCL), LGL-L, and solid tumors.
详细描述
This is an open-label Phase 1a (dose escalation)/1b (dose expansion) first-in-human study of KT-333 in adult patients. Patients with relapsed/refractory (R/R) lymphomas, LGL-L, T-PLL, and solid tumors will be enrolled in Phase 1a. Phase 1b will consist of separate cohorts of patients with R/R PTCL, CTCL, LGL-L, and solid tumors.
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
- •Phase 1a Only: Cytologically or pathologically confirmed Lymphomas (including Hodgkin's, B-cell, T-cell, Small Lymphocytic, or Natural-Killer (NK)-cell Lymphomas and LGL-L), T-PLL and solid tumors with the exception of chronic lymphocytic leukemia (CLL) Note: Patients with indolent non-Hodgkin's lymphoma (NHL) and small lymphocytic lymphoma (SLL) are only eligible if not require immediate cytoreductive therapy or if there are no available treatments with potential benefit.
- •Phase 1b Only: Histologically or pathologically confirmed PTCL, CTCL, LGL-L [T-cell LGL-L or Chronic Lymphoproliferative Disorder of NK-cells (CLPD-NK)], or solid tumors.
- •Fresh or archival formalin fixed paraffin embedded (FFPE) tumor tissue or 15 slides preferably collected within 6 months or 2 years prior to first dose of the study drug (for lymphoma and solid tumor patients respectively).
- •Phase 1a only: Lymphoma and Solid Tumor: Relapsed and/or refractory disease to at least 2 prior systemic standard of care treatments or for whom standard therapies are not available.
- •Phase 1a: LGL-L/T-PLL only: Relapsed and/or refractory disease to at least 1 prior systemic standard of care treatment or for whom standard therapies are not available.
- •Phase 1b only: All disease types: Relapsed and/or refractory disease to at least 1 prior systemic standard of care treatments or for whom standard therapies are not available.
- •LGL-L patients only (hematology specific criteria):
- •One of the following:
- •Severe neutropenia < 500/mm3, or,
- •Symptomatic anemia and/or,
- •Transfusion-dependent anemia.
- •ANC ≥ 200/μL at Screening and C1D1 (pre dose)
- •Platelet count ≥ 100,000/μL (assessed ≥ 7 days following last platelet transfusion in patients with thrombocytopenia requiring platelets).
- •LGL-L Patients Only (baseline disease characteristics):
- •CD3+CD8+ cell population >650/mm3;
- •CD3+CD8+CD57+ population >500/mm3;
- •Presence of a clonal T-cell receptor (within 1 month of diagnosis);
- •Note: patients with T-LGLL may be included with PI approval even if CD3+CD8+ cell population is<650/mm3 or CD3+CD8+CD57+ population is <500/mm3, though +TCR is required;
- •NK LGL is also permitted, provided there is a clonal NK-cell population noted with>500 cells/mm3
- •PTCL and solid tumors Only: Measurable disease at Screening. Solid tumor patients with non-measurable disease are allowed in Phase1a
- •T-PLL: Measurable disease per Lugano and/or atypical T lymphocytes quantifiable by flow cytometry or morphology in the peripheral blood or bone marrow.
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 at Screening and C1D1 (pre-dose).
- •Adequate bone marrow function at Screening and C1D1 (pre-dose) for all patients except those with LGL-L Adequate liver/kidney organ function at Screening and C1D1 (pre-dose) for all patients.
- •Women of childbearing potential (WOCBP) must agree to use highly effective contraceptive methods for the duration of study treatment and 6 months after the last dose of KT333.
排除标准
- •Known active uncontrolled or symptomatic central nervous system (CNS) metastases, carcinomatous meningitis, or leptomeningeal disease as indicated by clinical symptoms, cerebral edema, and/or progressive growth.
- •Note: Patients with solid tumors are eligible if their CNS metastases or cord compression have been treated (e.g., radiotherapy, stereotactic surgery) and they are clinically stable, off steroids for at least 4 weeks before first dose of study drug and have no evidence of progression at time of study enrollment.
- •Note: Patients with lymphomas are eligible if their CNS metastases or cord compression have been treated effectively (i.e. achieved CR) and there is no clinical or radiographic evidence of active lymphoma.
- •Diagnosis of Chronic Lymphocytic Leukemia (CLL).
- •History of or active concurrent malignancy other than lymphoma or solid tumors unless the patient has been disease-free for ≥ 2 years.
- •Patient has not recovered from any clinically significant adverse events (AEs) of previous treatments to pretreatment baseline or Grade 1 prior to first dose of study drug.
- •Ongoing unstable cardiovascular function.
- •Autologous hematopoietic stem cell transplant less than 3 months prior to first dose of study drug.
- •Prior allogenic hematopoietic or bone marrow transplant.
研究组 & 干预措施
Phase 1a Dose Escalation Lymphomas
KT-333 dosed IV weekly in 28 day cycles
干预措施: KT-333 (Drug)
Phase 1a Dose Escalation Solid Tumors
KT-333 dosed IV weekly in 28 day cycles
干预措施: KT-333 (Drug)
Phase 1b Dose Expansion PTCL
KT-333 dosed IV weekly in 28 day cycles
干预措施: KT-333 (Drug)
Phase 1b Dose Expansion CTCL
KT-333 dosed IV weekly in 28 day cycles
干预措施: KT-333 (Drug)
Phase 1b Dose Expansion LGL-L
KT-333 dosed IV weekly in 28 day cycles
干预措施: KT-333 (Drug)
Phase 1b Dose Expansion Solid Tumor
KT-333 dosed IV weekly in 28 day cycles
干预措施: KT-333 (Drug)
Phase 1a Dose Escalation LGL-L
KT-333 dosed IV weekly in 28 day cycles
干预措施: KT-333 (Drug)
Phase 1a Dose Escalation T-PLL
KT-333 dosed IV weekly in 28 day cycles
干预措施: KT-333 (Drug)
结局指标
主要结局
Dose Limiting Toxicities (DLTs)
时间窗: Within the first 28days of treatment
Number of Participants with protocol specified Dose Limiting Toxicities (DLTs) Phase 1a
Maximum Tolerated Dose (MTD)
时间窗: Within the first 28 days of treatment
To establish the Maximum Tolerated Dose (MTD) Phase 1a
Safety
时间窗: Safety will be assessed from the time ICF signature through 30 days post dose or prior to start of a new anticancer therapy
Changes in the ECG parameters, including heart rate and measures PR, QRS, QT, and QTc intervals as assessed by CTCAE v5.0 Phase 1a/1b
次要结局
- Half-life of KT-333 if data permits (T1/2)(Blood samples for PK analysis collected at multiple visits during cycle 1 and cycle 2 (each cycle is 28days))
- Amount of KT-333 dose excreted in urine from time zero to last collected time point (Ae0-t)(Urine samples for PK analysis collected at multiple visits during cycle 1 and cycle 2 (each cycle is 28days))
- Evidence of clinical activity of KT-333(From date of baseline scan until the date of first documented progression or date of death from any cause, whichever came first, about 18 months)
- Maximum Plasma Concentration of KT-333 (Cmax)(Blood samples for PK analysis collected at multiple visits during cycle 1 and cycle 2 (each cycle is 28days))
- Duration of Response (DOR)(From date of first of response to the date of documented first progression or death whichever comes first, about 18 months)
- Area under the plasma concentration versus time curve for KT-333(Blood samples for PK analysis collected at multiple visits during cycle 1 and cycle 2 (each cycle is 28days))
- Time of maximum plasma concentration of KT-333 (Tmax)(Blood samples for PK analysis collected at multiple visits during cycle 1 and cycle 2 (each cycle is 28days))