NCT05144347终止1 期
A Dose-Escalation and Expansion Study of the Safety and Pharmacokinetics of XL114 Administered in Subjects With Non-Hodgkin's Lymphoma
适应症
干预措施
相关药物
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 发起方
- Exelixis
- 入组人数
- 2
- 试验地点
- 4
- 主要终点
- Dose-Escalation Stage: Recommended Dose (RD) and/or Maximum Tolerated Dose (MTD) for XL114
研究概览
简要总结
This is a Phase 1, non-randomized, open-label, dose-escalation and expansion study, evaluating the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary clinical antitumor activity of XL114 administered alone orally to subjects with Non-Hodgkin's Lymphoma (NHL). The objectives of the study also include determining the recommended dose (RD) and/or maximum tolerated dose (MTD) of XL114.
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
- •Dose-Escalation Stage (Cohort A) and Cohort-Expansion Stage (B-E): The subject has received standard life-prolonging therapies or are not qualified to receive such therapies.
- •Dose-Escalation Stage (Cohort A): Subjects with histologically documented diagnosis of B-cell or T-cell Non-Hodgkin's Lymphoma as defined by the World Health Organization (WHO) classification. Note: Refer to exclusion criteria for lymphoma subtypes which are excluded from study participation.
- •Cohort-Expansion Stage Cohort B (ABC-DLBCL subtype): Subjects with histologically documented activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL) subtype. Note: De novo or transformed diffuse large B-cell lymphoma (DLBCL) from previously diagnosed indolent lymphoma (eg, follicular lymphoma) is allowed.
- •Cohort-Expansion Stage Cohort C (MCL): Subjects with histologically documented MCL with monoclonal B-cells that show a chromosome translocation t(11;14)(q13;q32) and/or overexpression of cyclin D
- •Cohort-Expansion Stage Cohort D (CLL/SLL): Subjects with histologically documented CLL/SLL per the International Workshop on Chronic Lymphocytic Leukemia (iwCLL) guidelines.
- •Cohort-Expansion Stage Cohort E, Biomarker Cohort (ABC-DLBCL, MCL, and SLL): Subjects with ABC-DLBCL, MCL, and SLL that fulfill the subject disease characteristics criteria as described for Cohorts B, C, or D.
- •Cohort-Expansion Stage: Subjects with ABC-DLBCL, MCL, and SLL must have measurable disease by revised criteria for response assessment of lymphoma.
- •Cohort-Expansion Stages: Must have archival tumor tissue available, which was collected up to 2 years prior to consent for this study. If archival tumor tissue is not available, a fresh tumor biopsy may be obtained (if safe to acquire) up to 60 days prior to first dose.
- •Biomarker Cohort: Subjects must provide a fresh tumor biopsy up to 60 days prior to first dose, at week 2, day 1 (W2D1) after initiation of XL114, and at disease progression. Note: The tumor tissue requirement in the Expansion and Biomarker cohorts doesn't apply for subjects with CLL.
- •Recovery to baseline or ≤ Grade 1 severity (Common Terminology Criteria for Adverse Events version 5 [CTCAE v5]) from AEs, unless AEs are clinically nonsignificant or stable.
- •Left ventricular ejection fraction (LVEF) > 50% as determined by echocardiogram (ECHO) or multigated acquisition (MUGA) scan per local standard.
- •Age 18 years or older on the day of consent.
- •Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0-1
- •Adequate organ and marrow function
- •Sexually active fertile subjects and their partners must agree to highly effective methods of contraception.
- •Female subjects of childbearing potential must not be pregnant at screening.
排除标准
- •Receipt of prior therapies as defined in the protocol
- •The following lymphoma types/manifestations are not eligible for this study: Burkitt's lymphoma (BL), Burkitt-like lymphoma (BLL), lymphoblastic lymphoma/leukemia (LBL), post-transplant lymphoproliferative disease (PTLD), primary mediastinal (thymic) large B-cell lymphoma (PMBL), lymphomas involving the central nervous system (CNS) or meninges
- •History of autoimmune hemolytic anemia (AIHA) or idiopathic thrombocytopenic purpura (ITP).
- •History of solid organ or allogeneic hematopoietic stem cell transplantation.
- •Concomitant anticoagulation with the oral anticoagulants apixaban, betrixaban, rivaroxaban, and dabigatran.
- •Use of a strong inhibitor or inducer of cytochrome P450 3A4 (CYP3A4) within 5 half-lives or 4 weeks prior to first dose of study treatment, whichever is shorter.
- •Uncontrolled, significant intercurrent or recent illness
- •Major surgery (eg, GI surgery) within 3 weeks before first dose of study treatment.
- •Corrected QT interval calculated by the Fridericia formula (QTcF) > 470 ms per electrocardiogram (ECG).
- •Pregnant or lactating females.
- •Inability to swallow XL114 tablets.
- •Diagnosis of another malignancy within 2 years before first dose of study treatment, except for superficial skin cancers, or localized, low-grade tumors deemed cured and not treated with systemic therapy
研究组 & 干预措施
XL114 Dose-Escalation Cohorts
Experimental
Subjects (Cohort A1-An) will accrue in cohorts of 3-12 subjects in a i3+3 design.
干预措施: XL114 (Drug)
XL114 Expansion Cohorts
Experimental
The recommended dose from the Dose-Escalation stage, will be used in subjects with activated B-cell-like diffuse large B-cell lymphoma [ABC-DLBCL] (Cohort B), mantle cell lymphoma [MCL] (Cohort C), chronic lymphocytic leukemia [CLL]/small lymphocytic lymphoma [SLL] (Cohort D). Subjects will also be enrolled in a Biomarker cohort (Cohort E).
干预措施: XL114 (Drug)
结局指标
主要结局
Dose-Escalation Stage: Recommended Dose (RD) and/or Maximum Tolerated Dose (MTD) for XL114
时间窗: 4-6 months
To determine the RD and/or MTD of XL114 administered orally in subjects with NHL
Cohort-Expansion Stage: Objective Response Rate (ORR)
时间窗: 4-6 months
To evaluate preliminary efficacy of XL114 by estimating the ORR based on lymphoma-specific response criteria as assessed by the Investigator
次要结局
- Dose-Escalation Stage: Area Under the Plasma Concentration-Time Curve Over the Last 24-hour Dosing Interval (AUC 0-24)(4-6 months)
- Cohort-Expansion Stage: Antitumor Activity of XL114 (Progression Free Survival [PFS])(4-6 months)
- Cohort-Expansion Stage: Antitumor Activity of XL114 (Duration of Response [DOR])(4-6 months)
- Tolerability of XL114, as evaluated by Dose Intensity, Dose Modifications, and Study Discontinuation due to AEs(4-6 months)
- Dose-Escalation Stage: Time to Maximum Plasma Concentration (Tmax)(4-6 months)
- Safety of XL114, as evaluated by Adverse Events (AEs)(4-6 months)
- Dose-Escalation Stage: Apparent Clearance (CL/F)(4-6 months)
- Cohort-Expansion Stage: Antitumor Activity of XL114 (Objective Response Rate [ORR])(4-6 months)
- Cohort-Expansion Stage: Overall Survival (OS) of XL114(4-6 months)
- Dose-Escalation Stage: Maximum Plasma Concentration (Cmax)(4-6 months)
- Dose-Escalation Stage: Terminal Half-Life(4-6 months)
研究者
研究点 (4)
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