A Phase 1/2 Open-label Study to Evaluate Safety, Tolerability, Pharmacokinetics, and Preliminary Anti-tumor Activity of ARV-6723 Administered as Monotherapy and in Combination With Pembrolizumab in Participants With Advanced Solid Tumors
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- Arvinas Inc.
- 入组人数
- 499
- 试验地点
- 3
- 主要终点
- Part A1: Number of Dose-Limiting Toxicities (DLTs) of ARV-6723
研究概览
简要总结
This is a study to evaluate the safety and potential anti-tumor activity of an investigational drug called ARV-6723, in participants with advanced solid tumors.
This is an open-label study which means that participants and study staff will know that all participants will receive ARV-6723. The investigational drug ARV-6723 will be given as an oral tablet on its own and also in combination with other drugs.
Researchers think that ARV-6723 can help the body's immune system to better recognize, attack, and destroy cancer cells in adults with advanced solid tumors. ARV-6723 is an investigational drug, and this is the first time ARV-6723 will be used in humans.
Depending on the treatment assignment, the investigational drug, ARV-6723, will be given as an oral tablet either on its own (monotherapy) or in combination with pembrolizumab, either through a vein (intravenously or IV) or through an injection beneath the skin (subcutaneously or SQ).
This study will include multiple parts:
In Part A1 (Phase 1a), different small groups of participants will receive lower to higher doses of ARV-6723 as monotherapy or in combination with standard-dose of pembrolizumab.
In Part A2 (Phase 1b), two groups of participants with specific tumor indication(s) (TBD) will receive one of two doses selected based on information from Part A1.
Details of Part B will be determined based on information generated from Part A.
研究设计
- 研究类型
- Interventional
- 分配方式
- 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
- •Part A1 dose escalation and A2 dose optimization: Participants must meet all of the following criteria:
- •Have a histologic or cytologic diagnosis of unresectable or metastatic solid tumor malignancy.
- •Have previously received at least one prior therapy targeting programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), cytotoxic T-lymphocyte antigen 4 (CTLA-4), lymphocyte-activation gene 3 (LAG-3), and/or another T-cell co-stimulatory or immune checkpoint pathway, in any treatment setting (including neoadjuvant or adjuvant).
- •Have received prior SOC therapy appropriate for their disease type and stage and have no remaining available treatment options with established clinical benefit; or, in the opinion of the investigator, are unlikely to tolerate or derive clinically meaningful benefit from appropriate SOC therapy; or have declined SOC therapy.
- •Participants must have demonstrated radiographic progression and have at least 1 measurable lesion per RECIST v1.1 that has not been previously irradiated or has demonstrated progression of disease since radiation therapy.
- •ECOG PS 0 or 1 or equivalent. Participants with ECOG PS 2 may be considered upon discussion with the Sponsor Medical Monitor.
- •Participants with adequate organ function.
排除标准
- •Exclusion Criteria (Part A)
- •Active brain metastases (new lesions identified on imaging, existing lesions showing progression per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1)/imaging characteristics or by clinical criteria, lesions requiring active interventions for symptom control).
- •Carcinomatous meningitis.
- •Known or suspected hypersensitivity to ARV-6723 or pembrolizumab or any of its excipients.
- •Active autoimmune disease or history of autoimmune diseases that may relapse.
- •History of severe immune-related adverse events (irAE) attributed to prior anti-PD-1/anti-CTLA-4/anti-LAG-3 therapy.
- •Prior treatment with any HPK1-targeting agent
- •Systemic anti-cancer therapy or radiation therapy within 14 days prior to study treatment start.
- •Current use of any prohibited concomitant medication(s) or herbal supplements which cannot be discontinued, prior to start of study intervention and for the duration of the study.
- •Baseline (screening) standard 12-lead electrocardiogram (ECG) that demonstrates clinically relevant abnormalities that may affect participant safety or interpretation of study results.
研究组 & 干预措施
Part A1a: Phase 1 Monotherapy dose escalation
Participants will receive the assigned dose of ARV-6723 orally once daily (QD) in tablet form, under fasted conditions in 21-day cycles. Treatment will continue at the investigator's discretion until disease progression, unacceptable toxicity, withdrawal of consent or death.
干预措施: ARV-6723 (Drug)
Part A1b: Phase 1 Combination therapy dose escalation
Participants will receive the assigned dose of ARV-6723 orally QD in tablet form, under fasted conditions along with pembrolizumab by intravenous (IV) infusion or subcutaneous (SQ) injection at fixed dose once every 3 weeks (Q3W) in 21-day cycles. Treatment will continue at the investigator's discretion until disease progression, unacceptable toxicity, withdrawal of consent or death.
干预措施: ARV-6723 (Drug)
Part A2b: Phase 1 Monotherapy dose optimization
Participants will receive the assigned dose of ARV-6723, based on Phase A1a, orally QD in tablet form, under fasted conditions in 21-day cycles. Treatment will continue at the investigator's discretion until disease progression, unacceptable toxicity, withdrawal of consent or death.
干预措施: ARV-6723 (Drug)
Part A2b: Phase 1 Combination therapy dose optimization
Participants will receive the assigned dose of ARV-6723, based on Phase A1b orally QD in tablet form, under fasted conditions along with pembrolizumab IV infusion or SQ injection at fixed dose Q3W in 21-day cycles. Treatment will continue at the investigator's discretion until disease progression, unacceptable toxicity, withdrawal of consent or death.
干预措施: ARV-6723 (Drug)
Part B: Phase 2 Monotherapy dose expansion
Participants will receive the assigned dose of ARV-6723, selected based on Part A in 21-day cycles. Treatment will continue at the investigator's discretion until disease progression, unacceptable toxicity, withdrawal of consent or death.
干预措施: ARV-6723 (Drug)
Part B: Phase 2 Combination dose expansion
Participants will receive the assigned dose of ARV-6723, selected based on Part A in combination with pembrolizumab by IV infusion or SQ injection n 21-day cycles. Treatment will continue at the investigator's discretion until disease progression, unacceptable toxicity, withdrawal of consent or death.
干预措施: ARV-6723 (Drug)
Part B: Phase 2 Standard of care (SOC)
Participants will receive SOC treatment regimens based on investigators choice and the tumor indications. Treatment will continue at the investigator's discretion until disease progression, unacceptable toxicity, withdrawal of consent or death.
干预措施: SOC (Drug)
Part B: Phase 2 Combination dose expansion
Participants will receive the assigned dose of ARV-6723, selected based on Part A in combination with pembrolizumab by IV infusion or SQ injection n 21-day cycles. Treatment will continue at the investigator's discretion until disease progression, unacceptable toxicity, withdrawal of consent or death.
干预措施: Pembrolizumab (Drug)
Part A1b: Phase 1 Combination therapy dose escalation
Participants will receive the assigned dose of ARV-6723 orally QD in tablet form, under fasted conditions along with pembrolizumab by intravenous (IV) infusion or subcutaneous (SQ) injection at fixed dose once every 3 weeks (Q3W) in 21-day cycles. Treatment will continue at the investigator's discretion until disease progression, unacceptable toxicity, withdrawal of consent or death.
干预措施: Pembrolizumab (Drug)
Part A2b: Phase 1 Combination therapy dose optimization
Participants will receive the assigned dose of ARV-6723, based on Phase A1b orally QD in tablet form, under fasted conditions along with pembrolizumab IV infusion or SQ injection at fixed dose Q3W in 21-day cycles. Treatment will continue at the investigator's discretion until disease progression, unacceptable toxicity, withdrawal of consent or death.
干预措施: Pembrolizumab (Drug)
结局指标
主要结局
Part A1: Number of Dose-Limiting Toxicities (DLTs) of ARV-6723
时间窗: 21 days from first ARV-6723 administration
Number of participants within a dose escalation cohort with adverse events (AEs) meeting protocol defined dose limiting toxicities during cycle 1 (21 days).
Part A1: Number of Participants With Adverse Events (AEs)
时间窗: From the first dose of ARV-6723 through at least 28 days after the last dose (up to approximately 4.7 years)
AEs as characterized by type, frequency, severity (as graded by National Cancer Institute Common Terminology Criteria for Adverse Events \[NCI CTCAE\]), timing, seriousness, and relationship to study intervention as a measure of safety and tolerability.
Part A2: Number of Participants With AEs
时间窗: From the first dose of ARV-6723 through at least 28 days after the last dose (up to approximately 4.7 years)
AEs as characterized by type, frequency, severity (as graded by National Cancer Institute Common Terminology Criteria for Adverse Events \[NCI CTCAE\]), timing, seriousness, and relationship to study intervention as a measure of safety and tolerability.
Part A2: Overall Response Rate (ORR) by computed tomography/magnetic resonance imaging (CT/MRI) Using Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1) Criteria Per Investigator Assessment
时间窗: Approximately 24 months
ORR is defined as the proportion of participants reaching a confirmed complete response (CR) or partial response (PR) to the study treatment based on investigator assessment using RECIST 1.1 criteria.
Part B: ORR by CT/MRI using RECIST v1.1 Criteria Per Investigator Assessment
时间窗: Approximately 24 months
ORR is defined as the proportion of participants reaching a confirmed complete response (CR) or partial response (PR) to the study treatment based on investigator assessment using RECIST 1.1 criteria.
次要结局
- Part B: ORR by CT/MRI Using iRECIST Criteria Per Investigator Assessment(Approximately 24 months)
- Part A1: Maximum Plasma or Blood Concentration (Cmax)(At predefined intervals throughout the treatment period, up to approximately 9 months after first dose.)
- Part B: Progression-Free Survival (PFS)(Approximately 24 months)
- Part A1: Lowest Plasma Concentration Immediately Prior to Dosing(Ctrough)(At predefined intervals throughout the treatment period, up to approximately 9 months after first dose.)
- Part B: Time to Response (TTR)(Approximately 24 months)
- Part B: Duration of Response (DOR)(Approximately 24 months)
- Part B: DCR by CT/MRI using RECIST v1.1 and iRECIST Criteria Per Investigator assessment(Approximately 24 months)
- Part A1: Apparent Plasma Clearance at Steady State (CL/F)(At predefined intervals throughout the treatment period, up to approximately 9 months after first dose.)
- Part A1: Time to Maximum Observed Plasma Concentration (Tmax)(At predefined intervals throughout the treatment period, up to approximately 9 months after first dose.)
- Part B: Number of Participants With AEs(From the first dose of ARV-6723 through at least 28 days after the last dose (up to approximately 4.7 years))
- Part A1: Apparent Volume of Distribution Divided by the Bioavailability of the Drug (Vz/F)(At predefined intervals throughout the treatment period, up to approximately 9 months after first dose.)
- Part A1: Terminal Elimination Half-Life (t½)(At predefined intervals throughout the treatment period, up to approximately 9 months after first dose.)
- Part A1: Effective Terminal Elimination Half-Life (t½)(At predefined intervals throughout the treatment period, up to approximately 9 months after first dose.)
- Part A1: Accumulation Ratio (Rac)(At predefined intervals throughout the treatment period, up to approximately 9 months after first dose.)
- Part A1: Overall Response Rate (ORR)(Approximately 24 months)
- Part A1: Disease Control Rate (DCR)(Approximately 24 months)
- Part A2: ORR by CT/MRI using iRECIST Criteria Per Investigator Assessment(Approximately 24 months)
- Part A2: Disease Control Rate (DCR) by CT/MRI using RECIST 1.1 and iRECIST criteria per investigator assessment(Approximately 24 months)
- Part A1: Area Under the Plasma or Blood Concentration-Time Profile During a Dosing Interval (AUCtau)(At predefined intervals throughout the treatment period, up to approximately 9 months after first dose.)
- Part A1: Area Under the Plasma or Blood Concentration Time Profile From Time Zero to the Time of the Last Quantifiable Concentration (Clast) (AUClast)(At predefined intervals throughout the treatment period, up to approximately 9 months after first dose.)