A Phase 1, Open-Label, Multicenter Study to Assess Safety, Tolerability, Pharmacokinetics, and Preliminary Anti-Tumor Activity of Ascending Doses of AZD4635 Both as Monotherapy and in Combination in Patients With Advanced Solid Malignancies
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- AstraZeneca
- 入组人数
- 313
- 试验地点
- 1
- 主要终点
- The incidence of Dose-Limiting Toxicities (DLTs) in patients receiving AZD4635 monotherapy orally.
研究概览
简要总结
This is a Phase 1, open-label, multicenter study of continuous oral dosing of AZD4635 administered to patients with advanced solid malignancies. Dosing will be escalated until a maximum-tolerated dose (MTD) is determined in patients. The MTD will be defined by dose-limiting toxicity. The study design allows an escalation of dose with intensive safety monitoring to ensure the safety of the patients. Expansion cohorts will further assess safety and preliminary anti-tumor activity in a variety of advanced solid tumor malignancies. Other dosing schedules and/or combinations may be evaluated based on the emerging PK and safety data.
The primary objectives of this study are to:
- Investigate the safety and tolerability of AZD4635 monotherapy when given orally (PO) to patients with advanced solid malignancies.
- Investigate the safety, tolerability, and pharmacokinetics (PK) of AZD4635 monotherapy capsule formulation when given to patients with advanced solid malignancies.
- Investigate the safety and tolerability of AZD4635 PO when given in combination with durvalumab, durvalumab plus oleclumab, or docetaxel to patients with advanced solid malignancies and to investigate the safety and tolerability of AZD4635 in combination with abiraterone acetate or enzalutamide in patients with mCRPC.
- Define the maximum-tolerated dose (MTD) of AZD4635 in combination with durvalumab.
- Define the recommended Phase 2 dose (RP2D) of AZD4635 in combination with abiraterone acetate or enzalutamide.
- Determine the safety, tolerability, and immune effects of AZD4635 when administered in combination with durvalumab to patients with non-small cell lung cancer (NSCLC) who have previously received immunotherapy (Phase 1b portion).
- Investigate the safety and tolerability of AZD4635 capsule formulation in combination with durvalumab and oleclumab when given to patients with mCRPC or advanced solid tumor malignancy.
- Define the RP2D of AZD4635 capsule formulation in combination with durvalumab and oleclumab when given to patients with mCRPC or advanced solid tumor malignancy.
- Investigate the safety and tolerability of AZD4635 capsule formulation in combination with docetaxel when given to patients with mCRPC or advanced solid tumor malignancy.
- Define the RP2D of AZD4635 capsule formulation in combination with docetaxel when given to patients with mCRPC or advanced solid tumor malignancy.
详细描述
The study will be conducted in two segments. The first segment of the study, designated Phase 1a, will be a dose escalation design in order to assess the safety, tolerability, pharmacokinetics (PK), and preliminary anti-tumor activity of ascending doses of AZD4635 as monotherapy, in combination with durvalumab or durvalumab plus oleclumab, in combination with docetaxel, and in combination with either abiraterone acetate or with enzalutamide.
A capsule formulation of AZD4635 will be evaluated in 3 arms (arms CA, CB, and CC). An oral nanoparticle suspension in water constituted extemporaneously by the patient will be administered in all other treatment arms. Most patients who started therapy with the nanoparticle suspension will transition to the capsule dosage form depending on the arm they are assigned to and emerging data. Active patients in arms C, D, E, F, G, H, I, J, K, KD, and L should be offered the option to transition to the capsule formulation at the discretion of the Investigator in discussion with the Medical Monitor. Patients in study arms AA and AE receiving AZD4635 as the nanoparticle suspension should change over to the capsule formulation as soon as possible at the discretion of the Investigator.
The dose escalation arms are described as follows:
- Arms A, B, and C (dose escalation of AZD4635 monotherapy).
- Arms CA, CB, and CC. In arm CA, the safety, tolerability and PK of the capsule formulation will be assessed in approximately 6 patients with advanced solid malignancies to ensure at least 5 patients have evaluable pharmacokinetic sampling. An additional 12 patients will be enrolled in this arm. Arm CB will assess the safety and tolerability and determine the RP2D of the AZD4635 capsule plus durvalumab and oleclumab in approximately 12 patients. Arm CC will assess the safety, tolerability and determine the RP2D of AZD4635 capsule plus docetaxel in approximately 12 patients .
- Arms D and E [dose escalation of AZD4635 in combination with durvalumab anti-programmed death-ligand 1 (PD-L1)].
Arms A through E enrolled 38 patients in Phase 1a in order to establish the Recommended Phase 2 Dose (RP2D) of the nanoparticle suspension formulation of AZD4635 as a single agent or in combination with durvalumab.
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 130 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- 未提供
排除标准
- 未提供
研究组 & 干预措施
Arm A
AZD4635 monotherapy as nanoparticle suspension 125 mg BID
干预措施: AZD4635 (Drug)
Arm E
AZD4635 as nanoparticle suspension 100 mg QD plus durvalumab
干预措施: AZD4635 (Drug)
Arm C
AZD4635 monotherapy as nanoparticle suspension 100 mg QD
干预措施: AZD4635 (Drug)
Arm D
AZD4635 as nanoparticle suspension 75 mg QD plus durvalumab
干预措施: AZD4635 (Drug)
Arm EA
AZD4635 as nanoparticle suspension plus enzalutamide
干预措施: AZD4635 (Drug)
Arm K
AZD4635 monotherapy as nanoparticle suspension in immunotherapy naïve patients with colorectal carcinoma.
干预措施: AZD4635 (Drug)
Arm CC
AZD4635 capsule formulation 50 mg QD or 75 mg QD plus docetaxel. The pharmacokinetics of the single dose AZD4635 capsule formulation will be characterized on Cycle 1 Day 1 in Arm CC. Steady-state pharmacokinetics will be assessed on Cycle 1 Day 15. Cycles will be administered in 3-week cycles to assess the safety and dose-limiting toxicity (DLT). After Cycle 1, PKs will be collected on Day 1 of every even numbered cycle (Cycles 2, 4, and 6).
干预措施: AZD4635 (Drug)
Arm CB
AZD4635 capsule formulation 50 mg QD or 75 mg QD plus durvalumab and oleclumab. The pharmacokinetics of AZD4635 capsule formulation will be characterized on Cycle 1, 2, and 4 (Day 1) in Arm CB. Steady-state pharmacokinetics will be assessed on Cycle 2 Day 15. Cycle 1 will be administered in a 3-week cycle to assess the safety and dose-limiting toxicity (DLT). PKs will also be collected on Day 1 of Cycles 3 and 5.
干预措施: AZD4635 (Drug)
Arm CA
AZD4635 capsule formulation monotherapy 75 mg, 150 mg, and 200 mg QD. A lower dose of 125 mg or 100 mg may be given. The pharmacokinetics of the single dose AZD4635 capsule formulation will be characterized on Cycle 1 Day 1 in Arm CA. Steady-state pharmacokinetics will be assessed on Cycle 1 Day 15. Cycle 1 and Cycle 2 will be administered in 3-week cycles to assess the safety and dose-limiting toxicity (DLT). After Cycle 1, PKs will be collected on Day 1 of every even numbered cycle (Cycles 2, 4, and 6).
干预措施: AZD4635 (Drug)
Arm L
AZD4635 monotherapy as nanoparticle suspension in immunotherapy naïve patients with other solid tumours.
干预措施: AZD4635 (Drug)
Arm KD
AZD4635 as nanoparticle suspension plus durvalumab in immunotherapy-naïve patients with colorectal carcinoma.
干预措施: AZD4635 (Drug)
Arm J
AZD4635 monotherapy as nanoparticle suspension in immunotherapy naïve patients with metastatic castration resistant prostate cancer. Patients will be allocated randomly (1:1) between Arms I and J.
干预措施: AZD4635 (Drug)
Arm I
AZD4635 as nanoparticle suspension plus durvalumab in immunotherapy naïve patients with metastatic castration resistant prostate cancer. Patients will be allocated randomly (1:1) between Arms I and J.
干预措施: AZD4635 (Drug)
Arm H
AZD4635 monotherapy as nanoparticle suspension in patients post immunotherapy with other solid tumours.
干预措施: AZD4635 (Drug)
Arm G
AZD4635 monotherapy as nanoparticle suspension in patients post immunotherapy with non-small cell lung cancer. Patients will be allocated randomly (1:1) between Arms F and G.
干预措施: AZD4635 (Drug)
Arm F
AZD4635 as nanoparticle suspension plus durvaluamb in patients post immunotherapy with non-small cell lung cancer. Patients will be allocated randomly (1:1) between Arms F and G.
干预措施: AZD4635 (Drug)
Arm AA
AZD4635 as nanoparticle suspension plus abiraterone acetate
干预措施: AZD4635 (Drug)
Arm B
AZD4635 monotherapy as nanoparticle suspension 75 mg QD
干预措施: AZD4635 (Drug)
Arm D
AZD4635 as nanoparticle suspension 75 mg QD plus durvalumab
干预措施: Durvalumab (Drug)
Arm E
AZD4635 as nanoparticle suspension 100 mg QD plus durvalumab
干预措施: Durvalumab (Drug)
Arm EA
AZD4635 as nanoparticle suspension plus enzalutamide
干预措施: Enzalutamide (Drug)
Arm AA
AZD4635 as nanoparticle suspension plus abiraterone acetate
干预措施: Abiraterone Acetate (Drug)
Arm F
AZD4635 as nanoparticle suspension plus durvaluamb in patients post immunotherapy with non-small cell lung cancer. Patients will be allocated randomly (1:1) between Arms F and G.
干预措施: Durvalumab (Drug)
Arm I
AZD4635 as nanoparticle suspension plus durvalumab in immunotherapy naïve patients with metastatic castration resistant prostate cancer. Patients will be allocated randomly (1:1) between Arms I and J.
干预措施: Durvalumab (Drug)
Arm KD
AZD4635 as nanoparticle suspension plus durvalumab in immunotherapy-naïve patients with colorectal carcinoma.
干预措施: Durvalumab (Drug)
Arm CB
AZD4635 capsule formulation 50 mg QD or 75 mg QD plus durvalumab and oleclumab. The pharmacokinetics of AZD4635 capsule formulation will be characterized on Cycle 1, 2, and 4 (Day 1) in Arm CB. Steady-state pharmacokinetics will be assessed on Cycle 2 Day 15. Cycle 1 will be administered in a 3-week cycle to assess the safety and dose-limiting toxicity (DLT). PKs will also be collected on Day 1 of Cycles 3 and 5.
干预措施: Durvalumab (Drug)
Arm CB
AZD4635 capsule formulation 50 mg QD or 75 mg QD plus durvalumab and oleclumab. The pharmacokinetics of AZD4635 capsule formulation will be characterized on Cycle 1, 2, and 4 (Day 1) in Arm CB. Steady-state pharmacokinetics will be assessed on Cycle 2 Day 15. Cycle 1 will be administered in a 3-week cycle to assess the safety and dose-limiting toxicity (DLT). PKs will also be collected on Day 1 of Cycles 3 and 5.
干预措施: Oleclumab (Drug)
Arm CC
AZD4635 capsule formulation 50 mg QD or 75 mg QD plus docetaxel. The pharmacokinetics of the single dose AZD4635 capsule formulation will be characterized on Cycle 1 Day 1 in Arm CC. Steady-state pharmacokinetics will be assessed on Cycle 1 Day 15. Cycles will be administered in 3-week cycles to assess the safety and dose-limiting toxicity (DLT). After Cycle 1, PKs will be collected on Day 1 of every even numbered cycle (Cycles 2, 4, and 6).
干预措施: Docetaxel (Drug)
结局指标
主要结局
The incidence of Dose-Limiting Toxicities (DLTs) in patients receiving AZD4635 monotherapy orally.
时间窗: 3 weeks (One Cycle)
A Bayesian Logistic Regression Model (BLRM) based approach will be used to identify the set of AZD4635 doses where the incidence of DLTs is no larger than 33%. In each arm, up to 3 patients will be initially assessed. The dose will be escalated to the next higher dose level if all 3 patients in the previous dose level complete the DLT evaluation period without a DLT. Following the first DLT, the BLRM model will be run and the output made available to the safety review committee (SRC) to guide further dosing decisions. Each dose cohort will include a maximum of 6 patients.
The incidence of Dose-Limiting Toxicities (DLTs) in patients receiving AZD4635 in combination with durvalumab.
时间窗: 7 weeks (Including Cycle 0)
A Bayesian Logistic Regression Model (BLRM) based approach will be used to identify the set of AZD4635 doses where the incidence of DLTs is no larger than 33%. In each arm, up to 3 patients will be initially assessed. The dose will be escalated to the next higher dose level if all 3 patients in the previous dose level complete the DLT evaluation period without a DLT. Following the first DLT, the BLRM model will be run and the output made available to the safety review committee (SRC) to guide further dosing decisions. Each dose cohort will include a maximum of 6 patients.
The incidence of Dose-Limiting Toxicities (DLTs) in patients receiving AZD4635 in combination with either abiraterone acetate or enzalutamide.
时间窗: 21 days (Cycle 1)
The starting dose of AZD4635 is 50 mg PO QD. Escalations of AZD4635 will be made based on emerging data, including nonclinical or clinical evidence, and assessment by the Safety Review Committee (SRC). Each dose cohort will include a maximum of 6 evaluable patients. An additional 6 patients will be treated at selected dose(s) to obtain further the safety, tolerability, and PK.
The incidence of adverse events
时间窗: Patients will be followed for either 21 days in Cycles 1 and 2 or 28 days in Cycles 3 and beyond to determine the incidence of adverse events.
Safety and tolerability will be assessed in monotherapy and combination cohorts by determining the incidence of adverse events, including abnormal laboratory results, physical examination findings, vital signs, and urinalysis.
次要结局
- Terminal elimination half-life (t½λz) of AZD4635 after single-dose administration in Cycle 0(Samples will be collected at pre-specified time points for up to one-week following a single-dose of AZD4635 (Cycle 0). The multiple-dose PK sampling will commence with Cycle 1 Day 1.)
- Area under the plasma concentration-time curve following single dose administration of AZD4635 in Cycle 0(Samples will be collected at pre-specified time points for up to one-week following a single-dose of AZD4635 (Cycle 0). The multiple-dose PK sampling will commence with Cycle 1 Day 1)
- Peak plasma concentration (Cmax) of AZD4635 after single-dose administration in Cycle 0(Samples will be collected at pre-specified time points for up to one-week following a single-dose of AZD4635 (Cycle 0). The multiple-dose PK sampling will commence with Cycle 1 Day 1.)
- Time to peak plasma concentration (tmax) of AZD4635 after single-dose administration in Cycle 0(Samples will be collected at pre-specified time points for up to one-week following a single-dose of AZD4635 (Cycle 0). The multiple-dose PK sampling will commence with Cycle 1 Day 1.)
- Terminal elimination rate constant (λz) of AZD4635 after single-dose administration in Cycle 0(Samples will be collected at pre-specified time points for up to one-week following a single-dose of AZD4635 (Cycle 0). The multiple-dose PK sampling will commence with Cycle 1 Day 1.)
- Apparent plasma clearance (CL/F) after single-dose administration of AZD4635 in Cycle 0(Samples will be collected at pre-specified time points for up to one-week following a single-dose of AZD4635 (Cycle 0). The multiple-dose PK sampling will commence with Cycle 1 Day 1.)
- Apparent volume of distribution (Vz/F) after single-dose administration of AZD4635 in Cycle 0(Samples will be collected at pre-specified time points for up to one-week following a single-dose of AZD4635 (Cycle 0). The multiple-dose PK sampling will commence with Cycle 1 Day 1.)
- Mean residence time (MRT) of AZD4635 after single-dose administration in Cycle 0(Samples will be collected at pre-specified time points for up to one-week following a single-dose of AZD4635 (Cycle 0). The multiple-dose PK sampling will commence with Cycle 1 Day 1.)
- Fraction of AZD4635 excreted unchanged in urine (fe) after single-dose administration in Cycle 0(Urine will be collected and pooled at specific intervals: pre-dose (spot urine), 0 to 4 hours, 4 to 8 hours, and 8 to 24 hours.)
- Renal clearance (CLR) of AZD4635 after single-dose administration in Cycle 0(Samples will be collected at pre-specified time points for up to one-week following a single-dose of AZD4635 (Cycle 0). The multiple-dose PK sampling will commence with Cycle 1 Day 1.)
- Amount of AZD4635 excreted unchanged in urine (Ae) after single-dose administration in Cycle 0(Urine will be collected and pooled at specific intervals: pre-dose (spot urine), 0 to 4 hours, 4 to 8 hours, and 8 to 24 hours.)
- Area under the plasma concentration-time curve within the dosing interval (AUCtau) following multiple-doses on Cycle 1 Day 15 in monotherapy arms and Cycle 1 Day 1 and Cycle 3 Day 15 in combination therapy arms.(Samples will be collected at pre-specified time points in the multiple-dose portion of the study beginning with Cycle 1 Day 1. Sampling be done on 1 of 3 schedules: i) Intensive sampling, ii) ECG-matched sampling, or iii) Sparse sampling.)
- The effect of AZD4635 on QTc interval(In screening and on Days 1, 2 and 15 in Cycle 1, Day 1 of each cycle thereafter, and at the end of treatment and at each progression-free follow-up visit.)
- Peak plasma concentration of AZD4635 at steady state (Cmax, ss) following multiple-doses on Cycle 1 Day 15 in monotherapy arms and Cycle 1 Day 1 and Cycle 3 Day 15 in combination therapy arms.(Samples will be collected at pre-specified time points in the multiple-dose portion of the study beginning with Cycle 1 Day 1. Sampling be done on 1 of 3 schedules: i) Intensive sampling, ii) ECG-matched sampling, or iii) Sparse sampling.)
- Time to peak plasma concentration of AZD4635 at steady state (tmax, ss) following multiple-doses on Cycle 1 Day 15 in monotherapy arms and Cycle 1 Day 1 and Cycle 3 Day 15 in combination therapy arms.(Samples will be collected at pre-specified time points in the multiple-dose portion of the study beginning with Cycle 1 Day 1. Sampling be done on 1 of 3 schedules: i) Intensive sampling, ii) ECG-matched sampling, or iii) Sparse sampling.)
- Minimum plasma concentration of AZD4635 at steady state (Cmin, ss) following multiple-doses on Cycle 1 Day 15 in monotherapy arms and Cycle 1 Day 1 and Cycle 3 Day 15 in combination therapy arms.(Samples will be collected at pre-specified time points in the multiple-dose portion of the study beginning with Cycle 1 Day 1. Sampling be done on 1 of 3 schedules: i) Intensive sampling, ii) ECG-matched sampling, or iii) Sparse sampling.)
- Apparent plasma clearance at steady state (CLss/F) following multiple-doses on Cycle 1 Day 15 in monotherapy arms and Cycle 1 Day 1 and Cycle 3 Day 15 in combination therapy arms.(Samples will be collected at pre-specified time points in the multiple-dose portion of the study beginning with Cycle 1 Day 1. Sampling be done on 1 of 3 schedules: i) Intensive sampling, ii) ECG-matched sampling, or iii) Sparse sampling.)
- Extent of accumulation of AZD4635 (Rac) after multiple dosing(Samples will be collected at pre-specified time points in the multiple-dose portion of the study beginning with Cycle 1 Day 1. Sampling will be done on 1 of 3 schedules: i) Intensive sampling, ii) ECG-matched sampling, or iii) Sparse sampling.)
- Time dependency of AZD4635 pharmacokinetic parameters (TCP) after multiple dosing.(Samples will be collected at pre-specified time points in the multiple-dose portion of the study beginning with Cycle 1 Day 1. Sampling will be done on 1 of 3 schedules: i) Intensive sampling, ii) ECG-matched sampling, or iii) Sparse sampling.)
- The concentration of durvalumab and anti-drug antibody in plasma when given in combination with AZD4635(Preinfusion and end of infusion on Day 1 of Cycles 2 and 5. Preinfusion of Day 1 of Cycles 3 and 8 and 90-days after the last dose of durvalumab.)
- Tumour Response(Tumour response will be assessed 6 weeks after the start of treatment and then every 8 weeks; after 18 months, assessments will be every 12 weeks.)
- Progression free survival(Patients will be restaged after 6 weeks (+/- 7 days) and every 8 weeks (+/- 7 days) thereafter, at the end of treatment visit if required, and at progression free follow up visits if they discontinue study treatment prior to progression.)