NCT06130553招募中1 期
PRIMROSE: A Modular Phase I/IIa, Multi-centre, Dose Escalation, and Expansion Study of AZD3470, a MTA Cooperative PRMT5 Inhibitor, as Monotherapy and in Combination With Anticancer Agents in Participants With Advanced/Metastatic Solid Tumors That Are MTAP Deficient
适应症
干预措施
相关药物
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- AstraZeneca
- 入组人数
- 334
- 试验地点
- 21
- 主要终点
- Incidence of adverse events (AEs) and serious adverse events (SAEs)
研究概览
简要总结
This is a first time in human (FTiH) Phase I/IIa, open-label, multi-centre study of AZD3470 in participants with advanced or metastatic solid tumors with MTAP deficiency. The study consists of several study modules, evaluating the safety, tolerability, pharmacokinetic (PK), pharmacodynamics, and preliminary efficacy of AZD3470 as monotherapy or in combination with other anti-cancer agents.
详细描述
This first time in human, open-label, multi-centre study of AZD3470 in participants with advanced or metastatic solid tumors with MTAP deficiency follows a modular design. Module 1 Part A will include the dose escalation cohorts. Part B will include the dose optimization and expansion cohorts. The purpose of the Phase 2 Module 2 is to evaluate the efficacy and safety of AZD3470 in combination with Dato-DXd versus Dato-DXd alone - dose optimization and expansion. New modules for combination treatments may be added in the future based on emerging data.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 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
- •(All Modules) Participants are ≥ 18 years (or the legal age of consent in the jurisdiction) at the time of signing the informed consent form.
- •Participants are able to provide written informed consent and are willing and able to comply with study procedures.
- •Participants are willing to provide archival and/or newly obtained (baseline) tumor tissue for central testing, including required biomarker assessment(s) (and any module-specific biomarker requirements).
- •Participants have tumors meeting the protocol-defined MTAP-deficiency requirement, based on acceptable prior testing and/or central testing per protocol.
- •Participants have received prior systemic therapy appropriate for the tumor type and disease stage and have disease progression on or after prior therapy; participants must have had ≥ 1 prior line of systemic treatment in the recurrent/metastatic (advanced) setting.
- •Participants have ECOG performance status 0-
- •Participants have life expectancy ≥ 12 weeks, in the opinion of the Investigator.
- •Participants have measurable disease per RECIST v1.
- •Participants have adequate organ and bone marrow function per protocol-defined laboratory/assessment criteria.
- •Participants have a treatment-free interval ≥ 3 weeks from prior anticancer therapy before starting study drug (with any additional protocol-defined washout requirements for certain therapies/procedures).
- •Contraception use by men and women is consistent with local regulations and protocol-defined requirements.
- •Additional Inclusion Criteria (Module 2: Non-squamous NSCLC) Participants have histologically or cytologically confirmed non-squamous NSCLC, Stage IIIB/IIIC not amenable to curative therapy or Stage IV.
- •Participants have documented radiographic extracranial disease progression while on or after the most recent treatment regimen for advanced/metastatic NSCLC (CNS-only progression is not eligible).
- •NSCLC of mixed histology is allowed if not predominantly squamous; no small cell or large cell neuroendocrine components.
- •Participants meet one of the following:
- •Tumor has a documented EGFR alteration eligible for EGFR-directed therapy (per protocol-defined criteria) and the participant has received prior systemic therapy appropriate for EGFR-altered advanced/metastatic NSCLC (per protocol), OR Tumor is negative for EGFR alterations eligible for EGFR-directed therapy, has no other known actionable genomic alterations for which locally approved/available targeted therapies exist (per protocol-defined criteria), meets any additional protocol-required biomarker criteria for this cohort (as applicable), and the participant has received prior systemic therapy appropriate for non-actionable-alteration advanced/metastatic NSCLC (per protocol).
排除标准
- •(All Modules) Participants have spinal cord compression, or symptomatic and unstable brain metastases, leptomeningeal disease, or primary CNS malignancy. Participants with asymptomatic, radiographically stable brain metastases who do not require steroids (or who have completed definitive therapy and are neurologically stable off steroids, per protocol) may be eligible.
- •Participants have a history of allogeneic organ transplantation. Participants have any clinically significant abnormal laboratory finding or severe and uncontrolled medical condition that, in the Investigator's opinion, makes participation unsafe, including active infection requiring systemic treatment.
- •Participants have clinically significant cardiovascular disease or risk factors (including reduced LVEF, cardiomyopathy, clinically active cardiovascular disease, recent major ischemic events or revascularization procedures, uncontrolled angina, severe valvular disease, uncontrolled hypertension, clinically significant heart failure, or recent stroke/TA clinically significant ECG abnormalities, prolonged QTc, or conditions/medications that increase risk of QTc prolongation or arrhythmic events)..
- •Participants require therapeutic anticoagulation for treatment of acute thromboembolic events, per protocol.
- •Participants have active hepatitis B or hepatitis C infection (including detectable viral load, per protocol-defined testing).
- •Participants have known HIV infection. Participants have current ILD/pneumonitis, or a history of (non-infectious) ILD/pneumonitis requiring systemic steroids or supplemental oxygen, or suspected ILD/pneumonitis that cannot be ruled out by screening imaging.
- •Participants have active gastrointestinal disease, malabsorption, or other GI condition/surgery that would significantly interfere with oral drug absorption or tolerability.
- •Participants have a history of another primary malignancy. Participants have unresolved clinically significant toxicity from prior anticancer therapy (typically Grade ≥ 2).
- •Participants have had prior treatment with a PRMT5 inhibitor Participants are pregnant, breastfeeding, or intend to become pregnant during study participation.
- •Additional Exclusion Criteria (Module 2 Only) Participants have inaccessible veins and/or inability to place required venous access (e.g., port), per Investigator judgment.
- •Participants have contraindication to required CNS imaging (brain MRI preferred or CT with contrast).
- •Participants have clinically significant corneal disease. Participants have known active tuberculosis infection, per clinical evaluation and local practice.
- •Participants have significant third-space fluid (e.g., pleural effusion/ascites) not amenable to required repeated drainage, per Investigator judgment.
- •Participants have severe pulmonary function compromise due to intercurrent pulmonary illness (e.g., severe COPD/asthma/restrictive lung disease, recent pulmonary embolism), per protocol.
- •Participants have recent radiotherapy that does not meet protocol-defined washout requirements and/or ongoing radiation-related toxicities requiring corticosteroids.
- •Participants have had prior treatment with protocol-prohibited anticancer therapies.
研究组 & 干预措施
Module 2: Dato-DXd alone
Experimental
Control arm
干预措施: Datopotamab deruxtecan (Drug)
Module 2: AZD3470 in combination with Dato-DXd
Experimental
Varying doses of AZD3470 in combination with Dato-Dxd
干预措施: AZD3470 (Drug)
Module 1: AZD3470 Monotherapy
Experimental
Part A dose escalation and back-fill cohorts and Part B dose optimization and expansion cohorts of varying doses of AZD3470
干预措施: AZD3470 (Drug)
Module 2: AZD3470 in combination with Dato-DXd
Experimental
Varying doses of AZD3470 in combination with Dato-Dxd
干预措施: Datopotamab deruxtecan (Drug)
结局指标
主要结局
Incidence of adverse events (AEs) and serious adverse events (SAEs)
时间窗: From time of informed consent to 28 days post last dose of AZD3470
Number of participants with AEs and SAEs
Incidence of dose-limiting toxicities (DLT)
时间窗: From first dose of study treatment until the end of Cycle 1 (each cycle is 21 days)
Incidence of dose-limiting toxicities (DLT) as determined by number of patients with at least 1 dose-limiting toxicity (DLT). DLT is defined as an AE (adverse event) or abnormal laboratory value that occurs during the DLT period (defined as 21 days after start of study intervention) that is assessed as unrelated to the disease, intercurrent illness, or concomitant medications and meets any DLT criteria defined in the clinical study protocol
次要结局
- Radiological response assessed by the Investigator evaluated according to RECIST v1.1 - ORR (Objective Response Rate)(From date of first dose of AZD3470 up until progression, or the last evaluable assessment in the absence of progression (approximately 2 years).)
- Radiological response assessed by the Investigator evaluated according to RECIST v1.1 - DoR (Duration of Response)(From date of first dose of AZD3470 up until progression, or the last evaluable assessment in the absence of progression (approximately 2 years).)
- Radiological response assessed by the Investigator evaluated according to RECIST v1.1 - Best percentage change in tumor size(From date of first dose of AZD3470 up until progression, or the last evaluable assessment in the absence of progression (approximately 2 years).)
- Radiological response assessed by the Investigator evaluated according to RECIST v1.1 - PFS (Progression Free Survival)(From date of first dose of AZD3470 up until progression, or the last evaluable assessment in the absence of progression (approximately 2 years).)
- Radiological response assessed by the Investigator evaluated according to RECIST v1.1 - DCR (Disease Control Rate) at 12 weeks(From date of first dose of AZD3470 up until progression, or the last evaluable assessment in the absence of progression (for each patient this is expected to be measured at 12 weeks).)
- Overall Survival (OS)(From date of first dose of AZD3470 up until the date of death due to any cause (approximately 2 years).)
- Module 1 Endpoints Part A (Dose escalation) Measurement of PK parameters: AUC(At predefined intervals throughout the treatment period (for each patient this is expected to be measured up to approximately 4 weeks))
- Module 1 Endpoints Part A (Dose escalation) Measurement of PK parameters: C-max(At predefined intervals throughout the treatment period (for each patient this is expected to be measured up to approximately 4 weeks))
- Module 1 Endpoints Part A (Dose escalation) Measurement of PK parameters: half life(At predefined intervals throughout the treatment period (for each patient this is expected to be measured up to approximately 4 weeks))
- Module 1 Endpoints Part A (Dose escalation) Measurement of PK parameters: Ae (excreted in urine)(At predefined intervals throughout the treatment period (for each patient this is expected to be measured up to approximately 4 weeks))
- Module 1 Endpoints Part A (Dose escalation) Measurement of PK parameters: Clr (renal clearance)(At predefined intervals throughout the treatment period (for each patient this is expected to be measured up to approximately 4 weeks))
- Module 1 Endpoints Part A drug-drug interaction (DDI) - Measurement of PK parameters of Midazolam: Cmax(At predefined intervals throughout the treatment period (for each patient this is expected to be measured up to approximately 4 weeks))
- Module 1 Endpoints Part A (DDI) - Measurement of PK parameters of Midazolam: AUC(At predefined intervals throughout the treatment period (for each patient this is expected to be measured up to approximately 4 weeks))
- Module 1 Endpoints Part A (DDI) - Measurement of PK parameters of Dextromethorphan: Cmax(At predefined intervals throughout the treatment period (for each patient this is expected to be measured up to approximately 4 weeks))
- Module 1 Endpoints Part A (DDI) - Measurement of PK parameters of Dextromethorphan: AUC(At predefined intervals throughout the treatment period (for each patient this is expected to be measured up to approximately 4 weeks))
- Module 1 Endpoints Part A pharmacodynamic backfill cohorts - Measurement of SDMA in tumor.(From screening baseline timepoint to up to four weeks on treatment timepoint.)
研究者
研究点 (21)
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