A Modular Phase I/II, Open-label, Multicentre Study to Evaluate the Safety, Tolerability, and Efficacy of AZD3470, a PRMT5 Inhibitor, as Monotherapy or in Combination With Anticancer Agent(s) in Participants With Haematologic Malignancies
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- AstraZeneca
- 入组人数
- 161
- 试验地点
- 48
- 主要终点
- Incidence and severity of adverse events (AEs) and serious adverse events (SAEs)
研究概览
简要总结
This study is designed to evaluate the safety, tolerability, PK, pharmacodynamics, and preliminary efficacy following oral administration of AZD3470 as a monotherapy, and in combination with other anticancer agents in participants with haematologic malignancies.
详细描述
This is a modular, Phase I/II, open-label, multicentre study of AZD3470 in participants with haematologic malignancies. The study consists of several study modules, each evaluating the safety, tolerability, PK, pharmacodynamics, and preliminary efficacy of orally administered AZD3470 as a monotherapy and in combination with other anticancer agent(s).
Module 1 Cohort 1 will evaluate AZD3470 monotherapy in adults and adolescents with r/r cHL who have received at least 2 prior lines of anticancer therapy. Part A (dose escalation) will assess AZD3470 at increasing doses to determine Maximum Tolerated Dose and Recommended Dose for Expansion in participants aged 18 years or older. Part B (dose optimization/expansion) will include participants to selected dose levels that were evaluated in Part A to support the recommended phase II dose (RP2D). Safety, tolerability, PK, preliminary efficacy, and food effect will be assessed. Adolescent participants (aged 12 years and older) will only be enrolled in Part B once sufficient supportive adult safety/PK data is reviewed and agreed upon with Safety Review Committee.
Module 1 Cohort 2 will evaluate AZD3470 monotherapy as a consolidation therapy in advanced stage (Stage III/IV) cHL participants aged 50 years or older, who have achieved a response (CR or PR) after at least 4 cycles of frontline standard of care therapy. Safety and tolerability, PK, Pharmacodynamics and preliminary efficacy will be evaluated.
Module 1 Cohort 3 will evaluate AZD3470 monotherapy in participants with r/r PTCL (PTCL NOS, ALCL, AITL) aged 18 years or older, who have received at least one prior anticancer therapy. Safety and tolerability, PK, Pharmacodynamics, and preliminary efficacy will be evaluated.
Module 2 Cohort 1 will evaluate AZD3470 in combination with pembrolizumab in r/r cHL participants aged 18 years or older, who have received at least one prior anticancer therapy. Part A (dose escalation) will include participants at select dose levels below or at the highest tolerable monotherapy dose in Module 1 Cohort 1.
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
- 12 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Core Inclusion criteria:
- •Adequate adult (ECOG) or adolescent (Karnofsy or Lanksy) Performance Score assessments
- •Adequate organ and bone marrow function.
- •Module 1 Cohort 1:
- •Part A (dose escalation): aged ≥ 18 years at the time of signing the informed consent.
- •Part B (optimization): aged ≥ 12 years of age. Adolescent participants must weigh ≥ 40 kg.
- •Histologically confirmed diagnosis of cHL based on WHO criteria
- •Previous treatment with at least 2 prior lines of therapy for the treatment of cHL (including at least 2 cycles of BV and anti-PD1) and have documented r/r active disease requiring treatment.
- •Participants must provide FFPE baseline tumour tissue.
- •At least 1 radiographically measurable, and/or FDG-avid lymphoma lesion ( >1.5 cm for nodal lesion and >1 cm for extranodal lesion).
- •Module 1 Cohort 2:
- •1- Participants must be at least 50 years of age or older at study entry. 2- Histologically confirmed diagnosis of cHL based on WHO criteria 3- Ann Arbor stages III or IV. 4- Participant must have previously received at least 4 cycles of SoC combination therapy with A-AVD, N-AVD, AVD, or ABVD (based on regional SOC, per investigator) as finite first-line induction therapy, and achieved at least a PR post-induction therapy.
- •5- Participants must provide FFPE baseline tumour tissue.
- •Module 1 Cohort 3:
- •Participants must be aged ≥ 18 years at the time of signing the informed consent.
- •Histologically confirmed diagnosis of PTCL NOS, systemic ALCL, or AITL based on WHO criteria.
- •2a- If pre-screening for MTAP deficiency is initiated, all participants must be MTAP deficient as determined by a local test.
- •3- Participants must have received at least 1 prior line of therapy for the treatment of PTCL and have exhausted all available therapies with demonstrated clinical benefit. Participants with ALCL must have received prior BV treatment.
- •4- Participants must provide FFPE baseline tumour tissue
- •Ability to provide an on-treatment biopsy (if the tumour is suitable for biopsy).
- •5- At least 1 radiographically measurable, and/or FDG-avid lymphoma lesions (> 1.5 cm for nodal lesion and >1 cm for extranodal lesion).
- •Module 2 Cohort 1:
- •1- Participants must be aged ≥ 18 years at the time of signing the informed consent.
- •2- Histologically confirmed diagnosis of cHL based on WHO criteria 3- At least 1 radiographically measurable, and/or FDG-avid lymphoma lesions (> 1.5 cm for nodal lesion and >1 cm for extranodal lesion).
- •4- Participant must have received at least 1 prior line of therapy for the treatment of cHL and have documented r/r active disease requiring treatment.
- •5- Participants must provide FFPE baseline tumour tissue.
排除标准
- •Core Exclusion criteria:
- •Any significant laboratory finding or any severe and uncontrolled medical condition.
- •Active CNS involvement by lymphoma, leptomeningeal disease, or spinal cord compression.
- •Serologic active HBV or HCV infection.
- •Known to have tested positive for HIV.
- •Active gastrointestinal disease or other condition that will interfere with oral therapy.
- •Any of the following ECG cardiac criteria: Mean resting QTcF > 470 msec, clinically important abnormalities in rhythm, conduction or morphology, and/or any factors that increase the risk of QTc prolongation or risk of arrhythmic events.
- •Undergone any of the following procedures within 6 months prior to first dose:
- •a) Coronary artery bypass graft, b) Percutaneous coronary intervention or heart valve replacement or repairment, c) Vascular stent implantation (venous stent is eligible), d) Acute coronary syndrome / myocardial infarction, e) Unstable or poorly controlled angina pectoris, f) Ventricular arrhythmias requiring continuous therapy, g) Uncontrolled atrial fibrillation, h) Haemorrhagic or thrombotic stroke (including transient ischaemic attacks) or any other CNS bleeding.
- •i) Acute venous or atrial thromboembolic event (unless considered stable or adequately treated with at least 3months of therapeutic anticoagulation).
- •Severe valvular heart disease.
- •Congestive heart failure Grade II to Grade IV.
- •Prior or current cardiomyopathy.
- •Uncontrolled hypertension.
- •History of significant haemoptysis or haemorrhage within4 weeks of the first dose of study treatment.
- •Unresolved toxicities of Grade > 1 from prior anti cancer therapy (excluding peripheral neuropathy, vitiligo, alopecia and endocrine disorders that are controlled with replacement hormone therapy, and asymptomatic laboratory abnormalities), unless immune-mediated.
- •History of another primary malignancy.
- •Received the following anticancer therapies: anti-lymphoma therapy (within 21 days), radiation therapy(within 28 days), allo-HSCT (within 180 days), auto-HSCT/cellular therapy (within 60 days), or MAT2A or PRMT5 inhibitor
- •Requires ongoing immunosuppressive therapy, including systemic corticosteroids.
- •Psychiatric illness/social situations/substance abuse disorders that would limit compliance with study requirements or compromise the ability to give written informed consent.
- •Use of prescription medications that are known as:
- •Strong or moderate inhibitors or inducers of CYP3A4, sensitive substrates of CYP3A4, inhibitors or substrates of CYP2D6, inhibitors and sensitive substrates of CYP2C8, and NTI substrates of CYP3A4, CYP2D6, and CYP2C
- •Received live, attenuated vaccine within 30 days prior to first dose of treatment.
- •Known hypersensitivity to AZD3470 or any of the excipients of the product.
- •Involvement in planning or conduct of the study (applies to both AstraZeneca staff and site staff).
- •Judgement by investigator that the participant is unlikely to comply with study procedures, restrictions, and requirements.
- •Previous enrolment in the present study.
- •Pregnant (confirmed with positive pregnancy test) or breastfeeding or intends to become pregnant during the study.
- •Concurrent enrolment in another clinical study, unless it is an observational (noninterventional) clinical study or the follow-up period of an interventional study.
- •Module 2 Cohort 1:
- •History of confirmed ILD, drug-induced ILD, radiation pneumonitis requiring steroid treatment or any evidence of clinically active ILD or pneumonitis.
- •≥Grade 3 immune-mediated AE while receiving prior checkpoint inhibitor immunotherapy, or any unresolved ≥Grade 2 immune-mediated AE.
- •History of immune-mediated myocarditis or pericarditis.
- •Experienced a toxicity that led to permanent discontinuation of prior immunotherapy.
- •Active or prior documented pathologically confirmed autoimmune or inflammatory disorders
- •Refractory to prior checkpoint inhibitor therapy (within 12 weeks of last dose)
- •Eligible for allogeneic or autologous stem cell transplant.
- •Received an allogeneic HSCT within 5 years of the first dose of study treatment; must not have active Graft-versus-host disease.
- •Participants with a known hypersensitivity to pembrolizumab or any of the excipients of the product.
研究组 & 干预措施
AZD3470 in combination with Pembrolizumab
Module 2 Cohort 1 will assess participants aged ≥18 years with r/r cHL who have received at least one prior line of anticancer therapy. Participants will receive treatment according to the protocol-defined limit, or until disease progression, unacceptable toxicity as judged by the investigator or until meeting any other discontinuation criteria, as defined in the clinical study protocol, whichever occurs first.
Part A (dose escalation) will evaluate the safety and tolerability of AZD3470 in combination with Pembrolizumab.
Part B (dose optimization/expansion) will evaluate dose optimization/expansion in certain dose levels of AZD3470 in combination with Pembrolizumab, based on cumulative data from dose escalation part (Part A).
干预措施: AZD3470 (Drug)
AZD3470 in combination with Pembrolizumab
Module 2 Cohort 1 will assess participants aged ≥18 years with r/r cHL who have received at least one prior line of anticancer therapy. Participants will receive treatment according to the protocol-defined limit, or until disease progression, unacceptable toxicity as judged by the investigator or until meeting any other discontinuation criteria, as defined in the clinical study protocol, whichever occurs first.
Part A (dose escalation) will evaluate the safety and tolerability of AZD3470 in combination with Pembrolizumab.
Part B (dose optimization/expansion) will evaluate dose optimization/expansion in certain dose levels of AZD3470 in combination with Pembrolizumab, based on cumulative data from dose escalation part (Part A).
干预措施: Pembrolizumab (Drug)
AZD3470 Monotherapy
Module 1 Cohort 1 evaluates safety, tolerability, efficacy of AZD3470 in r/r cHL participants with 2 prior lines of systemic anticancer therapy (including BV and anti-PD1). Participants will be treated according to protocol-defined windows.
Part A (dose escalation) assesses AZD3470 at increasing doses in participants aged ≥18 years, r/r cHL.
Part B (dose optimization/ expansion) includes participants at certain dose levels evaluated as tolerable in Part A and may include adolescent patients aged ≥12 years, upon SRC agreement.
Module 1 Cohort 2 evaluates the safety, tolerability, efficacy of AZD3470 as consolidation for Stage III/IV cHL participants aged ≥50 years after CR or PR to frontline SOC therapy (either N-AVD, A-AVD, AVD, ABVD)
Module 1 Cohort 3 evaluates the safety, tolerability, preliminary efficacy of AZD3470 in participants aged ≥18 years with r/r PTCL (PTCL NOS, ALCL, AITL subtypes) with at least 1 prior line of systemic anticancer therapy.
干预措施: AZD3470 (Drug)
结局指标
主要结局
Incidence and severity of adverse events (AEs) and serious adverse events (SAEs)
时间窗: From Screening until 28 days after the last dose of study medication.
AEs: Number of patients with adverse events by system organ class and preferred term. SAEs: Number of patients with serious adverse events by system organ class and preferred term.
Incidence of DLTs (Dose Escalation only)
时间窗: From first dose of AZD3470 to end of Cycle 1 (each cycle is 21 days).
In the Dose Escalation cohorts in Part A, the number of participants with at least 1 dose-limiting toxicity (DLT), which is any toxicity defined as a DLT in the Clinical Study Protocol.
Incidence and severity of adverse events (AEs) and serious adverse events (SAEs)
时间窗: From Screening continuously until 28 days after the last dose of study medication.
AEs: Number of patients with adverse events by system organ class and preferred term. SAEs: Number of patients with serious adverse events by system organ class and preferred term.
Incidence of DLTs (Dose Escalation Cohorts only)
时间窗: From first dose of AZD3470 to end of Cycle 1 (each cycle is 21 days).
In the Dose Escalation cohorts in Part A, the number of participants with at least 1 dose-limiting toxicity (DLT), which is any toxicity defined as a DLT in the Clinical Study Protocol.
次要结局
- Part A and Part B: Response endpoints - Objective Response Rate (ORR)/Complete Response Rate (CRR)(From first dose (Cycle 1 Day 1, each cycle is 21 days) until disease progression or the last evaluable assessment in the absence of progression (assessed approximately up to 2 years).)
- Part A and Part B: Response endpoints - Duration of Response (DoR)(From first dose (Cycle 1 Day 1, each cycle is 21 days) until disease progression or death, whichever comes first (assessed approximately up to 2 years).)
- Part A and Part B: Progression-free Survival (PFS)(Non-randomized study parts: from first dose (each cycle is 21 days) until disease progression or death, whichever comes first. Randomized parts: from date of randomization until disease progression or death, whichever comes first (approx up to 2 years).)
- Part A and Part B: Overall Survival (OS)(Non-randomized study parts: From first dose (Cycle 1 Day 1, each cycle is 21 days) until death. Randomized study parts: from date of randomization until the date of death due to any cause (assessed approximately up to 2 years).)
- Part A and Part B: Maximum observed plasma drug concentration (Cmax)(From Cycle 1 Day 1 (each cycle is 21 days) to EoT, at predefined intervals throughout the treatment period (for each patient this is expected to be approximately 6 months).)
- Part A: Dose normalised maximum observed plasma drug concentration (Cmax)(From Cycle 1 Day 1 (each cycle is 21 days) to EoT, at predefined intervals throughout the treatment period (for each patient this is expected to be approximately 6 months).)
- Part A: Accumulation ratio for maximum observed plasma drug concentration (Cmax)(From Cycle 1 Day 1 (each cycle is 21 days) to EoT, at predefined intervals throughout the treatment period (for each patient this is expected to be approximately 6 months).)
- Part A and Part B: Minimum observed plasma drug concentration (Cmin)(From Cycle 1 Day 1 (each cycle is 21 days) to EoT, at predefined intervals throughout the treatment period (for each patient this is expected to be approximately 6 months).)
- Part A and Part B: Time to reach peak or maximum observed concentration following drug administration (Tmax)(From Cycle 1 Day 1 (each cycle is 21 days) to EoT, at predefined intervals throughout the treatment period (for each patient this is expected to be approximately 6 months).)
- Part A and Part B: Area under the plasma concentration-curve over the dosing interval (AUCtau)(From Cycle 1 Day 1 (each cycle is 21 days) to EoT, at predefined intervals throughout the treatment period (for each patient this is expected to be approximately 6 months).)
- Part A: Dose normalized area under the plasma concentration-curve over the dosing interval (AUCtau)(From Cycle 1 Day 1 (each cycle is 21 days) to EoT, at predefined intervals throughout the treatment period (for each patient this is expected to be approximately 6 months).)
- Part A: Accumulation ratio for area under the plasma concentration-curve over the dosing interval (AUCtau)(From Cycle 1 Day 1 (each cycle is 21 days) to EoT, at predefined intervals throughout the treatment period (for each patient this is expected to be approximately 6 months).)
- Part A: Cumulative amount (%) of drug recovered unchanged in urine during dosing interval (Ae,tau)(From Cycle 1 Day 1 to end of Cycle 1 at predefined intervals throughout the cycle (each cycle is 21 days).)
- Part A: Renal clearance (Clr)(From Cycle 1 Day 1 to end of Cycle 1 at predefined intervals throughout the cycle (each cycle is 21 days).)
- Part B: Ratio of maximum observed plasma drug concentration (Cmax) under fed/fasted state(From Cycle 1 Day 1 to Cycle 2 Day 1 at predefined intervals (each cycle is 21 days).)
- Part B: Time to reach peak or maximum observed concentration following drug administration (Tmax) under fed conditions(From Cycle 1 Day 1 to Cycle 2 Day 1 at predefined intervals (each cycle is 21 days).)
- Part B: Time to reach peak or maximum observed concentration following drug administration (Tmax) under fasted conditions(From Cycle 1 Day 1 to Cycle 2 Day 1 at predefined intervals (each cycle is 21 days).)
- Part B: Ratio of area under the plasma concentration-curve over the dosing interval (AUCtau) under fed/fasted state(From Cycle 1 Day 1 to Cycle 2 Day 1 at predefined intervals (each cycle is 21 days).)
- Response endpoints as assessed by the investigator according to the Lugano Classification: Objective Response Rate (ORR)/Complete Response Rate (CRR)(From first dose (Cycle 1 Day 1, each cycle is 21 days) until disease progression or the last evaluable assessment in the absence of progression.)
- Response Endpoints as assessed by investigator according to the Lugano Classification: Conversation rate of Partial Response (PR) to Complete Response (CR)(From First dose (Cycle 1 Day 1, each cycle is 21 days) until disease progression or the last evaluable assessment in the absence of progression.)
- Response endpoints as assessed by the investigator according to the Lugano Classification: Duration of Response (DoR)(From date of first objective response until documented progression or death due to any cause or censoring (if progression or death have not occurred))
- Response endpoints as assessed by the investigator according to the Lugano Classification for CHL: The rate of durable CR(From date of first complete response until documented progression or death due to any cause or censoring (if progression or death have not occurred))
- Response Endpoints as assessed by the investigator according to the Lugano Classification: Progression-free Survival (PFS)(From first dose (each cycle is 21 days)/from randomisation (for non-randomized & randomized study parts respectively) until disease progression or death, or censoring (if progression or death have not occurred) whichever is first)
- Response Endpoints as assessed by the investigator according to the Lugano Classification: Overall Survival (OS)(From first dose (each cycle is 21 days)/from randomisation (for non-randomized & randomized study parts respectively) until disease progression or death, or censoring (if progression or death have not occurred) whichever is first)
- Measurement of Plasma PK parameters: AUC, Cmax, tmax, Ctrough, t1/2 λz, CL/F, and Vz/F(From Cycle 1 Day 1 (each cycle is 21 days) to EoT, at predefined intervals throughout the treatment period.)
- Measurement of Plasma PK parameters under fed or fasted conditions: Ratio of Cmax, Tmax, and AUCtau(From Cycle 1 Day 1 to Cycle 2 Day 1 at predefined intervals (each cycle is 21 days).)
- Urine PK parameters including Cumulative percentage of unchanged drug in urine (Ae,tau) during dosing interval and renal clearance(From Cycle 1 Day 1 to end of Cycle 1 at predefined intervals throughout the cycle (each cycle is 21 days).)
- Percentage change from baseline tumour SDMA mesaured by IHC.(From Screening to EoT, at predefined intervals throughout the treatment period.)