A Modular Open-label, Phase I/IIa Study to Assess the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Preliminary Efficacy of Ascending Doses of AZD4956 as Monotherapy, and in Combination With Anti-Cancer Agents in Participants With Advanced/Metastatic Homologous Recombination Repair Defective Solid Tumours
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- AstraZeneca
- 入组人数
- 180
- 试验地点
- 19
- 主要终点
- Parts A and B: Number of participants with adverse events (AEs) and serious adverse events (SAEs)
研究概览
简要总结
The purpose of this modular, first trial in human study is to assess the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of ascending dose levels (DLs) of AZD4956 monotherapy and in combination with other anti-cancer agents in participants with advanced/metastatic solid tumours with homologous recombination repair (HRR) deficiencies.
详细描述
The study consists of individual modules each evaluating the safety and tolerability of AZD4956 dosed as monotherapy, or with a specific combination partner. There are following 2 modules -
- Module 1: AZD4956 monotherapy
- Module 2: AZD4956 in combination with saruparib
Each module may further contain 2 parts-
- Part A (dose escalation/dose finding): To determine the safety, tolerability, PK, PD, and preliminary efficacy of AZD4956 as monotherapy or in combination.
- Part B (dose expansion): To further evaluate the safety and preliminary efficacy of AZD4956 in combination with other anti-cancer agents.
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 130 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Core Inclusion Criteria:
- •Documented locally advanced or metastatic solid tumour malignancy.
- •Eastern cooperative oncology group (ECOG) performance status of 0 or 1 with no deterioration over the previous 2 weeks prior to screening and first day of dosing.
- •Minimum life expectancy ≥ 12 weeks.
- •Adequate organ and marrow function.
- •Female participants must not breastfeed and must not donate or retrieve ova for their own use from screening to approximately 6 months after the last dose of study intervention.
- •Module 1 Inclusion Criteria:
- •Demonstrated evidence of disease progression.
- •Participants must have advanced or metastatic solid tumours.
- •Participants may have received up to one prior line of therapy with a poly (adenosine diphosphate-ribose) polymerase inhibitor (PARPi)-based regimen (either as a treatment or as maintenance).
- •Module 2 Inclusion Criteria:
- •Part A (AZD4956 in Combination with Saruparib Dose Escalation) and Part A-PD (PD Backfill Cohorts):
- •Participants must have one of the following conditions-
- •Histologically or cytologically confirmed carcinoma of the breast with recurrent locally advanced or metastatic disease and evidence of a predicted loss of function germline or somatic mutation.
- •Histologically or cytologically confirmed advanced ovarian, fallopian tube, or primary peritoneal cancer.
- •Histologically or cytologically confirmed adenocarcinoma of the prostate and advanced/metastatic castrate resistant prostate cancer (CRPC).
- •Histologically or cytologically confirmed advanced/metastatic pancreatic cancer.
- •Participants must have evaluable disease.
- •Participants in PD backfill cohorts must not have received prior therapy with a PARPi-based regimen (either as a treatment or as maintenance).
- •Part A (PD Backfill Cohorts) - Participants Undergoing Paired Biopsies:
- •- Participants must have a tumour suitable for biopsy.
- •Part A-Non-PD (Non-PD Backfill Cohorts) and Part B (Dose Expansion Cohorts):
- •Participants must have histologically or cytologically confirmed adenocarcinoma of the prostate and advanced/metastatic CRPC.
- •Participants must have documented metastatic disease by clear evidence of ≥ 1 bone lesion (defined as one lesion with positive uptake on bone scan) and/or ≥ 1 soft tissue lesion (measurable or non-measurable).
- •Participants must have received the prior approved systemic therapies for metastatic prostate cancer.
- •Participants must not have received prior therapy with a PARPi-based regimen (either as a treatment or as maintenance).
排除标准
- •Any significant laboratory finding or any severe and uncontrolled medical condition.
- •Participants with any known predisposition to bleeding.
- •Spinal cord compression or symptomatic and unstable brain metastases or leptomeningeal disease.
- •Allogenic organ transplantation.
- •Known to have active infection, including hepatitis B virus (HBV) or hepatitis C virus (HCV).
- •Known history of infection with human immunodeficiency virus (HIV).
- •Active gastrointestinal disease or other condition that will interfere significantly with the swallowing, absorption, distribution, metabolism or excretion of oral therapy.
- •Participants with history of myelodysplastic syndrome (MDS)/acute myeloid leukaemia (AML) or with features suggestive of MDS/AML.
- •Participants with a known hypersensitivity to the investigational product(s) or any of the excipients of the product(s).
- •Previous dosing with AZD4956.
研究组 & 干预措施
Module 2 Part A: AZD4956 + saruparib (Dose escalation)
Participants will receive AZD4956 at ascending dose levels in combination with saruparib.
干预措施: Saruparib (Drug)
Module 2 Part A: AZD4956 + saruparib (Dose escalation)
Participants will receive AZD4956 at ascending dose levels in combination with saruparib.
干预措施: AZD4956 (Drug)
Module 2 Part A Optional non-PD backfill cohort: AZD4956 + saruparib
Participants with metastatic castrate resistant prostate cancer (mCRPC) will receive AZD4956 in combination with saruparib.
干预措施: AZD4956 (Drug)
Module 1 Part A: AZD4956 monotherapy (Dose escalation)
Participants will receive AZD4956 as monotherapy at ascending dose levels.
干预措施: AZD4956 (Drug)
Module 2 Part B: AZD4956 + saruparib (Dose expansion)
Participants will receive AZD4956 in combination with saruparib.
干预措施: Saruparib (Drug)
Module 2 Part A Optional PD backfill cohort: AZD4956 + saruparib
Participants will receive AZD4956 in combination with saruparib.
干预措施: AZD4956 (Drug)
Module 2 Part A Optional PD backfill cohort: Saruparib monotherapy
Participants will receive saruparib monotherapy.
干预措施: Saruparib (Drug)
Module 2 Part A Optional non-PD backfill cohort: AZD4956 + saruparib
Participants with metastatic castrate resistant prostate cancer (mCRPC) will receive AZD4956 in combination with saruparib.
干预措施: Saruparib (Drug)
Module 2 Part B: AZD4956 + saruparib (Dose expansion)
Participants will receive AZD4956 in combination with saruparib.
干预措施: AZD4956 (Drug)
Module 2 Part A Optional PD backfill cohort: AZD4956 + saruparib
Participants will receive AZD4956 in combination with saruparib.
干预措施: Saruparib (Drug)
结局指标
主要结局
Parts A and B: Number of participants with adverse events (AEs) and serious adverse events (SAEs)
时间窗: From Screening (Day -28) to follow-up (up to 3.5 years)
To assess the safety and tolerability of AZD4956 monotherapy and in combination with anti-cancer agent(s).
Part B: Progression free survival (PFS)
时间窗: Up to 3.5 years
PFS is defined as the time from the start of treatment until the date of objective disease progression or death (by any cause in the absence of progression), regardless of whether the participants withdraw from study treatment or receive another anti-cancer therapy prior to progression.
Part A - Number of participants with dose-limiting toxicities (DLTs)
时间窗: Up to 28 days
To assess the safety and tolerability of AZD4956 monotherapy and in combination with anti-cancer agent(s).
次要结局
- Objective response (OR)(Up to 3.5 years)
- Duration of response (DoR)(Up to 3.5 years)
- Best Overall Response (BOR)(Up to 3.5 years)
- Time to response (TTR)(Up to 3.5 years)
- Disease control (DC)(Up to 3.5 years)
- Clinical benefit rate (CBR)(Up to 3.5 years)
- Part A: Progression free survival (PFS)(Up to 3.5 years)
- Percentage change from baseline in tumour size(Up to 3.5 years)
- Number of participants with cancer antigen 125 (CA125) response (for ovarian cancer participants)(From baseline up to 3.5 years)
- Radiological progression free survival (rPFS) (for prostate cancer participants)(Up to 3.5 years)
- Change from baseline in prostate specific antigen 50 (PSA50) response rate (for prostate cancer participants)(From baseline up to 3.5 years)
- Change from baseline in PSA90 response rate (for prostate cancer participants)(From baseline up to 3.5 years)
- Change from baseline in PSA undetectable rate(At 3, 6 and 9 months)
- Time to PSA50/90 response (for prostate cancer participants)(Up to 3.5 years)
- Time to PSA progression (for prostate cancer participants)(Up to 3.5 years)
- PSA PFS at 6 months (PSA-6)(At 6 months)
- Area under the concentration-time curve (AUC)(From date of first dose of study intervention up to 59 days after first dose)
- Maximum concentration (Cmax)(From date of first dose of study intervention up to 59 days after first dose)
- Time to maximum concentration (Tmax)(From date of first dose of study intervention up to 59 days after first dose)
- Individual and cumulative percentage of dose excreted unchanged in urine from time t1 to time t2 (fe(t1-t2))(From date of first dose of study intervention up to 16 days after first dose)
- Renal clearance (CLR)(From date of first dose of study intervention up to 16 days after first dose)
- Individual and cumulative amount of unchanged drug excreted into urine from time t1 to time t2 (Ae(t1-t2))(From date of first dose of study intervention up to 16 days after first dose)
- Change in amount of KRAB-associated protein-1 phosphorylated on serine 824 [pKAP1 (Ser824)] biomarker in tumour cells at baseline and during treatment(From Baseline up to 3.5 years)