A Phase I, Multicenter Dose-Escalation Study to Assess the Tolerability, Pharmacokinetics and Preliminary Anti-tumor Activity of AZD5153 in Patients With Relapsed/Refractory Malignant Solid Tumors, Including Lymphomas
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- AstraZeneca
- 入组人数
- 49
- 试验地点
- 1
- 主要终点
- Incidence of dose-limiting toxicity (DLT).
研究概览
简要总结
This is a first-time-in-man (FTIM) multicenter, dose escalation study designed to investigate the safety, pharmacokinetics, and pharmacodynamics of AZD5153 in patients with malignant solid tumors, including lymphomas.
详细描述
The trial will be conducted in two parts, dose escalation and dose expansion. AZD5153 will be investigated as a monotherapy and in combination with olaparib.
AZD5153 monotherapy (dose escalation):
This part of the study will enroll patients with advanced solid malignancies, including lymphoma, and test safety and tolerability of AZD5153 administered as a monotherapy. The dose escalation will proceed by two-fold increments or through lower doses suggested by the CRM until an MTD as defined by dose-limiting toxicity is reached.
Single daily (QD) and twice daily (BID) dosing schedules will be explored in the monotherapy cohort. Additional dose levels or dosing schedules may be evaluated and recommended by study Safety Review Committee (SRC) based on the emerging PK and safety data.
When the AZD5153 monotherapy MTD is established, an expansion cohort consisting of up to 12 additional evaluable patients may be enrolled to confirm the safety and tolerability of the MTD. The dose expansion will be initiated and will enroll patients with histologically or cytologically confirmed platinum resistant or platinum-refractory high grade serous ovarian (HGSO) cancer.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non 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
- 未提供
排除标准
- •Patients who have been treated with most recent chemotherapy, radiotherapy, hormonal therapy, immunotherapy or investigational drugs within 21 days or 5 half-lives (whichever is shorter) from enrollment.
- •Minimum wash-out period for previous PARPi therapy is at least 14 days or 5 half-lives whichever is shorter, or until toxicity from previous PARPi therapy has fully recovered.
- •Patient received more than 5 prior lines of treatment for an advanced solid tumor (including HGSO cancer, TNBC, mCRPC, or PDAC). Patients with lymphoma will be able to enroll without a restriction in the number of previous therapies received, if they otherwise meet eligibility criteria.
- •Major surgery (excluding placement of vascular access) ≤ 21 days from the beginning of enrollment or minor surgical procedures ≤ 7 days. No waiting is required following implantable port and catheter placement.
- •Patient is unable to swallow oral medications or has a gastrointestinal disorder (e.g., malabsorption) that would jeopardize intestinal absorption of AZD5153 and olaparib.
- •Treatment with any of the following:
- •Patient has had prescription or non-prescription drugs or other products known to be strong or moderate inhibitors/inducers of CYP3A4/5, or CYP3A4/5 sensitive substrates or substrates with a narrow therapeutic range, which cannot be discontinued 2 weeks prior to the first day of dosing and withheld throughout the study until 2 weeks after the last dose of AZD5153 and/or olaparib.
- •Drugs that are sensitive substrates of the transporters P-gp, UGT1A1, BCRP, OATP1B1, OAT3, OCT1, OCT2, MATE1 and MATE2K.
- •Herbal preparations/medications are not allowed throughout the study. These herbal medications include, but are not limited to: St. John's wort, kava, ephedra (ma huang), ginkgo biloba, dehydroepiandrosterone, yohimbe, saw palmetto, and ginseng. Patients should stop using these herbal medications 14 days prior to the first dose of AZD5153 and/or olaparib.
- •Drugs known to prolong QT interval or induce Torsades de Pointes.
- •Refractory nausea and vomiting, previous significant bowel resection that would preclude adequate absorption of study drug and chronic gastrointestinal disease including active or prior documented inflammatory bowel disease.
- •Patient has a history of tuberculosis.
- •Patients receiving a live attenuated vaccine ≤28 days before the first dose of study drug.
- •Spinal cord compression or brain metastases unless asymptomatic, treated and stable and not requiring steroids for at least 4 weeks prior to start of study treatment.
- •A diagnosis of MDS or secondary AML (for olaparib combination dose escalation only)
- •As judged by the Investigator, any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension, active bleeding diatheses, or active infection including hepatitis B, hepatitis C, human immunodeficiency virus (HIV) or other comorbidity that renders the patient unsuitable for participation in the study. Screening for chronic conditions is not required.
- •Any of the following cardiac criteria:
- •Mean resting corrected QT interval (QTcF) >450 msec obtained from 3 electrocardiograms (ECGs).
- •Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG e.g., complete left bundle branch block, third degree heart block.
- •Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age.
- •History of hypersensitivity to active or inactive excipients of AZD5153 and/or olaparib or drugs with a similar chemical structure or class to AZD5153 and/or olaparib.
- •Patients with non-Hodgkin lymphoma (NHL) at high risk for developing tumor lysis syndrome are not eligible for the monotherapy dose escalation part of this study.
- •Judgment by the Investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements.
- •Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol.
研究组 & 干预措施
AZD5153 Monotherapy
Patients will be enrolled in cohorts of up to 6 patients each in a dose escalating scheme to determine maximum tolerated dose (MTD). AZD5153 will be taken once per day (QD) or two times per day (BID) for 21 days as an oral capsule. Once the MTD is finalized, patients may be enrolled into an expansion cohort at the MTD.
干预措施: AZD5153 (Drug)
AZD5153 + Olaparib Combination Therapy
Patients will be enrolled in cohorts of up to 6 patients each in a dose escalating scheme to determine MTD. AZD5153 will be taken as oral capsules BID in combination with 300 mg olaparib BID for 21 days.
干预措施: AZD5153 (Drug)
AZD5153 + Olaparib Combination Therapy
Patients will be enrolled in cohorts of up to 6 patients each in a dose escalating scheme to determine MTD. AZD5153 will be taken as oral capsules BID in combination with 300 mg olaparib BID for 21 days.
干预措施: Olaparib (Drug)
结局指标
主要结局
Incidence of dose-limiting toxicity (DLT).
时间窗: From the first dose of study treatment up to last day of cycle 1 (21 days)
DLTs will be determined from monitoring adverse events (AEs), and abnormal laboratory tests (clinical chemistry, hematology, and urinalysis), physical examinations, vital signs (blood pressure and pulse), and electrocardiogram (ECG).
次要结局
- Antitumor activity of AZD5153 in patients by assessing progression free survival (PFS).(Up to 1 year)
- Antitumor activity of AZD5153 in patients by assessing the disease control rate (DCR).(Up to 1 year)
- Antitumor activity of AZD5153 in patients by assessing overall response rate (ORR).(Up to 1 year)
- Peak plasma concentration (Cmax)(Samples for single dose PK will be collected at prespecified time points on Day 1, Cycle 1 pre-dose on Day 2. Multiple-dose PK will be assessed from samples taken on Days 15 and 16 of Cycle 1.)
- The urine concentration of AZD5153 and its co-former (if appropriate).(Urine will be collected pre-dose (spot sample), and volumetrically from 0-6, 6-12, 12-24 hours on Day 1 and Day 15 of Cycle 1.)
- The effect of AZD 5153 on QTc interval.(ECGs will be performed at prespecified time points on Days 1 and 2 and 15 and 16 of Cycle 1.)
- Antitumor activity of AZD5153 in patients by assessing duration of response (DoR).(Up to 1 year)
- Area under the plasma concentration versus time curve (AUC).(Samples for single dose PK will be collected at prespecified time points on Day 1, Cycle 1 pre-dose on Day 2. Multiple-dose PK will be assessed from samples taken on Days 15 and 16 of Cycle 1.)
- Time to reach peak plasma concentration (tmax).(Samples for single dose PK will be collected at prespecified time points on Day 1, Cycle 1 pre-dose on Day 2. Multiple-dose PK will be assessed from samples taken on Days 15 and 16 of Cycle 1.)
- Elimination half-lfe (t1/2).(Samples for single dose PK will be collected at prespecified time points on Day 1, Cycle 1 pre-dose on Day 2. Multiple-dose PK will be assessed from samples taken on Days 15 and 16 of Cycle 1.)
- Volume of distribution (Vd).(Samples for single dose PK will be collected at prespecified time points on Day 1, Cycle 1 pre-dose on Day 2. Multiple-dose PK will be assessed from samples taken on Days 15 and 16 of Cycle 1.)
- Clearance (CL).(Samples for single dose PK will be collected at prespecified time points on Day 1, Cycle 1 pre-dose on Day 2. Multiple-dose PK will be assessed from samples taken on Days 15 and 16 of Cycle 1.)