A Modular Phase I, Open-Label, Multicentre Study to Assess the Safety, Tolerability, Pharmacokinetics and Preliminary Anti-tumour Activity of Ceralasertib in Combination With Cytotoxic Chemotherapy and/or DNA Damage Repair/Novel Anti-cancer Agents in Patients With Advanced Solid Malignancies.
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 发起方
- AstraZeneca
- 入组人数
- 358
- 试验地点
- 29
- 主要终点
- The number of subjects with adverse events/serious adverse events
研究概览
简要总结
This is a modular, phase I/ phase 1 b, open-label, multicentre study of ceralasertib administered orally in combination with cytotoxic chemotherapy regimens and/or novel anti-cancer agents, to patients with advanced malignancies. The study design allows an investigation of optimal combination dose of ceralasertib with other anti-cancer treatments, with intensive safety monitoring to ensure the safety of the patients. The initial combination to be investigated is ceralasertib with carboplatin. The second combination to be investigated is ceralasertib with Olaparib. The third combination to be investigated is ceralasertib with durvalumab. The fourth module will investigate the effect of food on ceralasertib absorption and the effect of ceralasertib on ECG parameter. The fifth module to be investigated is ceralasertib with AZD5305.
详细描述
This is a modular, phase I, two part, open-label, multicentre study of ceralasertib, administered orally, in combination with cytotoxic chemotherapy regimens and/or novel anti-cancer agents, to patients with advanced/metastatic solid malignancies. The study design allows an escalation of the dose of ceralasertib in combination with the standard dose and schedule of either cytotoxic chemotherapies and/or novel anti-cancer agents, with intensive safety monitoring to ensure the safety of the patients. There are two parts to each combination module of this study; part A, dose escalation and an optional part B, cohort expansions in particular patient groups. The initial combination module will be with Carboplatin (module 1). The second combination will be with Olaparib (module 2). The third combination will be with durvalumab (module 3), the fourth combination will be AZD5305 (Module 5). The option to start further combination modules will be the decision of the Safety Review Committee (SRC), based on emerging preclinical data and, safety and tolerability information from the initial combination. Combinations of ceralasertib with novel anti-cancer agents may also be explored. Once a minimally biologically active dose of ceralasertib, for that combination module, has been identified from part A of that module, the SRC may decide to commence part B if deemed to be necessary. This may include cohort expansions of specific patient groups to explore preliminary anti-tumour activity or the effect of food or particular drug combinations on drug pharmacokinetics. The fourth module will investigate the effect of food on ceralasertib absorption and whether ceralasertib has an effect on QT.
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
- •Principal Inclusion criteria:
- •Aged at least 18
- •The presence of a solid malignant tumour that is not considered appropriate for further standard treatment
- •Module 2 Part B study expansions, and Module 3: patients must have a tumour at least 1 cm in size that can be measured using a CT or MRI scan
- •Module 2 Part B All (except B5): No previous treatment with PARP inhibitor.
- •Module 2 Part B1 Study expansion: advanced gastric adenocarcinoma (including GEJ) patients with ATM deficient tumours
- •Module 2 Part B2 Study expansion: advanced gastric adenocarcinoma (including GEJ) patients with ATM proficient tumours
- •Module 2 Part B3 Study expansion: Second or thrid line HER2 negative breast cancer
- •Module 2 Part B4 Study expansion: Second or third line triple negative breast cancer (TNBC)
- •Module 2 Part B5 Study expansion: BRCAm or RAD51C/Dm or PALB2m or HRD positive status ovarian cancer patient who are Platinum Sensitive Relapsed and have previously progressed on a licensed PARPi
- •Module 3: advanced recurrent or metastatic non-small cell lung cancer, or head and neck squamous cell carcinoma
- •Module 4: any advanced solid tumours except gastric, gastro-oesophageal, oesophageal or colorectal cancer with a small bowel resection
- •Module 4: Ability to comply with an overnight fast of at least 10 hours prior to dosing and 4 hours after dosing as mandated, and ability to eat a high fat meal as mandated
- •Module 5 All: Ovarian fallopian tube or primary peritonial cancer, previous treatment with PARP inhibitor, platinum-sensitive relapsed ovarian cancer
- •Module 5 Part B: known or suspected BRCA mutation, PALB2 mutation, RAD51C/D mutation or HRD positive status
排除标准
- •A diagnosis of ataxia telangiectasia
- •Prior exposure to an ATR inhibitor
- •Bad reaction to ceralasertib
- •Module 2: Contra-indicated for treatment with olaparib
- •Module 3: Contra-indicated for treatment with durvalumab
- •Module 4: Mean resting corrected QT interval (QTc) >470 msec or history of familial long QT syndrome.
- •Module 4: Patients with type I or type II diabetes
- •Module 5: Known hypersensitivity to PARP including AZD5305
研究组 & 干预措施
Module 2 Part A1
Module 2 Part A1: ascending doses of ceralasertib will be administered alone to define the maximum tolerated dose (MTD) and/or a continuous, tolerable Recommended Dose (RD) to take into Module 2 Part A2.
干预措施: Administration of ceralasertib (Drug)
Module 2 Part B1
Module 2 Part B1: Patients with second line 'ATM deficient' gastric adenocarcinoma including GEJ adenocarcinoma will receive ceralasertib with olaparib, at dose, frequency and schedule recommended from Module 2 Part A2.
干预措施: Administration of ceralasertib in combination with olaparib (Drug)
Module 2 Part A2
Module 2 Part A2: ascending doses of ceralasertib will be administered in combination with olaparib to patients to define the dose, frequency and schedule of ceralasertib and olaparib to take into Module 2 Part B.
干预措施: Administration of ceralasertib in combination with olaparib (Drug)
Module 2 Part B2
Module 2 part B2: Patients with second line 'ATM proficient' gastric adenocarcinoma including GEJ adenocarcinoma will receive ceralasertib with olaparib, at dose, frequency and schedule recommended from Module 2 Part A2.
干预措施: Administration of ceralasertib in combination with olaparib (Drug)
Module 3 Part B
Module 3 Part B: cohort expansions of ceralasertib in combination with durvalumab in HNSCC or NSCLC patients at dose, frequency and schedule from Module 3 Part A.
干预措施: Administation of ceralasertib in combination with durvalumab (Drug)
Module 3 Part A
Module 3 Part A: cohort escalation of ceralasertib in combination with durvalumab in HNSCC or NSCLC patients to define the dose, frequency and schedule of ceralasertib and durvalumab to take into Module 3 Part B. Additionally, Module 3 Part A will include a serial tumour biopsy cohort to evaluate the Proof of Mechanism of ceralasertib in HNSCC and NSCLC patients.
干预措施: Administation of ceralasertib in combination with durvalumab (Drug)
Module 4 (FE/QT)
Ceralasertib monotherapy will be administered on a number of days during Cycle 0 to assess the effect of food on ceralasertib absorption and effect of ceralasertib on ECG parameters under various conditions (fasted, fed, steady state). From C1 onwards, patients who participated in C0 will be allocated to either ceralasertib in combination with olaparib or durvalumab, or ceralasertib monotherapy and assessed for safety.
干预措施: Administration of ceralasertib and olaparib (Drug)
Module 5 Part A
Module 5 Part A: ascending doses of ceralasertib will be administered in combination with AZD5305 to patients to define the MTD, RP2D.
In case this first dose level is not tolerated, alternative schedules will be evaluated.
干预措施: Administration of ceralasertib in combination with AZD5305 (Drug)
Module 4 (FE/QT)
Ceralasertib monotherapy will be administered on a number of days during Cycle 0 to assess the effect of food on ceralasertib absorption and effect of ceralasertib on ECG parameters under various conditions (fasted, fed, steady state). From C1 onwards, patients who participated in C0 will be allocated to either ceralasertib in combination with olaparib or durvalumab, or ceralasertib monotherapy and assessed for safety.
干预措施: Administration of ceralasertib and durvalumab (Drug)
Module 1 Part B
Module 1 Part B: patients with advanced lung adenocarcinoma with low expression of ATM will receive ceralasertib and carboplatin, at the dose, frequency and schedule recommended from Module 1 Part A.
干预措施: Administration of ceralasertib in combination with carboplatin (Drug)
Module 1 Part A
Module 1 Part A: ascending doses of ceralasertib in combination with carboplatin AUC5 will be administered to patients to define the maximum tolerated dose (MTD) and/or a continuous, tolerable Recommended Dose (RD).
干预措施: Administration of ceralasertib in combination with carboplatin (Drug)
Module 2 Part B4
Module Part B4: Patients with second or third line triple negative breast cancer with no known BRCA mutations. This expansion will be enriched for patients with disease harbouring a HRR-related gene mutation (HRRm) will receive ceralasertib with olaparib, at dose, frequency and schedule recommended from Module 2 Part A2.
干预措施: Administration of ceralasertib in combination with olaparib (Drug)
Module 5 Part B
Module 5 Part B: cohort expansions of ceralasertib in combination with AZD5305 in ovarian patients at dose, frequency and schedule from Module 5 Part A.
干预措施: Administration of ceralasertib in combination with AZD5305 (Drug)
Module 2 Part B5
Patients with BRCA mutant or RAD51C/D mutant (either germline or somatic) or HRD-positive status epithelial ovarian, fallopian tube, or primary peritoneal cancer according to local testing. Patients must be platinum sensitive and previously progressed on a licensed PARPi. The cohort will be split into 2 groups: Cohort 1 - without intervening chemotherapy following progression on a PARPi, Cohort 2 - with intervening chemotherapy following progression on a PARPi. Patients will receive ceralasertib and olaparib, at the RP2D dose, frequency and schedule established from Module 2 Part A2.
干预措施: Administration of ceralasertib in combination with olaparib (Drug)
Module 2 Part B3
Module 2 Part B3: Patient with second or third line breast cancer with BRCA mutations (somatic or germline), excluding HER2 positive breast cancer will receive ceralasertib with olaparib, at dose, frequency and schedule recommended from Module 2 Part A2.
干预措施: Administration of ceralasertib in combination with olaparib (Drug)
Module 4 (FE/QT)
Ceralasertib monotherapy will be administered on a number of days during Cycle 0 to assess the effect of food on ceralasertib absorption and effect of ceralasertib on ECG parameters under various conditions (fasted, fed, steady state). From C1 onwards, patients who participated in C0 will be allocated to either ceralasertib in combination with olaparib or durvalumab, or ceralasertib monotherapy and assessed for safety.
干预措施: Administration of ceralasertib monotherapy (Drug)
结局指标
主要结局
The number of subjects with adverse events/serious adverse events
时间窗: From baseline until 28 days after discontinuation of study treatment for Module 1, 2 and 5 or until 90 days after discontinuation of study treatment for Module 3 and 4
Number of patients with adverse events and with serious adverse events including abnormal clinical observations, DLT, abnormal Electrocardiogram (ECG) parameters, abnormal laboratory assessments and abnormal vital signs that changed from baseline.
Module 4 only: Effect of food on ceralasertib absorption by Intensive PK assessments after a single oral dose of ceralasertib (Part A)
时间窗: From 0h to 24h on Day 2 and Day15 in Cycle 0 (Part A) - Cycle 0 is 15 days
Intensive PK sampling at defined timepoints to measure Geometric mean and 90% CI for the ratio of fed: fasted in area under the plasma concentration time curve from zero to the last measurable time point (AUC0-t), area under the plasma concentration time curve from zero to infinity (AUC)
Module 4 only: Effect of ceralasertib on ECG parameters (HR, PR, QRS and QTcF) by ECG recordings
时间窗: From 0h to 24h on Day 2, Day 8 and Day15 in Cycle 0 (Part A) - Cycle 0 is 15 days
Change from baseline HR, PR, QRS and QTcF (ΔHR, ΔPR, ΔQRS and ΔQTcF) Categorical outliers for QTcF, HR, PR, and QRS Frequency of treatment emergent T and U wave abnormalities If a substantial HR effect is observed (i.e., the absolute value of the largest least squares \[LS\] mean ΔHR is greater than 10bpm in the by-time point analysis), other correction methods such as individualised and optimised individualised HR corrected QT interval (QTcI) will be explored and compared. The method that removes the HR dependence of the QT interval most efficiently will be chosen as the primary correction method.
次要结局
- Time to observed Cmax (Tmax) for ceralasertib(At predefined intervals throughout the ceralasertib treatment period (approximately 8 weeks for Module 1 and 16 weeks + IP disc. for Module 2+3))
- Time to observed Cmax (Tmax) for Carboplatin(At predefined intervals throughout the Carboplatin treatment period (approximately 4 weeks for Module 1))
- Area under the plasma concentration-time curve (AUC) for Carboplatin(At predefined intervals throughout the Carboplatin treatment period (approximately 4 weeks for Module 1))
- Time to observed Cmax (Tmax) for Olaparib(At predefined intervals throughout the Olaparib treatment period (approximately 12 weeks for Module 2))
- Maximum Observed Plasma Concentration (Cmax) of durvalumab(At predefined intervals throughout the durvalumab treatment period (approximately 28 weeks + 90days post IP disc. for Module 3))
- Time to observed Cmax (Tmax) for durvalumab(At predefined intervals throughout the durvalumab treatment period (approximately 28 weeks + 90days post IP disc. for Module 3))
- Area under the plasma concentration-time curve (AUC) for durvalumab(At predefined intervals throughout the durvalumab treatment period (approximately 28 weeks + 90days post IP disc. for Module 3))
- Module 4 only: Effect of food on ceralasertib absorption by clearance in a fasted and fed state (Part A)(Part A (Cycle 0 Day 2/Day 8/Day 15) - each cycle is of 15 days)
- Maximum Observed Plasma Concentration (Cmax) of Carboplatin(At predefined intervals throughout the Carboplatin treatment period (approximately 4 weeks for Module 1))
- Area under the plasma concentration-time curve (AUC) for ceralasertib(At predefined intervals throughout the ceralasertib treatment period (approximately 8 weeks for Module 1 and 16 weeks + IP disc. for Module 2+3))
- Maximum Observed Plasma Concentration (Cmax) of ceralasertib(At predefined intervals throughout the ceralasertib treatment period (approximately 8 weeks for Module 1 and 16 weeks + IP disc. for Module 2+3))
- Maximum Observed Plasma Concentration (Cmax) of Olaparib(At predefined intervals throughout the Olaparib treatment period (approximately 12 weeks for Module 2))
- Area under the plasma concentration-time curve (AUC) for Olaparib(At predefined intervals throughout the Olaparib treatment period (approximately 12 weeks for Module 2))
- Module 4 only: Effect of food on ceralasertib absorption by Tmax in a fasted and fed state (Part A)(Part A (Cycle 0 Day 2/Day 8/Day 15) - each cycle is of 15 days)
- Survival assessment /status(From first dose to confirmed progressive disease (approximately 1 year))
- Best objective response(From first dose to confirmed progressive disease (approximately 1 year))
- Percentage change in tumour size(From first dose to confirmed progressive disease (approximately 1 year))
- Assessment of pharmacodynamic biomarker changes(Biopsies of tumour at baseline and last day of dosing)
- Objective response rate(From first dose to confirmed progressive disease (approximately 1 year))
- Durable response rate(From first documented response to confirmed progressive disease (approximately 1 year))
- Progression free survival(From first dose to confirmed progressive disease (approximately 1 year))
- Module 4: Safety and tolerability in terms of AE and SAE as recorded in safety measures(From baseline until 28 days after discontinuation of study treatment for Module 4 Part B cohort 1 and cohort 3, or until 90 days after discontinuation of study treatment for Module 4 Part B cohort 2)
- Module 4 only: Effect of food on ceralasertib absorption by Cmax in a fasted and fed state (Part A)(Part A (Cycle 0 Day 2/Day 8/Day 15) - each cycle is of 15 days)
- Module 4 only: Effect of food on ceralasertib absorption by apparent volume of distribution in a fasted and fed state (Part A)(Part A (Cycle 0 Day 2/Day 8/Day 15) - each cycle is of 15 days)
- Module 4 only: Effect of food on ceralasertib absorption by terminal half-life and terminal rate constant in a fasted and fed state (Part A)(Part A (Cycle 0 Day 2/Day 8/Day 15) - each cycle is of 15 days)
- Module 4: The number of subjects with adverse events/serious adverse events(From baseline until 28 days after discontinuation of study treatment for Module 4 Part B cohort 1 and cohort 3, or until 90 days after discontinuation of study treatment for Module 4 Part B cohort 2)
- Module 5 only: Maximum Observed Plasma Concentration (Cmax) of AZD5305(At predefined intervals throughout AZD5305 treatment period (approximately 8 weeks + IP disc))
- Module 5 only: Time to observed Cmax (Tmax) for AZD5305(At predefined intervals throughout AZD5305 treatment period (approximately 8 weeks + IP disc))
- Module 5 only: Area under the plasma concentration-time curve (AUC) for AZD5305(At predefined intervals throughout AZD5305 treatment period (approximately 8 weeks + IP disc))