Adv Solid Malig - H&N SCC, ATM Pro / Def NSCLC, Gastric, Breast and Ovarian Cancer Clinical Trial
Official title:
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.
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.
| Status | Recruiting |
| Enrollment | 466 |
| Est. completion date | August 5, 2026 |
| Est. primary completion date | August 5, 2026 |
| Accepts healthy volunteers | No |
| Gender | All |
| Age group | 18 Years to 130 Years |
| Eligibility | 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 Principal exclusion criteria - 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 |
| Country | Name | City | State |
|---|---|---|---|
| Australia | Research Site | Nedlands | |
| Belgium | Research Site | Leuven | |
| Belgium | Research Site | Liège | |
| Canada | Research Site | Edmonton | Alberta |
| Canada | Research Site | London | Ontario |
| Canada | Research Site | Montréal | Quebec |
| Canada | Research Site | Toronto | Ontario |
| France | Research Site | Bordeaux | |
| France | Research Site | Lyon Cedex 08 | |
| France | Research Site | Saint Herblain | |
| France | Research Site | Villejuif | |
| Hungary | Research Site | Budapest | |
| Hungary | Research Site | Kecskemét | |
| Korea, Republic of | Research Site | Goyang-si | |
| Korea, Republic of | Research Site | Seongnam-si | |
| Korea, Republic of | Research Site | Seoul | |
| Korea, Republic of | Research Site | Seoul | |
| Korea, Republic of | Research Site | Seoul | |
| Korea, Republic of | Research Site | Seoul | |
| Spain | Research Site | Barcelona | |
| Spain | Research Site | Madrid | |
| Spain | Research Site | Sevilla | |
| United Kingdom | Research Site | Bristol | |
| United Kingdom | Research Site | Cambridge | |
| United Kingdom | Research Site | Coventry | |
| United Kingdom | Research Site | London | |
| United Kingdom | Research Site | London | |
| United Kingdom | Research Site | London | |
| United Kingdom | Research Site | London | |
| United Kingdom | Research Site | Manchester | |
| United Kingdom | Research Site | Oxford | |
| United Kingdom | Research Site | Sutton | |
| United Kingdom | Research Site | Sutton | |
| United Kingdom | Research Site | Withington | |
| United States | Research Site | Boston | Massachusetts |
| United States | Research Site | Boston | Massachusetts |
| United States | Research Site | Charlotte | North Carolina |
| United States | Research Site | Duarte | California |
| United States | Research Site | Duarte | California |
| United States | Research Site | Irvine | California |
| United States | Research Site | Los Angeles | California |
| United States | Research Site | Los Angeles | California |
| United States | Research Site | New York | New York |
| United States | Research Site | Newport Beach | California |
| United States | Research Site | Philadelphia | Pennsylvania |
| Lead Sponsor | Collaborator |
|---|---|
| AstraZeneca |
United States, Australia, Belgium, Canada, France, Hungary, Korea, Republic of, Spain, United Kingdom,
| Type | Measure | Description | Time frame | Safety issue |
|---|---|---|---|---|
| Primary | The number of subjects with adverse events/serious adverse events | 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. | 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 | |
| Primary | Module 4 only: Effect of food on ceralasertib absorption by Intensive PK assessments after a single oral dose of ceralasertib (Part A) | 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) |
From 0h to 24h on Day 2 and Day15 in Cycle 0 (Part A) - Cycle 0 is 15 days | |
| Primary | Module 4 only: Effect of ceralasertib on ECG parameters (HR, PR, QRS and QTcF) by ECG recordings | Change from baseline HR, PR, QRS and QTcF (?HR, ?PR, ?QRS and ?QTcF) 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 ?HR 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. |
From 0h to 24h on Day 2, Day 8 and Day15 in Cycle 0 (Part A) - Cycle 0 is 15 days | |
| Secondary | Maximum Observed Plasma Concentration (Cmax) of ceralasertib | Blood samples will be collected to assess plasma concentration of ceralasertib at a series of time points to derive Cmax. | At predefined intervals throughout the ceralasertib treatment period (approximately 8 weeks for Module 1 and 16 weeks + IP disc. for Module 2+3) | |
| Secondary | Time to observed Cmax (Tmax) for ceralasertib | Blood samples will be collected to assess plasma concentration of ceralasertib at a series of time points to derive Tmax. | At predefined intervals throughout the ceralasertib treatment period (approximately 8 weeks for Module 1 and 16 weeks + IP disc. for Module 2+3) | |
| Secondary | Area under the plasma concentration-time curve (AUC) for ceralasertib | Blood samples will be collected to assess plasma concentration of ceralasertib at a series of time points to derive AUC. | At predefined intervals throughout the ceralasertib treatment period (approximately 8 weeks for Module 1 and 16 weeks + IP disc. for Module 2+3) | |
| Secondary | Maximum Observed Plasma Concentration (Cmax) of Carboplatin | Blood samples will be collected to assess plasma concentration of Carboplatin at a series of time points to derive Cmax. | At predefined intervals throughout the Carboplatin treatment period (approximately 4 weeks for Module 1) | |
| Secondary | Time to observed Cmax (Tmax) for Carboplatin | Blood samples will be collected to assess plasma concentration of Carboplatin at a series of time points to derive Tmax. | At predefined intervals throughout the Carboplatin treatment period (approximately 4 weeks for Module 1) | |
| Secondary | Area under the plasma concentration-time curve (AUC) for Carboplatin | Blood samples will be collected to assess plasma concentration of Carboplatin at a series of time points to derive AUC. | At predefined intervals throughout the Carboplatin treatment period (approximately 4 weeks for Module 1) | |
| Secondary | Maximum Observed Plasma Concentration (Cmax) of Olaparib | Blood samples will be collected to assess plasma concentration of Olaparib at a series of time points to derive Cmax. | At predefined intervals throughout the Olaparib treatment period (approximately 12 weeks for Module 2) | |
| Secondary | Time to observed Cmax (Tmax) for Olaparib | Blood samples will be collected to assess plasma concentration of Olaparib at a series of time points to derive Tmax. | At predefined intervals throughout the Olaparib treatment period (approximately 12 weeks for Module 2) | |
| Secondary | Area under the plasma concentration-time curve (AUC) for Olaparib | Blood samples will be collected to assess plasma concentration of Olaparib at a series of time points to derive AUC. | At predefined intervals throughout the Olaparib treatment period (approximately 12 weeks for Module 2) | |
| Secondary | Maximum Observed Plasma Concentration (Cmax) of durvalumab | Blood samples will be collected to assess plasma concentration of durvalumab at a series of time points to derive Cmax. | At predefined intervals throughout the durvalumab treatment period (approximately 28 weeks + 90days post IP disc. for Module 3) | |
| Secondary | Time to observed Cmax (Tmax) for durvalumab | Blood samples will be collected to assess plasma concentration of durvalumab at a series of time points to derive Tmax. | At predefined intervals throughout the durvalumab treatment period (approximately 28 weeks + 90days post IP disc. for Module 3) | |
| Secondary | Area under the plasma concentration-time curve (AUC) for durvalumab | Blood samples will be collected to assess plasma concentration of durvalumab at a series of time points to derive AUC. | At predefined intervals throughout the durvalumab treatment period (approximately 28 weeks + 90days post IP disc. for Module 3) | |
| Secondary | Assessment of pharmacodynamic biomarker changes | Evaluation of ceralasertib activity in the tumour by assessment of pharmacodynamic biomarker changes which may include, but are not limited to functional ATR inhibition, ctDNA and CTCs. | Biopsies of tumour at baseline and last day of dosing | |
| Secondary | Best objective response | Best objective response will be determined for each patient based on the best response recorded from start of study treatment to end of treatment, including any assessments for confirmation after the end of treatment using RECIST 1.1. | From first dose to confirmed progressive disease (approximately 1 year) | |
| Secondary | Objective response rate | Objective response rate is defined as the percentage of patients who have at least one response of CR or PR prior to any evidence of progression (as defined by RECIST 1.1) that is confirmed at least 4 weeks later. | From first dose to confirmed progressive disease (approximately 1 year) | |
| Secondary | Percentage change in tumour size | Percentage change in tumour size will be determined for patients with measurable disease at baseline and is derived at each visit by the percentage change from baseline in the sum of the diameters of TLs. The best percentage change in tumour size will be the patient's value representing the largest decrease (or smallest increase) from baseline in tumour size using RECIST 1.1. | From first dose to confirmed progressive disease (approximately 1 year) | |
| Secondary | Durable response rate | Duration of response will be defined as the time from the date of first documented response until date of documented progression or death in the absence of disease progression, the end of response should coincide with the date of progression or death from any cause used for the PFS endpoint using RECIST 1.1. | From first documented response to confirmed progressive disease (approximately 1 year) | |
| Secondary | Progression free survival | Progression free survival (PFS) is defined as the time from start of treatment (first dose of ceralasertib) until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the subject withdraws from therapy or receives another anti-cancer therapy prior to progression using RECIST 1.1. | From first dose to confirmed progressive disease (approximately 1 year) | |
| Secondary | Survival assessment /status | Module 2 only. To be obtained for all patients who received ceralasertib and olaparib in part A2, B1, B2, B3, B4 and B5. | From first dose to confirmed progressive disease (approximately 1 year) | |
| Secondary | Module 4: Safety and tolerability in terms of AE and SAE as recorded in safety measures | Safety measures: AEs assessments (CTCAE grading) | 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 | |
| Secondary | Module 4 only: Effect of food on ceralasertib absorption by Cmax in a fasted and fed state (Part A) | Intensive PK sampling at defined timepoints to measure geometric mean and 90% CI for the ratio of fed: fasted in Cmax - Maximum plasma concentration (Cmax) | Part A (Cycle 0 Day 2/Day 8/Day 15) - each cycle is of 15 days | |
| Secondary | Module 4 only: Effect of food on ceralasertib absorption by Tmax in a fasted and fed state (Part A) | Intensive PK sampling at defined timepoints to measure geometric mean and 90% CI for the ratio of fed: fasted in Tmax - time to reach maximum plasma concentration (Tmax) | Part A (Cycle 0 Day 2/Day 8/Day 15) - each cycle is of 15 days | |
| Secondary | Module 4 only: Effect of food on ceralasertib absorption by clearance in a fasted and fed state (Part A) | Intensive PK sampling at defined timepoints to measure geometric mean and 90% CI for the ratio of fed: fasted in apparent clearance following oral administration (CL/F) | Part A (Cycle 0 Day 2/Day 8/Day 15) - each cycle is of 15 days | |
| Secondary | Module 4 only: Effect of food on ceralasertib absorption by apparent volume of distribution in a fasted and fed state (Part A) | Intensive PK sampling at defined timepoints to measure geometric mean and 90% CI for the ratio of fed: fasted in apparent volume of distribution (Vz/F) | Part A (Cycle 0 Day 2/Day 8/Day 15) - each cycle is of 15 days | |
| Secondary | 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) | Intensive PK sampling at defined timepoints to measure geometric mean and 90% CI for the ratio of fed: fasted in terminal rate constant (?z), and terminal half-life (t1/2) | Part A (Cycle 0 Day 2/Day 8/Day 15) - each cycle is of 15 days | |
| Secondary | Module 4: The number of subjects with adverse events/serious adverse events | Number of patients with adverse events and with serious adverse events including abnormal clinical observations, abnormal vital signs, and abnormal laboratory assessments that changed from baseline | 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 | |
| Secondary | Module 5 only: Maximum Observed Plasma Concentration (Cmax) of AZD5305 | Blood samples will be collected to assess plasma concentration of AZD5305 at a series of time points to derive Cmax. | At predefined intervals throughout AZD5305 treatment period (approximately 8 weeks + IP disc) | |
| Secondary | Module 5 only: Time to observed Cmax (Tmax) for AZD5305 | Blood samples will be collected to assess plasma concentration of AZD5305 at a series of time points to derive Tmax. | At predefined intervals throughout AZD5305 treatment period (approximately 8 weeks + IP disc) | |
| Secondary | Module 5 only: Area under the plasma concentration-time curve (AUC) for AZD5305 | Blood samples will be collected to assess plasma concentration of AZD5305 at a series of time points to derive AUC. | At predefined intervals throughout AZD5305 treatment period (approximately 8 weeks + IP disc) |