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Ascending Doses of Ceralasertib in Combination With Chemotherapy and/or Novel Anti Cancer Agents
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.
Study details:
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.
Eligibility criteria
Researchers look for people who fit a certain description, called eligibility criteria. See if you qualify.
Inclusion criteria
Exclusion criteria
Eligibility
Age eligible for study : 18 and older
Healthy volunteers accepted : No
Gender eligible for study: All
Things to know
Study dates
Study start: 2014-10-31
Primary completion: 2025-03-18
Study completion finish: 2025-03-18
Study type
TREATMENT
Phase
PHASE1
PHASE2
Trial ID
NCT02264678
Intervention or treatment
DRUG: Administration of ceralasertib
DRUG: Administration of ceralasertib in combination with olaparib
DRUG: Administation of ceralasertib in combination with durvalumab
DRUG: Administration of ceralasertib monotherapy
DRUG: Administration of ceralasertib and olaparib
DRUG: Administration of ceralasertib and durvalumab
DRUG: Administration of ceralasertib in combination with AZD5305
DRUG: Administration of ceralasertib in combination with carboplatin
Conditions
- • Adv Solid Malig - H&N SCC, ATM Pro / Def NSCLC, Gastric, Breast and Ovarian Cancer
Find a site
Closest Location:
Research Site
Research sites nearby
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Research Site
Nedlands, Not Specified, Australia
Study Plan
This section provides details of the study plan, including how the study is designed and what the study is measuring.
How is the study designed?
Participant Group/Arm | Intervention/Treatment |
---|---|
EXPERIMENTAL: Module 2 Part A1
| DRUG: Administration of ceralasertib
|
EXPERIMENTAL: Module 2 Part A2
| DRUG: Administration of ceralasertib in combination with olaparib
|
EXPERIMENTAL: Module 2 Part B1
| DRUG: Administration of ceralasertib in combination with olaparib
|
EXPERIMENTAL: Module 2 Part B2
| DRUG: Administration of ceralasertib in combination with olaparib
|
EXPERIMENTAL: Module 2 Part B3
| DRUG: Administration of ceralasertib in combination with olaparib
|
EXPERIMENTAL: Module 2 Part B4
| DRUG: Administration of ceralasertib in combination with olaparib
|
EXPERIMENTAL: Module 3 Part A
| DRUG: Administation of ceralasertib in combination with durvalumab
|
EXPERIMENTAL: Module 3 Part B
| DRUG: Administation of ceralasertib in combination with durvalumab
|
EXPERIMENTAL: Module 2 Part B5
| DRUG: Administration of ceralasertib in combination with olaparib
|
EXPERIMENTAL: Module 4 (FE/QT)
| DRUG: Administration of ceralasertib monotherapy
|
EXPERIMENTAL: Module 5 Part A
| DRUG: Administration of ceralasertib in combination with AZD5305
|
EXPERIMENTAL: Module 5 Part B
| DRUG: Administration of ceralasertib in combination with AZD5305
|
EXPERIMENTAL: Module 1 Part A
| DRUG: Administration of ceralasertib in combination with carboplatin
|
EXPERIMENTAL: Module 1 Part B
| DRUG: Administration of ceralasertib in combination with carboplatin
|
What is the study measuring?
Primary outcome
Primary Outcome Measure | Primary Outcome Description | Primary Outcome Time Frame |
---|---|---|
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 |
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 |
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 (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. | From 0h to 24h on Day 2, Day 8 and Day15 in Cycle 0 (Part A) - Cycle 0 is 15 days |
Secondary outcome
Secondary Outcome Measure | Secondary Outcome Description | Secondary Outcome Time Frame |
---|---|---|
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) |
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) |
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) |
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) |
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) |
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) |
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) |
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) |
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) |
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) |
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) |
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) |
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 |
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) |
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) |
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) |
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) |
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) |
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) |
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 |
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 |
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 |
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 |
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 |
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 (λz), and terminal half-life (t1/2) | 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 | 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 |
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) |
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) |
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) |
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