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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT02264678




Registration number
NCT02264678
Ethics application status
Date submitted
30/07/2014
Date registered
15/10/2014

Titles & IDs
Public title
Ascending Doses of Ceralasertib in Combination With Chemotherapy and/or Novel Anti Cancer Agents
Scientific 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.
Secondary ID [1] 0 0
2014-002233-66
Secondary ID [2] 0 0
D5330C00004
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Adv Solid Malig - H&N SCC, ATM Pro / Def NSCLC, Gastric, Breast and Ovarian Cancer 0 0
Condition category
Condition code
Human Genetics and Inherited Disorders 0 0 0 0
Other human genetics and inherited disorders
Cancer 0 0 0 0
Breast
Cancer 0 0 0 0
Ovarian and primary peritoneal

Intervention/exposure
Study type
Interventional(has expanded access)
Description of intervention(s) / exposure
Treatment: Drugs - Administration of ceralasertib
Treatment: Drugs - Administration of ceralasertib in combination with olaparib
Treatment: Drugs - Administation of ceralasertib in combination with durvalumab
Treatment: Drugs - Administration of ceralasertib monotherapy
Treatment: Drugs - Administration of ceralasertib and olaparib
Treatment: Drugs - Administration of ceralasertib and durvalumab
Treatment: Drugs - Administration of ceralasertib in combination with AZD5305
Treatment: Drugs - Administration of ceralasertib in combination with carboplatin

Experimental: 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.

Experimental: 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.

Experimental: 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.

Experimental: 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.

Experimental: 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.

Experimental: 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.

Experimental: 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.

Experimental: 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.

Experimental: 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.

Experimental: 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.

Experimental: 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.

Experimental: 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.

Experimental: 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).

Experimental: 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.


Treatment: Drugs: Administration of ceralasertib
An oral formulation of ceralasertib will be used. In Module 2 Part A1, patients will receive a single dose of ceralasertib on Day 1, followed by 4 to 6 days washout, before multiple dosing.

Treatment: Drugs: Administration of ceralasertib in combination with olaparib
An oral formulations of ceralasertib and olaparib will be used. In Module 2 Part A2, patients will receive either a single or twice daily dose of ceralasertib followed by 4 to 6 days washout, before multiple dosing with ceralasertib and olaparib. In Module 2 Part B, patients will receive ceralasertib and olaparib at the dose, frequency and schedule recommended from Module 2 Part A2. Cycle 0 may be omitted at the discretion of the sponsor.

Treatment: Drugs: Administation of ceralasertib in combination with durvalumab
An oral formulation of ceralasertib will be used. Durvalumab is given via IV infusion. In Module 3 Part A, patients will receive an initial single dose of ceralasertib on Day 1, followed by multiple dosing in combination with durvalumab. In Module 3 Serial Tumour Biopsy Extension and Part B expansion cohorts, patients will receive ceralasertib at the dose, frequency and schedule recommended from Module 3 Part A, in combination with durvalumab.

Treatment: Drugs: Administration of ceralasertib monotherapy
Module 4 Part A and Module 4 Part B Cohort 3: During C0, patients will receive ceralasertib monotherapy orally once a day on 3 non-consecutive days and ceralasertib twice a day on 5 consecutive days. After the patients have completed C0 (Part A) they may transition to Module 4 Part B cohort 3 where they will continue to receive ceralasertib monotherapy

Treatment: Drugs: Administration of ceralasertib and olaparib
Module 4 Part B Cohort 1:

After completion of Part A (C0), the patient may transition to Part B and be allocated to receive ceralasertib in combination with olaparib as decided by the investigator.

Treatment: Drugs: Administration of ceralasertib and durvalumab
Module 4 Part B Cohort 2:

After completion of Part A (C0), the patient may transition to Part B and be allocated to receive ceralasertib in combination with durvalumab as decided by the investigator.

Treatment: Drugs: Administration of ceralasertib in combination with AZD5305
An oral formulations of ceralasertib and AZD5305 will be used. In Module 5 Part A, patients will receive a single dose of ceralasertib on cycle 0 Day 1 as per dose level cohort. In Module 5 Part B, patients will receive ceralasertib and AZD5305: C1 onwards (as per dose level cohort allocated).

Treatment: Drugs: Administration of ceralasertib in combination with carboplatin
An oral formulation of ceralasertib will be used. In Module 1 Part A, patients will receive a single dose of ceralasertib on Day 1, followed by multiple dosing in combination with carboplatin. A maximum of 6 cycles (21 days per cycle) of treatment will be given. In Module 1 Part B, patients will receive ceralasertib and carboplatin at the dose, frequency and schedule recommended from Module 1 Part A.
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
The number of subjects with adverse events/serious adverse events
Timepoint [1] 0 0
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 outcome [2] 0 0
Module 4 only: Effect of food on ceralasertib absorption by Intensive PK assessments after a single oral dose of ceralasertib (Part A)
Timepoint [2] 0 0
From 0h to 24h on Day 2 and Day15 in Cycle 0 (Part A) - Cycle 0 is 15 days
Primary outcome [3] 0 0
Module 4 only: Effect of ceralasertib on ECG parameters (HR, PR, QRS and QTcF) by ECG recordings
Timepoint [3] 0 0
From 0h to 24h on Day 2, Day 8 and Day15 in Cycle 0 (Part A) - Cycle 0 is 15 days
Secondary outcome [1] 0 0
Maximum Observed Plasma Concentration (Cmax) of ceralasertib
Timepoint [1] 0 0
At predefined intervals throughout the ceralasertib treatment period (approximately 8 weeks for Module 1 and 16 weeks + IP disc. for Module 2+3)
Secondary outcome [2] 0 0
Time to observed Cmax (Tmax) for ceralasertib
Timepoint [2] 0 0
At predefined intervals throughout the ceralasertib treatment period (approximately 8 weeks for Module 1 and 16 weeks + IP disc. for Module 2+3)
Secondary outcome [3] 0 0
Area under the plasma concentration-time curve (AUC) for ceralasertib
Timepoint [3] 0 0
At predefined intervals throughout the ceralasertib treatment period (approximately 8 weeks for Module 1 and 16 weeks + IP disc. for Module 2+3)
Secondary outcome [4] 0 0
Maximum Observed Plasma Concentration (Cmax) of Carboplatin
Timepoint [4] 0 0
At predefined intervals throughout the Carboplatin treatment period (approximately 4 weeks for Module 1)
Secondary outcome [5] 0 0
Time to observed Cmax (Tmax) for Carboplatin
Timepoint [5] 0 0
At predefined intervals throughout the Carboplatin treatment period (approximately 4 weeks for Module 1)
Secondary outcome [6] 0 0
Area under the plasma concentration-time curve (AUC) for Carboplatin
Timepoint [6] 0 0
At predefined intervals throughout the Carboplatin treatment period (approximately 4 weeks for Module 1)
Secondary outcome [7] 0 0
Maximum Observed Plasma Concentration (Cmax) of Olaparib
Timepoint [7] 0 0
At predefined intervals throughout the Olaparib treatment period (approximately 12 weeks for Module 2)
Secondary outcome [8] 0 0
Time to observed Cmax (Tmax) for Olaparib
Timepoint [8] 0 0
At predefined intervals throughout the Olaparib treatment period (approximately 12 weeks for Module 2)
Secondary outcome [9] 0 0
Area under the plasma concentration-time curve (AUC) for Olaparib
Timepoint [9] 0 0
At predefined intervals throughout the Olaparib treatment period (approximately 12 weeks for Module 2)
Secondary outcome [10] 0 0
Maximum Observed Plasma Concentration (Cmax) of durvalumab
Timepoint [10] 0 0
At predefined intervals throughout the durvalumab treatment period (approximately 28 weeks + 90days post IP disc. for Module 3)
Secondary outcome [11] 0 0
Time to observed Cmax (Tmax) for durvalumab
Timepoint [11] 0 0
At predefined intervals throughout the durvalumab treatment period (approximately 28 weeks + 90days post IP disc. for Module 3)
Secondary outcome [12] 0 0
Area under the plasma concentration-time curve (AUC) for durvalumab
Timepoint [12] 0 0
At predefined intervals throughout the durvalumab treatment period (approximately 28 weeks + 90days post IP disc. for Module 3)
Secondary outcome [13] 0 0
Assessment of pharmacodynamic biomarker changes
Timepoint [13] 0 0
Biopsies of tumour at baseline and last day of dosing
Secondary outcome [14] 0 0
Best objective response
Timepoint [14] 0 0
From first dose to confirmed progressive disease (approximately 1 year)
Secondary outcome [15] 0 0
Objective response rate
Timepoint [15] 0 0
From first dose to confirmed progressive disease (approximately 1 year)
Secondary outcome [16] 0 0
Percentage change in tumour size
Timepoint [16] 0 0
From first dose to confirmed progressive disease (approximately 1 year)
Secondary outcome [17] 0 0
Durable response rate
Timepoint [17] 0 0
From first documented response to confirmed progressive disease (approximately 1 year)
Secondary outcome [18] 0 0
Progression free survival
Timepoint [18] 0 0
From first dose to confirmed progressive disease (approximately 1 year)
Secondary outcome [19] 0 0
Survival assessment /status
Timepoint [19] 0 0
From first dose to confirmed progressive disease (approximately 1 year)
Secondary outcome [20] 0 0
Module 4: Safety and tolerability in terms of AE and SAE as recorded in safety measures
Timepoint [20] 0 0
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 outcome [21] 0 0
Module 4 only: Effect of food on ceralasertib absorption by Cmax in a fasted and fed state (Part A)
Timepoint [21] 0 0
Part A (Cycle 0 Day 2/Day 8/Day 15) - each cycle is of 15 days
Secondary outcome [22] 0 0
Module 4 only: Effect of food on ceralasertib absorption by Tmax in a fasted and fed state (Part A)
Timepoint [22] 0 0
Part A (Cycle 0 Day 2/Day 8/Day 15) - each cycle is of 15 days
Secondary outcome [23] 0 0
Module 4 only: Effect of food on ceralasertib absorption by clearance in a fasted and fed state (Part A)
Timepoint [23] 0 0
Part A (Cycle 0 Day 2/Day 8/Day 15) - each cycle is of 15 days
Secondary outcome [24] 0 0
Module 4 only: Effect of food on ceralasertib absorption by apparent volume of distribution in a fasted and fed state (Part A)
Timepoint [24] 0 0
Part A (Cycle 0 Day 2/Day 8/Day 15) - each cycle is of 15 days
Secondary outcome [25] 0 0
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)
Timepoint [25] 0 0
Part A (Cycle 0 Day 2/Day 8/Day 15) - each cycle is of 15 days
Secondary outcome [26] 0 0
Module 4: The number of subjects with adverse events/serious adverse events
Timepoint [26] 0 0
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 outcome [27] 0 0
Module 5 only: Maximum Observed Plasma Concentration (Cmax) of AZD5305
Timepoint [27] 0 0
At predefined intervals throughout AZD5305 treatment period (approximately 8 weeks + IP disc)
Secondary outcome [28] 0 0
Module 5 only: Time to observed Cmax (Tmax) for AZD5305
Timepoint [28] 0 0
At predefined intervals throughout AZD5305 treatment period (approximately 8 weeks + IP disc)
Secondary outcome [29] 0 0
Module 5 only: Area under the plasma concentration-time curve (AUC) for AZD5305
Timepoint [29] 0 0
At predefined intervals throughout AZD5305 treatment period (approximately 8 weeks + IP disc)

Eligibility
Key inclusion criteria
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
Minimum age
18 Years
Maximum age
130 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 1
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
31/10/2014
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
15/12/2026
Actual
Sample size
Target
466
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
Recruitment hospital [1] 0 0
Research Site - Nedlands
Recruitment postcode(s) [1] 0 0
6009 - Nedlands
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
California
Country [2] 0 0
United States of America
State/province [2] 0 0
Massachusetts
Country [3] 0 0
United States of America
State/province [3] 0 0
New York
Country [4] 0 0
United States of America
State/province [4] 0 0
North Carolina
Country [5] 0 0
United States of America
State/province [5] 0 0
Pennsylvania
Country [6] 0 0
Belgium
State/province [6] 0 0
Leuven
Country [7] 0 0
Belgium
State/province [7] 0 0
Liège
Country [8] 0 0
Canada
State/province [8] 0 0
Alberta
Country [9] 0 0
Canada
State/province [9] 0 0
Ontario
Country [10] 0 0
Canada
State/province [10] 0 0
Quebec
Country [11] 0 0
France
State/province [11] 0 0
Bordeaux
Country [12] 0 0
France
State/province [12] 0 0
Lyon Cedex 08
Country [13] 0 0
France
State/province [13] 0 0
Saint Herblain
Country [14] 0 0
France
State/province [14] 0 0
Villejuif
Country [15] 0 0
Hungary
State/province [15] 0 0
Budapest
Country [16] 0 0
Hungary
State/province [16] 0 0
Kecskemét
Country [17] 0 0
Korea, Republic of
State/province [17] 0 0
Goyang-si
Country [18] 0 0
Korea, Republic of
State/province [18] 0 0
Seongnam-si
Country [19] 0 0
Korea, Republic of
State/province [19] 0 0
Seoul
Country [20] 0 0
Spain
State/province [20] 0 0
Barcelona
Country [21] 0 0
Spain
State/province [21] 0 0
Madrid
Country [22] 0 0
Spain
State/province [22] 0 0
Sevilla
Country [23] 0 0
United Kingdom
State/province [23] 0 0
Bristol
Country [24] 0 0
United Kingdom
State/province [24] 0 0
Cambridge
Country [25] 0 0
United Kingdom
State/province [25] 0 0
Coventry
Country [26] 0 0
United Kingdom
State/province [26] 0 0
London
Country [27] 0 0
United Kingdom
State/province [27] 0 0
Manchester
Country [28] 0 0
United Kingdom
State/province [28] 0 0
Oxford
Country [29] 0 0
United Kingdom
State/province [29] 0 0
Sutton
Country [30] 0 0
United Kingdom
State/province [30] 0 0
Withington

Funding & Sponsors
Primary sponsor type
Commercial sector/industry
Name
AstraZeneca
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
AstraZeneca Clinical Study Information Center
Address 0 0
Country 0 0
Phone 0 0
1-877-240-9479
Fax 0 0
Email 0 0
[email protected]
Contact person for scientific queries

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

Supporting document/s available: Study protocol
When will data be available (start and end dates)?
AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
Available to whom?
When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
Available for what types of analyses?
How or where can data be obtained?
IPD available at link: https://astrazenecagroup-dt.pharmacm.com/DT/Home


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

No documents have been uploaded by study researchers.


Results not provided in https://clinicaltrials.gov/study/NCT02264678