Ascending Doses of Ceralasertib in Combination With Chemotherapy and/or Novel Anti Cancer Agents
Study Details
Study Description
Brief Summary
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
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1/Phase 2 |
Detailed Description
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 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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| 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). |
Drug: 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.
|
| 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. |
Drug: 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.
|
| 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. |
Drug: 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.
|
| 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. |
Drug: 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.
|
| 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. |
Drug: 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.
|
| 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. |
Drug: 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.
|
| 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. |
Drug: 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.
|
| 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. |
Drug: 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.
|
| 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. |
Drug: 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.
|
| 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. |
Drug: 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.
|
| 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. |
Drug: 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.
|
Outcome Measures
Primary Outcome Measures
- Safety and tolerability in terms of AE and SAE (including death), as recorded in safety measures. [From baseline until 28 days after discontinuation of study treatment for Module 1 and 2 or until 90 days after discontinuation of study treatment for Module 3]
Safety measures include AEs, SAEs, ECG, physical examination, pulse, blood pressure, body temperature, weight and laboratory variables
Secondary Outcome Measures
- 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)]
Blood samples will be collected to assess plasma concentration of ceralasertib at a series of time points to derive Cmax.
- 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)]
Blood samples will be collected to assess plasma concentration of ceralasertib at a series of time points to derive Tmax.
- 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)]
Blood samples will be collected to assess plasma concentration of ceralasertib at a series of time points to derive AUC.
- Maximum Observed Plasma Concentration (Cmax) of Carboplatin [At predefined intervals throughout the Carboplatin treatment period (approximately 4 weeks for Module 1)]
Blood samples will be collected to assess plasma concentration of Carboplatin at a series of time points to derive Cmax.
- Time to observed Cmax (Tmax) for Carboplatin [At predefined intervals throughout the Carboplatin treatment period (approximately 4 weeks for Module 1)]
Blood samples will be collected to assess plasma concentration of Carboplatin at a series of time points to derive Tmax.
- Area under the plasma concentration-time curve (AUC) for Carboplatin [At predefined intervals throughout the Carboplatin treatment period (approximately 4 weeks for Module 1)]
Blood samples will be collected to assess plasma concentration of Carboplatin at a series of time points to derive AUC.
- Maximum Observed Plasma Concentration (Cmax) of Olaparib [At predefined intervals throughout the Olaparib treatment period (approximately 12 weeks for Module 2)]
Blood samples will be collected to assess plasma concentration of Olaparib at a series of time points to derive Cmax.
- Time to observed Cmax (Tmax) for Olaparib [At predefined intervals throughout the Olaparib treatment period (approximately 12 weeks for Module 2)]
Blood samples will be collected to assess plasma concentration of Olaparib at a series of time points to derive Tmax.
- Area under the plasma concentration-time curve (AUC) for Olaparib [At predefined intervals throughout the Olaparib treatment period (approximately 12 weeks for Module 2)]
Blood samples will be collected to assess plasma concentration of Olaparib at a series of time points to derive AUC.
- 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)]
Blood samples will be collected to assess plasma concentration of durvalumab at a series of time points to derive Cmax.
- 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)]
Blood samples will be collected to assess plasma concentration of durvalumab at a series of time points to derive Tmax.
- 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)]
Blood samples will be collected to assess plasma concentration of durvalumab at a series of time points to derive AUC.
- Assessment of pharmacodynamic biomarker changes [Biopsies of tumour at baseline, last day of dosing and following progression of disease]
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.
- Best objective response [At baseline and every 6 weeks (module 1) and every 8 weeks (module 2 & 3) until disease progression or withdrawal from study]
To obtain a preliminary assessment of the anti-tumour activity of the combination of ceralasertib and carboplatin (module 1), olaparib (module 2) and durvulamab (module 3) by evaluation of tumour response (objective response rate, duration of response, change in tumour size) and progression free survival using RECIST version 1.1
- Objective response rate [At baseline and every 6 weeks (module 1) and every 8 weeks (module 2 & 3) until disease progression or withdrawal from study]
To obtain a preliminary assessment of the anti-tumour activity of the combination of ceralasertib and carboplatin (module 1) and olaparib (module 2) and durvalumab (module 3) by evaluation of tumour response (objective response rate, duration of response, change in tumour size) and progression free survival using RECIST version 1.1
- Percentage change in tumour size [At baseline and every 6 weeks (module 1) and every 8 weeks (module 2 & 3) until disease progression or withdrawal from study]
To obtain a preliminary assessment of the anti-tumour activity of the combination of ceralasertib and carboplatin (module 1) and olaparib (module 2) and durvalumab (module 3) by evaluation of tumour response (objective response rate, duration of response, change in tumour size) and progression free survival using RECIST version 1.1
- Durable response rate [At baseline and every 6 weeks (module 1) and every 8 weeks (module 2 & 3) until disease progression or withdrawal from study]
To obtain a preliminary assessment of the anti-tumour activity of the combination of ceralasertib and carboplatin (module 1) and olaparib (module 2) and durvalumab (module 3) by evaluation of tumour response (objective response rate, duration of response, change in tumour size) and progression free survival using RECIST version 1.1
- Progression free survival [At baseline and every 6 weeks (module 1) and every 8 weeks (module 2 & 3) until disease progression or withdrawal from study]
To obtain a preliminary assessment of the anti-tumour activity of the combination of ceralasertib and carboplatin (module 1) and olaparib (module 2) and durvalumab (module 3) by evaluation of tumour response (objective response rate, duration of response, change in tumour size) and progression free survival using RECIST version 1.1
- Survival assessment /status [Every 8 weeks (+/- 1 week) after objective disease progression]
Module 2 only. To be obtained for all patients who received ceralasertib and olaparib in part A2, B1, B2, B3, B4 and B5.
Eligibility Criteria
Criteria
Principal Inclusion criteria:
-
Aged at least 18
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The presence of a solid malignant tumour that is not considered appropriate for further standard treatment
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Module 1 and 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
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Module 1 Part B Study expansion: second line lung adenocarcinoma with ATM deficient tumours.
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Module 2 Part B All - No previous treatment with PARP inhibitor.
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Module 2 Part B1 Study expansion: advanced gastric adenocarcinoma (including GEJ) patients with ATM deficient tumours
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Module 2 Part B2 Study expansion: advanced gastric adenocarcinoma (including GEJ) patients with ATM proficient tumours
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Module2 Part B3 Study expansion: Second or thrid line HER2 negative breast cancer
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Module 2 Part B4 Study expansion: Second or third line triple negative breast cancer (TNBC)
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Module 2 Part B5 Study expansion: BRCA mutant or RAD51C/D mutant or HRD positive status ovarian cancer patient who are Platinum sensitive and have previously progressed on a licensed PARPi
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Module 3: advanced recurrent or metastatic non-small cell lung cancer, or head and neck squamous cell carcinoma
Principal exclusion criteria
-
A diagnosis of ataxia telangiectasia
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Prior exposure to an ATR inhibitor
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Bad reaction to ceralasertib
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Module 1: Contra-indicated for treatment with carboplatin
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Module 2: Contra-indicated for treatment with olaparib
-
Module 3: Contra-indicated for treatment with durvalumab
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Research Site | Duarte | California | United States | 91010 |
| 2 | Research Site | Los Angeles | California | United States | 90024 |
| 3 | Research Site | Los Angeles | California | United States | 90089 |
| 4 | Research Site | Newport Beach | California | United States | 92663 |
| 5 | Research Site | Boston | Massachusetts | United States | 02215 |
| 6 | Research Site | New York | New York | United States | 10065 |
| 7 | Research Site | Bordeaux | France | 33076 | |
| 8 | Research Site | Lyon Cedex 08 | France | 69373 | |
| 9 | Research Site | Saint Herblain | France | 44805 | |
| 10 | Research Site | Villejuif | France | 94805 | |
| 11 | Research Site | Goyang-si | Korea, Republic of | 10408 | |
| 12 | Research Site | Seongnam-si | Korea, Republic of | 13620 | |
| 13 | Research Site | Seoul | Korea, Republic of | 03080 | |
| 14 | Research Site | Seoul | Korea, Republic of | 03722 | |
| 15 | Research Site | Seoul | Korea, Republic of | 05505 | |
| 16 | Research Site | Seoul | Korea, Republic of | 135-710 | |
| 17 | Research Site | Bristol | United Kingdom | BS2 8ED | |
| 18 | Research Site | Cambridge | United Kingdom | CB2 0QQ | |
| 19 | Research Site | Coventry | United Kingdom | CV2 2DX | |
| 20 | Research Site | London | United Kingdom | SW3 6JJ | |
| 21 | Research Site | London | United Kingdom | W12 0HS | |
| 22 | Research Site | London | United Kingdom | W1G 6AD | |
| 23 | Research Site | London | United Kingdom | W1T 7HA | |
| 24 | Research Site | Manchester | United Kingdom | M20 4GJ | |
| 25 | Research Site | Oxford | United Kingdom | OX3 7LE | |
| 26 | Research Site | Sutton | United Kingdom | SM2 5PT | |
| 27 | Research Site | Withington | United Kingdom | M20 4BX |
Sponsors and Collaborators
- AstraZeneca
Investigators
None specified.Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- D5330C00004