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Ascending Doses of Ceralasertib in Combination With Chemotherapy and/or Novel Anti Cancer Agents

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02264678
Recruitment Status : Recruiting
First Posted : October 15, 2014
Last Update Posted : July 27, 2020
Sponsor:
Information provided by (Responsible Party):
AstraZeneca

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
Adv Solid Malig - H&N SCC, ATM Pro / Def NSCLC, Gastric, Breast and Ovarian Cancer Drug: Administration of ceralasertib in combination with carboplatin Drug: Administration of ceralasertib Drug: Administration of ceralasertib in combination with olaparib Drug: Administation of ceralasertib in combination with durvalumab Phase 1 Phase 2

Expanded Access : An investigational treatment associated with this study has been approved for sale to the public.   More info ...

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 322 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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.
Actual Study Start Date : October 31, 2014
Estimated Primary Completion Date : January 24, 2022
Estimated Study Completion Date : January 24, 2022


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 (either germline or somatic) 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 a 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.




Primary Outcome Measures :
  1. Safety and tolerability in terms of AE and SAE (including death), as recorded in safety measures. [ Time Frame: 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 :
  1. Maximum Observed Plasma Concentration (Cmax) of ceralasertib [ Time Frame: 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.

  2. Time to observed Cmax (Tmax) for ceralasertib [ Time Frame: 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.

  3. Area under the plasma concentration-time curve (AUC) for ceralasertib [ Time Frame: 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.

  4. Maximum Observed Plasma Concentration (Cmax) of Carboplatin [ Time Frame: 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.

  5. Time to observed Cmax (Tmax) for Carboplatin [ Time Frame: 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.

  6. Area under the plasma concentration-time curve (AUC) for Carboplatin [ Time Frame: 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.

  7. Maximum Observed Plasma Concentration (Cmax) of Olaparib [ Time Frame: 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.

  8. Time to observed Cmax (Tmax) for Olaparib [ Time Frame: 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.

  9. Area under the plasma concentration-time curve (AUC) for Olaparib [ Time Frame: 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.

  10. Maximum Observed Plasma Concentration (Cmax) of durvalumab [ Time Frame: 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.

  11. Time to observed Cmax (Tmax) for durvalumab [ Time Frame: 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.

  12. Area under the plasma concentration-time curve (AUC) for durvalumab [ Time Frame: 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.

  13. Assessment of pharmacodynamic biomarker changes [ Time Frame: 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.

  14. Best objective response [ Time Frame: 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

  15. Objective response rate [ Time Frame: 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

  16. Percentage change in tumour size [ Time Frame: 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

  17. Durable response rate [ Time Frame: 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

  18. Progression free survival [ Time Frame: 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

  19. Survival assessment /status [ Time Frame: Every 8 weeks (+/- 1 week) after objective disease progression ]
    Module 2 only. To be obtained for all patients with gastric adenocarcinoma who received ceralasertib and olaparib in part A2, B1, B2, B3 and B4



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 130 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 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
  • Module 1 Part B Study expansion: second line lung adenocarcinoma with ATM deficient tumours.
  • Module 2 Part B All - 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
  • Module2 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: BRCA mutant ovarian cancer patient who are Platinum sensitive and have previously progressed on a PARPi 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
  • Prior exposure to an ATR inhibitor
  • Bad reaction to ceralasertib
  • Module 1: Contra-indicated for treatment with carboplatin
  • Module 2: Contra-indicated for treatment with olaparib
  • Module 3: Contra-indicated for treatment with durvalumab

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02264678


Contacts
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Contact: AstraZeneca Clinical Study Information Center 1-877-240-9479 information.center@astrazeneca.com
Contact: AstraZeneca Cancer Study Locator Service 677 400 4656 astrazeneca@emergingmed.com

Locations
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United States, California
Research Site Recruiting
Los Angeles, California, United States, 90033
Research Site Withdrawn
Los Angeles, California, United States, 90048
Research Site Recruiting
Newport Beach, California, United States, 92663
United States, Massachusetts
Research Site Recruiting
Boston, Massachusetts, United States, 02215
United States, Minnesota
Research Site Withdrawn
Rochester, Minnesota, United States, 55905
United States, New York
Research Site Recruiting
New York, New York, United States, 10065
United States, Tennessee
Research Site Withdrawn
Nashville, Tennessee, United States, 37204
France
Research Site Recruiting
Saint Herblain, France, 44805
Research Site Recruiting
Villejuif, France, 94805
Korea, Republic of
Research Site Not yet recruiting
Goyang-si, Korea, Republic of, 10408
Research Site Recruiting
Seongnam-si, Korea, Republic of, 13620
Research Site Recruiting
Seoul, Korea, Republic of, 03080
Research Site Recruiting
Seoul, Korea, Republic of, 03722
Research Site Not yet recruiting
Seoul, Korea, Republic of, 05505
Research Site Recruiting
Seoul, Korea, Republic of, 135-710
United Kingdom
Research Site Suspended
Cambridge, United Kingdom, CB2 0QQ
Research Site Recruiting
Cambridge, United Kingdom, CB2 0RE
Research Site Recruiting
London, United Kingdom, W1T 7HA
Research Site Recruiting
Withington, United Kingdom, M20 4BX
Sponsors and Collaborators
AstraZeneca
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Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT02264678    
Other Study ID Numbers: D5330C00004
First Posted: October 15, 2014    Key Record Dates
Last Update Posted: July 27, 2020
Last Verified: July 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: 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 Materials: Study Protocol
Time Frame: 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.
Access Criteria: 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.
URL: https://astrazenecagroup-dt.pharmacm.com/DT/Home

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by AstraZeneca:
ATM deficient, ATM proficient, HER2 negative, Breast, Gastric, Head & Neck, Lung, Ovarian
Additional relevant MeSH terms:
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Carboplatin
Durvalumab
Olaparib
Antineoplastic Agents
Antineoplastic Agents, Immunological
Poly(ADP-ribose) Polymerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action