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Also known as Administration of ceralasertib, AZD6738, Ceralasertib taken orally
Ceralasertib · 10 trials · 9 indications
The superiority of ceralasertib plus durvalumab combination therapy relative to docetaxel will be demonstrated by assessment of OS (HR with 95% CI and p-value) in participants with advanced NSCLC after second- or third-line therapy and without actionable genomic alterations. OS is defined as time from randomisation until the date of death due to any cause.
Objective response rate (ORR) is defined as the proportion of participants who have a complete response (CR) or partial response (PR) per RECIST 1.1.
ATRiBRAVE will evaluate the efficacy of ceralasertib followed by durvalumab plus nab-paclitaxel in patients with TNBC, whose tumor relapsed following treatment with curative intent for early disease, which must have included ICIs and chemotherapy as part of the radical locoregional therapy (either adjuvant, neoadjuvant or both).
ORR was defined as the proportion of participants who had a complete response (CR) or partial response (PR) prior to any evidence of progression (as defined by Response Evaluation Criteria in Solid Tumours \[RECIST\] 1.1) that is confirmed at least 4 weeks later. As per planned in protocol, this outcome measure was assessed only for main study.
Changes in CD8+ T-cell infiltration of tumours induced by ceralasertib monotherapy was assessed in baseline, on-treatment and off-treatment tumour biopsies As per planned in protocol, this outcome measure was assessed only for biopsy study.
Changes in CD8+ T-cell infiltration of tumours induced by ceralasertib monotherapy was assessed in baseline and off-treatment tumour biopsies As per planned in protocol, this outcome measure was assessed only for biopsy study.
Changes in CD8+ T-cell infiltration of tumours induced by ceralasertib monotherapy was assessed in baseline, on-treatment and off-treatment tumour biopsies As per planned in protocol, this outcome measure was assessed only for biopsy study.
Changes in CD8+ T-cell infiltration of tumours induced by ceralasertib monotherapy was assessed in baseline and off-treatment tumour biopsies As per planned in protocol, this outcome measure was assessed only for biopsy study.
ORR is defined as the percentage of participants who have at least one response of complete response (CR) or partial response (PR) prior to any evidence of progression (as defined by response evaluation criteria in solid tumours \[RECIST\] 1.1) that is confirmed at least 4 weeks later. The CR is defined as disappearance of all target and non-target lesions and no new lesions. The PR is defined as \>= 30% decrease in the sum of the diameters of target lesions compared to baseline and no new non-target lesion. Due to an increased frequency and early onset of Grade≥3 hematological toxicity noted among the participants receiving 240 mg of Ceralsertib, the sponsor decreased the dose to 160mg. Therefore, patients with the 240 mg BID starting dose were not included in the efficacy analyses for both study cohorts.
Composite response rate is defined as the investigator assessed radiological response by RECIST 1.1 for soft tissue and visceral lesions and Prostate Cancer Working Group 3 (PCWG3) for bone lesions, confirmed prostate specific antigen (PSA) decline of more than 50%, and/or confirmed circulating tumour cell \[CTC\] conversion from unfavorable (\>=5 cells/7.5 ml blood) to favorable (\<5 cells). Due to an increased frequency and early onset of Grade≥3 hematological toxicity noted among the participants receiving 240 mg of Ceralsertib, the sponsor decreased the dose to 160mg. Therefore, patients with the 240 mg BID starting dose were not included in the efficacy analyses for both study cohorts.
A patient will be said to have had an overall objective response if they have a complete/partial response as assessed radiologically according to RECIST 1.1 at any point during trial treatment. A second scan to confirm response will be taken ≥ 4 weeks after the first scan showing an objective response.
Dose-limiting toxicity as described in the protocol that is not related to disease progression, intercurrent illness or concomitant medications and that, despite optional therapeutic intervention, meets protocol-defined criteria.
Number of subjects with adverse events as a measure of safety and tolerability including changes in vital signs, electrocardiograms (ECGs), safety and laboratory parameters
To investigate prognosis-correlated immune activation due to DDR inhibition by monitoring the induction of immunologically relevant genes in tumours of patients treated with study investigational agent(s)
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.
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)
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.
| Arm | Type | Description |
|---|---|---|
| Group A: Ceralasertib plus durvalumab combination therapy | EXPERIMENTAL | Participants will be administered ceralasertib orally followed by durvalumab administered intravenously. |
| Group B: Docetaxel monotherapy | ACTIVE_COMPARATOR | Participants will be administered docetaxel (standard of care) administered intravenously. |
| Group A | EXPERIMENTAL | Ceralasertib plus durvalumab combination therapy Participants will be administered orally ceralasertib followed by IV durvalumab each 28 days cycle. |
| TNBC patients treated with ceralasertib, durvalumab e nab-paclitaxel | EXPERIMENTAL | Patients will be assessed for eligibility during the 28-day screening period prior to enrollment. Enrolled patients will be treated with: * Ceralasertib at 240 mg administered orally, twice daily on Days -6 to 0 prior to Day 1 Cycle 1 and thereafter on Days 22 to 28 (priming period) of Cycle 1 and every subsequent cycle; * Durvalumab at 1500 mg administered via IV infusion on Day 1 of every 28-day cycle; Nab-paclitaxel at 100 mg/m2 administered via IV infusion on Days 1,8 and 15 of every 28- day cycle. A safety run-in phase will be carried out at the start of the present study using a 3+3 de-escalating schema down to -2 ceralasertib dose level. Nab- paclitaxel or durvalumab doses will not be de-escalated. Once the definitive dose for ceralasertib is established, treatment will be continued until progression or unacceptable toxicity, which ever come first. |
| Main study: Ceralasertib + Durvalumab | EXPERIMENTAL | Participants will receive ceralasertib on Days 1 to 7 plus durvalumab Day 8, once in 28 days (Q28D), until progressive disease, unacceptable toxicity, withdrawal of consent, or if a study treatment discontinuation criterion is met. |
| Main study: Ceralasertib | EXPERIMENTAL | Participants will receive ceralasertib on Days 1 to 7, Q28D, until progressive disease, unacceptable toxicity, withdrawal of consent, or if a study treatment discontinuation criterion is met. |
| Biopsy Sub-study: Ceralasertib + Durvalumab | EXPERIMENTAL | From Cycle 1, participants will receive combination of ceralasertib twice daily (BD) Days 1 to 7 plus durvalumab Day 8, Q28D, until progressive disease, unacceptable toxicity, withdrawal of consent, or a study treatment discontinuation criterion is met. |
| Biopsy study: Ceralasertib | EXPERIMENTAL | During Cycle 0, participants will receive ceralasertib on Days 1 to 7, followed by an off-treatment period between Days 8 to 28. |
| Cohort A | EXPERIMENTAL | Eligible participants (ATM altered AST), will receive oral dose of Ceralasertib as monotherapy. |
| Cohort B | EXPERIMENTAL | Eligible participants (ATM altered mCRPC), will receive oral dose of Ceralasertib as monotherapy. |
| 1A: ceralasertib (AZD6738) | EXPERIMENTAL | Women with relapsed ovarian (fallopian tube / primary peritoneal) and endometrial (uterus) clear cell carcinomas with loss of ARID1A expression treated with single agent AZD6738. |
| 1B: ceralasertib (AZD6738) + olaparib | EXPERIMENTAL | In second stage of trial, opening of this cohort depends on response rate in cohort 1A during first stage of trial. Women with relapsed ovarian (fallopian tube / primary peritoneal) and endometrial (uterus) clear cell carcinomas with loss of ARID1A expression treated with AZD6738 in combination with olaparib. |
| 2: ceralasertib (AZD6738) + olaparib | EXPERIMENTAL | Women with relapsed ovarian (fallopian tube / primary peritoneal) and endometrial (uterus) clear cell carcinomas with NO loss of ARID1A expression treated with AZD6738 in combination with olaparib. |
| 3: ceralasertib (AZD6738) + olaparib | EXPERIMENTAL | Women with other rare relapsed gynaecological cancers (endometrioid ovarian carcinoma, endometrioid endometrial carcinoma, cervical adenocarcinoma, cervical squamous, ovarian carcinosarcoma and endometrial carcinosarcoma) irrespective of ARID1A status, treated with AZD6738 in combination with olaparib. |
| 4: ceralasertib (AZD6738) + durvalumab | EXPERIMENTAL | Women with endometrial cancers (serous, clear cell, endometroid, carcinosarcoma) with ARID1A loss. |
| 5: ceralasertib (AZD6738) + durvalumab | EXPERIMENTAL | Women with endometrial cancers (serous, clear cell, endometroid, carcinosarcoma) with NO loss of ARID1A. |
| Ceralasertib in Combination with Durvalumab | EXPERIMENTAL | This is a sequential group treatment/dose-escalation study with 2 cohorts with no masking. |
| Ceralasertib monotherapy | EXPERIMENTAL | This is a sequential group treatment/dose-escalation study with 2 cohorts with no masking. |
| AZD6738 | EXPERIMENTAL | AZD6738 (160 mg) tablet twice daily continuous dosing for a minimum of 9 days and a maximum of 21 days. |
| Olaparib | EXPERIMENTAL | Olaparib (300 mg) tablets administered orally twice daily continuously for a minimum of 9 days and a maximum of 21 days. |
| Module 2 Part A1 | EXPERIMENTAL | 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. |
| Module 2 Part A2 | EXPERIMENTAL | 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. |
| Module 2 Part B1 | EXPERIMENTAL | 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. |
| Module 2 Part B2 | EXPERIMENTAL | 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. |
| Module 2 Part B3 | EXPERIMENTAL | 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. |
| Module 2 Part B4 | EXPERIMENTAL | 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. |
| Module 3 Part A | EXPERIMENTAL | 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. |
| Module 3 Part B | EXPERIMENTAL | 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. |
| Module 2 Part B5 | EXPERIMENTAL | 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. |
| Module 4 (FE/QT) | EXPERIMENTAL | 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. |
| Module 5 Part A | EXPERIMENTAL | 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. |
| Module 5 Part B | EXPERIMENTAL | 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. |
| Module 1 Part A | EXPERIMENTAL | 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). |
| Module 1 Part B | EXPERIMENTAL | 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. |
| Name | Type | Description |
|---|---|---|
| Ceralasertib | DRUG | Participants will receive ceralasertib oral tablets. |
| Durvalumab | DRUG | Participants will receive durvalumab as an intravenous infusion. |
| Docetaxel | DRUG | Participants will received docetaxel as an intravenous infusion. |
| Nab-paclitaxel | DRUG | 100mg/m2 i.v. day 1,8,15 (q28) |
| Olaparib | DRUG | PARP inhibitor |
| Administration of ceralasertib | DRUG | 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. |
| Administration of ceralasertib in combination with olaparib | DRUG | 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. |
| Administation of ceralasertib in combination with durvalumab | DRUG | 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. |
| Administration of ceralasertib monotherapy | DRUG | 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 |
| Administration of ceralasertib and olaparib | DRUG | 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. |
| Administration of ceralasertib and durvalumab | DRUG | 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. |
| Administration of ceralasertib in combination with AZD5305 | DRUG | 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). |
| Administration of ceralasertib in combination with carboplatin | DRUG | 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. |
Inclusion Criteria: * Histologically or cytologically documented NSCLC that is locally advanced or metastatic according to Version 8 of the IASLC Staging Manual in Thoracic Oncology. * Documented epidermal growth receptor factor (EGFR) and anaplastic lymphoma kinase (ALK) wild-type status as determ...
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Ceralasertib is an investigational oral small molecule ATR inhibitor being developed by AstraZeneca for advanced solid tumors. It is being studied in cancers including non-small cell lung cancer, triple negative breast cancer, gastric, ovarian, and head and neck cancers, both as a single agent and in combination with other therapies such as durvalumab.
Ceralasertib targets ATR, a kinase involved in the DNA damage response. By inhibiting ATR, ceralasertib interferes with cancer cell DNA repair mechanisms, particularly in tumors with DNA damage repair deficiencies such as ATM alterations. It is classified as an ATR inhibitor and is being evaluated in biomarker-selected patient populations.
Ceralasertib is being developed by AstraZeneca PLC, which trades under the ticker AZN. AstraZeneca is the sponsor of the clinical trials evaluating ceralasertib in various solid tumor indications.
Ceralasertib is in Phase 1 clinical development. It is an investigational agent and has not been approved by the FDA or any regulatory authority. The Phase 1 trials are evaluating its safety, pharmacokinetics, and preliminary activity in advanced solid tumors.
Ceralasertib is being studied in several clinical trials, including NCT05941897, a Phase 2 trial of ceralasertib plus durvalumab in advanced or metastatic non-small cell lung cancer; NCT05582538, a Phase 2 trial in triple negative breast cancer; NCT05514132, a Phase 1 trial in Chinese patients with advanced solid tumors; and NCT05469919, a completed Phase 1 trial in Japanese patients.
No, ceralasertib and durvalumab are different drugs. Ceralasertib is an ATR inhibitor, while durvalumab is an anti-PD-L1 immunotherapy. Ceralasertib is often studied in combination with durvalumab in clinical trials, but they are separate agents with distinct mechanisms of action.