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Ceralasertib · 9 trials · 8 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)
| 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. |
| 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 |
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 small molecule being studied in oncology for advanced solid tumours, metastatic triple negative breast cancer, advanced or metastatic non-small cell lung cancer, gynaecological cancers, melanoma, and head and neck squamous cell carcinoma. It is being evaluated as monotherapy and in combination with durvalumab and nab-paclitaxel.
Ceralasertib targets ATR, the ataxia telangiectasia and Rad3-related protein kinase. It is an ATR inhibitor, which is a class of drugs that block DNA damage repair pathways in cancer cells. By inhibiting ATR, Ceralasertib may enhance the effects of DNA-damaging agents and immunotherapies.
Ceralasertib is being developed by AstraZeneca PLC, a multinational pharmaceutical company listed on the NASDAQ under the ticker AZN. AstraZeneca is conducting clinical trials of Ceralasertib across multiple cancer types and in various countries.
Ceralasertib is in Phase 1 and Phase 2 clinical trials. It is not FDA approved and remains investigational. Active studies include a Phase 2 trial in melanoma and a Phase 2 trial in metastatic triple negative breast cancer, while earlier Phase 1 studies have been completed.
Ceralasertib is being studied in several clinical trials. NCT05061134 is an active Phase 2 trial of Ceralasertib alone or with durvalumab in melanoma. NCT05582538 is a recruiting Phase 2 trial in metastatic triple negative breast cancer. Completed trials include NCT03022409 and NCT05469919.
Ceralasertib is also known by the code name AZD6738. It is the same drug, an ATR inhibitor developed by AstraZeneca. Researchers and clinical trial listings may use either name to refer to this investigational compound.