Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
Also known as Adavosertib (AZD1775), AZD1775, MK1775
Adavosertib · 10 trials · 11 indications
The objective response rate (ORR) was defined as the percentage of participants achieving complete response (CR) or partial response (PR) based on RECIST 1.1 criteria on treatment. Per RECIST 1.1 for target lesions: CR is complete disappearance of all target lesions and PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. PR or better overall response assumes at a minimum incomplete response/stable disease (SD) for the evaluation of non-target lesions and absence of new lesions.
Per Response Evaluation Criteria in Solid Tumours (RECIST) v1.1 for target lesions (TLs) and assessed by computed tomography (CT) or magnetic resonance imaging (MRI): Complete response (CR), Disappearance of all target lesions; Partial response (PR), \>=30% decrease in the sum of the diameters of TL, taking as reference the baseline sum of diameters.
Measured by the rate of progression-free survival at 6 months (PFS6) using RECIST v.1.1.
Investigate the safety and tolerability of adavosertib
Investigate the safety and tolerability of adavosertib
DLTs are defined as: 1. Grade 4 haematologic toxicity for ≥7 days, including infection with febrile neutropenia, or Grade 4 thrombocytopenia. 2. Grade 3 thrombocytopenia associated with Grade ≥2 bleeding. 3. Non-haematologic toxicity ≥Grade 3. 4. Grade 3 nausea, vomiting, or diarrhoea that does not respond within 48 hours. 5. Grade 4 nausea, vomiting, and diarrhoea. 6. ALT or AST ≥5 x but ≤8 x ULN that does not resolve to Grade 2 within 5 days. ALT or AST \>8 x ULN or total bilirubin \>5 x ULN is a DLT regardless of duration. 7. AST or ALT \>3 x ULN and concurrent increase in total bilirubin \> 2 x ULN (Hy's Law) without evidence of cholestasis or alternative explanations (viral hepatitis, disease progression in the liver). 8. Grade ≥2 pneumonitis that does not resolve to ≤ Grade 1 within 7 days. 9. Clinically significant or unacceptable toxicity that does not respond to supportive care, or results in a disruption of dosing for \>7 days.
The MTD will be determined through dose-escalation using a 3+3 cohort design. If less than one-third of evaluable patients in a given cohort (0 of 3 patients or 1 of 6 patients) experiences a DLT; escalation may proceed to the next higher dose level. If one of the first 3 patients enrolled in a given cohort experiences a dose-limiting toxicity (DLT), at least 3 additional patents will be enrolled in that cohort. If a DLT is observed in one-third or more of patients, the dose at which this occurs will be considered not tolerated and the MTD will have been exceeded. The highest dose level(s) at which less than one-third of patients (0 of 3 patients or 1 of 6 patients) experiences a DLT will be declared the MTD.
The MTD will be determined through dose-escalation using a 3+3 cohort design. If less than one-third of evaluable patients in a given cohort (0 of 3 patients or 1 of 6 patients) experiences a DLT; escalation may proceed to the next higher dose level. If one of the first 3 patients enrolled in a given cohort experiences a dose-limiting toxicity (DLT), at least 3 additional patents will be enrolled in that cohort. If a DLT is observed in one-third or more of patients, the dose at which this occurs will be considered not tolerated and the MTD will have been exceeded. The highest dose level(s) at which less than one-third of patients (0 of 3 patients or 1 of 6 patients) experiences a DLT will be declared the MTD.
The MTD will be determined through dose-escalation using a 3+3 cohort design. If less than one-third of evaluable patients in a given cohort (0 of 3 patients or 1 of 6 patients) experiences a DLT; escalation may proceed to the next higher dose level. If one of the first 3 patients enrolled in a given cohort experiences a dose-limiting toxicity (DLT), at least 3 additional patents will be enrolled in that cohort. If a DLT is observed in one-third or more of patients, the dose at which this occurs will be considered not tolerated and the MTD will have been exceeded. The highest dose level(s) at which less than one-third of patients (0 of 3 patients or 1 of 6 patients) experiences a DLT will be declared the MTD.
The maximum tolerated dose (MTD) of the AZD1775/olaparib combination will be the highest dose level at which less than one-third of patients experience a DLT during Cycle 1. Toxicity will be graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.03.
Treatment-emergent adverse events will be assessed through reports of clinical events and changes from baseline in vital signs and laboratory parameters.
The AZD1775 dose is considered safe and tolerable if ≤ 1 of 6 patients experiences a DLT.
The number of patients with treatment-emergent adverse events was analyzed on the safety analysis set which was comprised of all patients who received at least one dose of the investigational drug.
The number of treatment-emergent adverse events was counted in the safety analysis set which was comprised of all patients who received at least one dose of the investigational drug.
The number of patients with TEAEs during AZD1775 Monotherapy Cycle was analyzed in the safety analysis set which was comprised of all patients who received at least one dose of the investigational drug.
The number of patients with clinically important changes in haematology and coagulation TEAEs was analyzed in the safety analysis set which was comprised of all patients who received at least one dose of the investigational drug.
The number of patients with clinically important changes in clinical chemistry TEAEs was analyzed in the safety analysis set which was comprised of all patients who received at least one dose of the investigational drug.
The number of patients with clinically important changes in vital sign TEAEs was analyzed in the safety analysis set which was comprised of all patients who received at least one dose of the investigational drug.
| Arm | Type | Description |
|---|---|---|
| cisplatin + AZD1775 | EXPERIMENTAL | Treatment will consist of one cycle of cisplatin monotherapy (cisplatin 75 mg/m2 IV x1) followed by combination therapy of AZD1775 plus cisplatin starting 21 days(1 cycle) later. AZD1775 will be administered 200 mg as twice daily oral dosing predetermined dosing schedule, in combination with Cisplatin predetermined dosage every 21 days. At least 10 patients will undergo a research biopsy within 5-48 hours after beginning cisplatin (Cycle 1 Day 1) and then again within 5-8 hours after the last dose of AZD1775 in cycle 2 (Cycle 2 Day 3). |
| Adavosertib | EXPERIMENTAL | Subjects will receive adavosertib 300 mg administered orally, once daily on Days 1 to 5 and Days 8 to 12 of a 21-day treatment cycle. |
| Part A: AZD1775 | EXPERIMENTAL | -AZD1775 will be taken by mouth daily on days 1 through 5 and days 8 through 12 of each 21-day cycle |
| Part B: AZD1775 in Carcinosarcoma | EXPERIMENTAL | -AZD1775 will be taken by mouth daily on days 1 through 5 and days 8 through 12 of each 21-day cycle |
| Part C: AZD1775 in Uterine Serous with biopsiable disease | EXPERIMENTAL | -AZD1775 will be taken by mouth daily on days 1 through 5 and days 8 through 12 of each 21-day cycle |
| Arm A (adavosertib + gemcitabine) | EXPERIMENTAL | Adavosertib (175 mg PO) will be taken on Days 1-2, 8-9, and 15-16. Gemcitabine 800 mg/m² will be administered IV on days 1, 8, and 15 of each 28 day cycle. |
| Arm B (adavosertib + paclitaxel) | EXPERIMENTAL | Five doses of adavosertib (225 mg PO BID) will be taken in approximate 12 hour intervals over 2.5 days weekly (Days 1-3, 8-10, and 15-17). Weekly paclitaxel 80 mg/m² IV will be administered according to institutional standards on Day 1, 8, and 15 of each 28 day cycle. |
| Arm C/C2 (adavosertib + carboplatin) | EXPERIMENTAL | Arm C: Five doses of adavosertib (225 mg PO BID) will be taken in approximate 12 hour intervals over 2.5 days (Days 1-3). Carboplatin AUC 5 IV will be administered according to institutional standards on Day 1 of each 21-Day cycle. Arm C2: Five doses of adavosertib (225 mg PO BID) 2.5 days per dosing week (QW), on Weeks 1 (D1-3), 2 (D8-10) and 3 (D15-17), or on Weeks 1 (D1-3) and 2 (D8-10) ( 2 weeks on followed by 1 week off.) Carboplatin AUC 5 IV will be administered according to institutional standards on Day 1 of each 21 day cycle. |
| Arm D (adavosertib + PLD) | EXPERIMENTAL | Five doses of adavosertib (175 mg or 225 mg) will be taken in approximate 12 hour intervals over 2.5 days (Days 1, 2, and 3) of each 28-day cycle. PLD will administered IV on Day 1 of each cycle. |
| Adavosertib (AZD1775) monotherapy | EXPERIMENTAL | Dose escalation of adavosertib monotherapy for patients with advanced solid tumours |
| Adavosertib (AZD1775) in combination with gemcitabine | EXPERIMENTAL | Dose escalation of adavosertib in combination with gemcitabine for patients with advanced solid tumours |
| Dose Schedule A | EXPERIMENTAL | In Schedule A, patients will receive MEDI4736 (durvalumab) by intravenous on Day 1, and AZD1775 (adavosertib) twice daily orally on Days 1-5 and Days 15-19 of a 28-day cycle. In all dose schedules, dexamethasone will be administered as an anti-emetic on the first day of the AZD1775 (adavosertib). |
| Dose Schedule B | EXPERIMENTAL | In Schedule B, patients will receive MEDI4736 (durvalumab) by intravenous on Day 1, and AZD1775 (adavosertib) twice daily orally on Days 15-17 and Days 22-24 of a 28-day cycle. In Schedule B there will be a 7-day AZD1775 (adavosertib) lead-in to enable serial PK measurements prior to initiating MEDI4736 on Day 1. In all dose schedules, dexamethasone will be administered as an anti-emetic on the first day of the AZD1775 (adavosertib) consecutive dosing day blocks including the lead-in portion of Schedules B, C, and D. Additional alternative dose levels and/or schedules may also be explored if emerging data suggest these would be more appropriate. |
| Dose Schedule C | EXPERIMENTAL | In Schedule C, patients will receive MEDI4736 (durvalumab) by intravenous on Day 1, and AZD1775 (adavosertib) twice daily orally on Days 8-10, Days 15-17, and Days 22-24 of a 28-day cycle. In Schedule C there will be a 7-day AZD1775 (adavosertib) lead-in to enable serial PK measurements prior to initiating MEDI4736 (durvalumab) on Day 1. In all dose schedules, dexamethasone will be administered as an anti-emetic on the first day of the AZD1775 (adavosertib) consecutive dosing day blocks including the lead-in portion of Schedules B, C, and D. Additional alternative dose levels and/or schedules may also be explored if emerging data suggest these would be more appropriate. |
| Dose Schedule D | EXPERIMENTAL | In Schedule D, patients will receive MEDI4736 (durvalumab) by intravenous on Day 1, and AZD1775 (adavosertib) one time per day orally on Days 15-19, and Days 22-26 of a 28-day cycle. In Schedule D there will be a 9-day lead-in period with AZD1775 (adavosertib) being dosed on Days -9 to -5 to enable serial PK measurements prior to initiating MEDI4736 (durvalumab) on Day 1. In all dose schedules, dexamethasone will be administered as an anti-emetic on the first day of the AZD1775 (adavosertib) consecutive dosing day blocks including the lead-in portion of Schedules B, C, and D. Additional alternative dose levels and/or schedules may also be explored if emerging data suggest these would be more appropriate. |
| AZD1775 | EXPERIMENTAL | This is a single-arm study in which all patients will receive AZD1775 orally. Patients will continue to receive treatment with AZD1775 until disease progression, intolerable toxicity, or discontinuation criteria are met. |
| AZD1775 (6 doses/week) + Olaparib | EXPERIMENTAL | In this Arm, AZD1775 will be given twice daily over 3 days (6 doses) on Days 1-3 of Week 1 and Days 8-10 of Week 2. Olaparib will be given orally BID on Days 1-14. All patients will enter an olaparib sub-study in order to assess multiple dose pharmacokinetics of olaparib prior to entering the main study. In the olaparib PK sub-study patients will take olaparib for 3 consecutive days and venous blood samples will be collected on Day 3. The PK sub-study must be initiated 10 days prior to the Cycle 1 Day 1 administration of the AZD1775 and olaparib combination. The patient will experience a short gap in treatment (approximately 4-5 days) between Day 3 of the olaparib PK sub-study and Cycle 1 Day 1 AZD1775 and olaparib combined dosing. |
| AZD1775 (10 doses/week) + Olaparib | EXPERIMENTAL | In this Arm, AZD1775 will be given twice daily over 5 days (10 doses) on Days 1-5 of Week 1 and Days 8-12 of Week 2. Olaparib will be given orally BID on Days 1-14. All patients will enter an olaparib sub-study in order to assess multiple dose pharmacokinetics of olaparib prior to entering the main study. In the olaparib PK sub-study patients will take olaparib for 3 consecutive days and venous blood samples will be collected on Day 3. The PK sub-study must be initiated 10 days prior to the Cycle 1 Day 1 administration of the AZD1775 and olaparib combination. The patient will experience a short gap in treatment (approximately 4-5 days) between Day 3 of the olaparib PK sub-study and Cycle 1 Day 1 AZD1775 and olaparib combined dosing. |
| Paclitaxel | EXPERIMENTAL | Commercially available paclitaxel will be administered at a dosage of 175 mg/m2 as a 3-hour IV infusion on Cycle Day 1 of a 21-day cycle for 6 cycles. |
| Carboplatin | EXPERIMENTAL | Following the paclitaxel infusion, carboplatin will be administered at a dose of AUC 5 as an IV infusion on Cycle Day 1 of a 21-day cycle for 6 cycles. According to the Cancer Therapy Evaluation Program Information Letter Regarding the AUC Based Dosing of Carboplatin, the maximum carboplatin dose should not exceed the target AUC (mg\*min/mL)\*150 mL/min, but it may be less (Ivy et al 2010). For this study, the maximum dose of carboplatin cannot exceed a total dose of 750 mg. |
| Name | Type | Description |
|---|---|---|
| Cisplatin | DRUG | chemotherapy |
| AZD1775 | DRUG | Wee1 tyrosine kinase inhibitor |
| Adavosertib | DRUG | The subjects will receive oral adavosertib 300 mg, once daily on Days 1 to 5 and Days 8 to 12 of a 21-day treatment cycle. |
| Paclitaxel | DRUG | Paclitaxel will be administered as a 1-hour IV infusion (± 10 minutes) at a dose of 80 mg/m2 according to institutional standards on Days 1, 8, and 15 of each 28 Day cycle. Patients should be pre-medicated with corticosteroids, diphenhydramine and/or H2 antagonists according to institutional standards. |
| Carboplatin | DRUG | Carboplatin, at a dose calculated to produce an AUC of 5 will be administered by intravenous infusion according to institutional standards on Day 1 of each 21 Day cycle. The carboplatin dose will be calculated using the Calvert Formula based on the patient's glomerular filtration rate (GFR) which is estimated by using the creatinine clearance. |
| Gemcitabine | DRUG | Gemcitabine 800 mg/m² will be administered IV on Days 1, 8, and 15 of each 28-Day cycle. |
| PLD | DRUG | PLD (pegylated liposomal doxorubicin) 40 mg/m² IV will be given on Day 1 of each 28-Day cycle. |
| Adavosertib (AZD1775) | DRUG | Adavosertib taken orally |
| MEDI4736 | DRUG | MEDI4736 (durvalumab) will be administered by IV infusion. |
| Olaparib | DRUG | AZD1775 will be given twice daily (PO BID) over 5 days (10 doses) on Days 1-5 and 8-12 of each 21 day cycle combined with olaparib PO BID on Days 1-14 of each 21 day cycle. Olaparib will be given orally BID on Days 1-14. |
| AZD 1775 | DRUG | AZD1775 will be taken orally approximately every 12 hours over 3 days at the start of week 1 and week 2 of each 21-day cycle (Days 1-3 and 8-10), for a total of 12 doses with each treatment cycle. AZD1775 should be taken approximately 2 hours before or 2 hours after food. |
Inclusion Criteria: * Participants must have histologically or cytologically confirmed invasive breast cancer, with stage IV disease. Patients without pathologic or cytologic confirmation of metastatic disease should have unequivocal evidence of metastasis from physical examination or radiologic ev...
Adavosertib is an investigational small molecule WEE1 inhibitor developed by AstraZeneca PLC for oncology indications. It has been studied in advanced solid tumours, uterine serous carcinoma, and platinum-resistant ovarian, fallopian tube, or primary peritoneal cancer, including tumors with P53 mutation. It is not approved and remains in clinical development.
Adavosertib has been studied as a treatment for uterine serous carcinoma in a completed Phase 2 trial, NCT04590248, which enrolled 109 female patients aged 18 and older across the United States, Canada, France, Italy, and Spain. It is investigational and not approved for this or any other indication.
Adavosertib targets WEE1, a kinase involved in cell cycle regulation, and acts as an inhibitor of that target. By inhibiting WEE1, the drug interferes with the checkpoint that controls entry into mitosis. This mechanism has been explored in tumor types with P53 mutation, where WEE1 inhibition may be relevant.
Adavosertib is developed by AstraZeneca PLC, which trades under the ticker AZN. AstraZeneca is the sponsor of the clinical trials evaluating the drug in advanced solid tumours, uterine serous carcinoma, and platinum-resistant ovarian, fallopian tube, or primary peritoneal cancer.
Adavosertib is in Phase 1 development overall, with completed Phase 1 and Phase 2 trials. It is investigational and has not been approved by the FDA or any other regulatory agency. The completed studies include NCT04590248, NCT04462952, and NCT02272790.
Adavosertib has been evaluated in three completed trials: NCT04590248 in uterine serous carcinoma, NCT04462952 in Japanese patients with advanced solid tumours, and NCT02272790 in platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer with P53 mutation. No trials are currently active.
Yes, Adavosertib is also known as AZD1775. The name AZD1775 appears in trial listings such as NCT04462952. Adavosertib has also been studied in combination regimens, including with olaparib, which are sometimes referenced by their dosing schedules.