Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
Also known as MK-1775
adavosertib · 2 trials · 2 indications
PFS was defined as the time from randomization to progressive disease (based on blinded independent central radiologic review) or death, whichever occurred earlier. Tumor response was evaluated every 6 weeks during treatment by diagnostic anatomic imaging and objective response assessments were performed based on enhanced RECIST 1.1 criteria. According to enhanced RECIST 1.1, progressive disease was the appearance of one or more new lesions, OR an unambiguous increase in the sum of target lesion volumes with both 1) \>20% increase in the sum of volumes (SOV) of all target lesions (taking as reference the nadir) and 2) greater than two times the variability of the measurements estimated by the sponsor and/or its designees. PFS was analyzed for Part 2 participants only using the Kaplan-Meier method and median PFS was reported in weeks. Per protocol, Part 1 participants were not included in this analysis.
DLTs assessed during first 21-day cycle of Part 1 and defined as toxicities that met pre-defined severity criteria, were possibly, probably, or definitely related to triplet therapy, and could possibly result in a change in the given dose. Hematologic DLTs included Grade (Gr) 3 or Gr 4 neutropenia with fever \>38.5°C and/or infection requiring antibiotic or anti-fungal treatment, and any Gr 4-5 hematological toxicity EXCEPT Gr 4 anemia, leukopenia, lymphopenia, neutropenia lasting \<7 days, and thrombocytopenia lasting \<4 days, except if a platelet transfusion was required. Non-hematologic DLT defined as any Gr 3, 4, or 5 nonhematologic toxicity EXCEPT: Gr 3 nausea, vomiting, diarrhea, or dehydration judged by Investigator and SPONSOR to occur in setting of inadequate compliance with supportive care measures and last for less than 48 hours, alopecia of any grade, inadequately treated hypersensitivity reactions, or clinically non-significant, treatable or reversible lab abnormalities.
An AE was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the SPONSOR's products, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which is temporally associated with the use of the SPONSOR's product was also an AE. The percentage of participants that experienced at least one AE was reported for each treatment arm.
An AE was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the SPONSOR's products, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which is temporally associated with the use of the SPONSOR's product was also an AE. The percentage of participants that discontinued study treatment (paclitaxel, carboplatin, or MK-1775) due to an AE was reported for each treatment arm.
DLTs were adverse events (AEs) considered at least possibly related to study drug that prevented escalation of the drug dose. Hematologic DLTs were any grade (Gr) 4-5 toxicity EXCEPT: Gr 4 anemia and Gr 4 leukopenia, Gr 4 neutropenia lasting for \<7 days, Gr 4 thrombocytopenia lasting for \<4 days except if a platelet transfusion is required, and Gr 3/Gr 4 neutropenia with fever \>38.5°C and/or infection requiring antibiotic or anti-fungal treatment. Non-hematologic DLT was defined as any Gr 3, 4, or 5 non-hematologic toxicity EXCEPT: nausea, vomiting, diarrhea, or dehydration (all Gr 3) occurring in a setting of inadequate compliance with supportive care measures and lasting for \<48 hours, alopecia of any grade, inadequately treated hypersensitivity reactions, and clinically non-significant, treatable or reversible lab abnormalities including liver function tests, uric acid, etc.
The pCDC2 level in skin cells was used as a marker to evaluate MK-1775 activity. Analysis was done by immunohistochemistry and the percentage of total CDC2-positive cells that were pCDC2 positive (% pCDC2-positive cells) at baseline and 8 hours after MK-1775 dosing were reported for participants in Part 1, 2-A, and 2-B/3 treatment groups with available data per protocol.
The pCDC2 level in skin cells was used as a marker to evaluate MK-1775 activity. Analysis was done by immunohistochemistry and the percentage of total pCDC2 at baseline and 24 hours after MK-1775 dosing were reported for participants in the Part 2-B/3 MK-1775 QD x2 Multi Dose plus Gemcitabine treatment groups with available data per protocol.
The pCDC2 level in skin cells was used as a marker to evaluate MK-1775 activity. Analysis was done by immunohistochemistry and the percentage of total pCDC2 at baseline and at 48 hours after MK-1775 dosing were reported for participants in the Part 2-B/3 MK-1775 (150 mg, 200 mg, 250) BID x 2.5 Multi Dose plus cisplatin 75 mg/m\^2 groups and the 325 mg BID x2.5 Multi Dose + Carboplatin group with available data per protocol.
MK-1775 was measured in the plasma at 8 hours after dosing (Day 1 for single dose of monotherapy, Day 2 of single-dose combination therapy and QD x 2 Combination dosing, and Day 3 dose for BID X 2.5 combination dosing) for participants with available data.
The mean cumulative amount of MK-1775 excreted unchanged in urine after a single oral dose was measured during the initial monotherapy cycle of the study. For this outcome measure, samples were collected and analyzed only for the MK-1775 monotherapy arms of the study at defined intervals after the Day 1 dose of monotherapy. Part 2 MK-1775 combination arms were not sampled per protocol.
| Arm | Type | Description |
|---|---|---|
| Part 1: adavosertib 225 mg + paclitaxel +carboplatin | EXPERIMENTAL | During the open-label run-in, participants receive 225 mg adavosertib twice daily (BID) starting on Day 1 of Cycle 1 (cycle=21 days) for a total of 5 doses. Participants receive adavosertib in combination with paclitaxel (175 mg/m2) and carboplatin (area under the curve \[AUC\] 5). |
| Part 2: adavosertib 225 mg + paclitaxel +carboplatin | EXPERIMENTAL | During Part 2, participants receive 225 mg adavosertib BID starting on Day 1 of each 21 day cycle for a total of 5 doses. Participants receive adavosertib in combination with paclitaxel (175 mg/m2) and carboplatin (AUC 5). |
| Part 2: Placebo + paclitaxel +carboplatin | PLACEBO_COMPARATOR | During Part 2, participants receive matched placebo to adavosertib BID starting on Day 1 of each 21 day cycle for a total of 5 doses. Participants receive placebo in combination with paclitaxel (175 mg/m2) and carboplatin (AUC 5). |
| adavosertib 325 mg Single Dose | EXPERIMENTAL | Participants received adavosertib 325 mg, orally, on Day 1. |
| adavosertib 650 mg Single Dose | EXPERIMENTAL | Participants received adavosertib 650 mg, orally, on Day 1. |
| adavosertib 1300 mg Single Dose | EXPERIMENTAL | Participants received adavosertib 1300 mg, orally, on Day 1. |
| adavosertib 100 mg Single Dose + Gemcitabine 1000 mg/m^2 | EXPERIMENTAL | Participants received gemcitabine 1000 mg/m\^2 as an intravenous (IV) infusion on Days 1, 8, and 15 in each 4-week cycle plus adavosertib 100 mg single dose, orally, on Day 2 of each cycle. |
| adavosertib 200 mg Single Dose + Gemcitabine 1000 mg/m^2 | EXPERIMENTAL | Participants received gemcitabine 1000 mg/m\^2 as an IV infusion on Days 1, 8, and 15 in each 4-week cycle plus adavosertib 200 mg single dose, orally, on Day 2 of each cycle. |
| adavosertib 100 mg Single Dose + Cisplatin 75 mg/ m^2 | EXPERIMENTAL | Participants received cisplatin 75 mg/ m\^2 as an IV infusion on Day 1 of each 3 week cycle plus adavosertib 100 mg single dose orally, on Day 2 of each cycle. |
| adavosertib 200 mg Single Dose + Cisplatin 75 mg/ m^2 | EXPERIMENTAL | Participants received cisplatin 75 mg/ m\^2 as an IV infusion on Day 1 of each 3 week cycle plus adavosertib 200 mg single dose orally, on Day 2 of each cycle. |
| adavosertib 100 mg Single Dose + Carboplatin AUC 5 | EXPERIMENTAL | Participants received carboplatin at an area under the time curve concentration of 5 mg/min/ml (AUC5) as an IV infusion on Day 1 of each 3 week cycle plus adavosertib 100 mg single dose orally, on Day 2 of each cycle. |
| adavosertib 200 mg Single Dose + Carboplatin AUC 5 | EXPERIMENTAL | Participants received carboplatin AUC5 as an IV infusion on Day 1 of each 3 week cycle plus adavosertib 200 mg single dose orally, on Day 2 of each cycle. |
| adavosertib 325 mg Single Dose + Carboplatin AUC 5 | EXPERIMENTAL | Participants received carboplatin AUC5 as an IV infusion on Day 1 of each 3 week cycle plus adavosertib 325 mg single dose orally, on Day 2 of each cycle. |
| adavosertib 25 mg BID x2.5 Multi Dose + Gemcitabine 1000 mg/ m^2 | EXPERIMENTAL | Participants received gemcitabine 1000 mg/m\^2 as an IV infusion on Days 1, 8, and 15 of each 4-week cycle plus adavosertib 25 mg orally twice daily (BID) for 2.5 days, starting concomitantly with the IV infusion of gemcitabine on Day 1 and followed by 4 additional doses of adavosertib 25 mg at approximately 12 hour intervals on Days 1-3, 8-9, and 15-17 of each cycle. |
| adavosertib 50/25 mg BID x2.5 Multi + Gemcitabine 1000 mg/ m^2 | EXPERIMENTAL | Participants received gemcitabine 1000 mg/m\^2 as an IV infusion on Days 1, 8, and 15 of each 4 week cycle plus adavosertib 50 mg orally BID for 2.5 days, starting concomitantly with the IV infusion of gemcitabine on Day 1 and followed by 4 doses of adavosertib 25 mg at approximately 12 hour intervals on Days 1-3, 8-9, and 15-17 of each 4 week cycle. |
| adavosertib 50 mg BID x2.5 Multi + Gemcitabine 1000 mg/ m^2 | EXPERIMENTAL | Participants received gemcitabine 1000 mg/m\^2 as an IV infusion given once weekly for 3 consecutive weeks of a 4 week cycle plus adavosertib 50 mg orally BID for 2.5 days, starting concomitantly with the IV infusion of gemcitabine on Day 1 and followed by 4 additional doses of adavosertib 50 mg at approximately 12 hour intervals on Days 1-3, 8-9, and 15-17 of each 4 week cycle. |
| adavosertib 100 mg QD x2 Multi + Gemcitabine 1000 mg/ m^2 | EXPERIMENTAL | Participants received gemcitabine 1000 mg/m\^2 as an IV infusion on Days 1, 8, and 15 of each 4 week cycle plus adavosertib 100 mg orally once daily (QD) on Days 1, 2, 8, 9, 15, and 16 of each 4 week cycle. |
| adavosertib 125 mg QD x2 Multi + Gemcitabine 1000 mg/ m^2 | EXPERIMENTAL | Participants received gemcitabine 1000 mg/m\^2 as an IV infusion on Days 1, 8, and 15 of each 4 week cycle plus adavosertib 125 mg orally QD on Days 1, 2, 8, 9, 15, and 16 of each 4 week cycle. |
| adavosertib 150 mg QD x2 Multi + Gemcitabine 1000 mg/ m^2 | EXPERIMENTAL | Participants received gemcitabine 1000 mg/m\^2 as an IV infusion on Days 1, 8, and 15 of each 4 week cycle plus adavosertib 150 mg orally QD on Days 1, 2, 8, 9, 15, and 16 of each 4 week cycle. |
| adavosertib 175 mg QD x2 Multi Dose + Gemcitabine 1000 mg/ m^2 | EXPERIMENTAL | Participants received gemcitabine 1000 mg/m\^2 as an IV infusion given on Days 1, 8, and 15 of each 4 week cycle plus adavosertib 175 mg orally QD on Days 1, 2, 8, 9, 15, and 16 of each 4 week cycle. |
| adavosertib 200 mg QD x2 Multi Dose + Gemcitabine 1000 mg/ m^2 | EXPERIMENTAL | Participants received gemcitabine 1000 mg/m\^2 as an IV infusion on Days 1, 8, and 15 of each 4 week cycle plus adavosertib 200 mg orally QD on Days 1, 2, 8, 9, 15, and 16 of each 4 week cycle. |
| adavosertib 50 mg BID x2.5 Multi Dose + Cisplatin 75 mg/ m^2 | EXPERIMENTAL | Participants received cisplatin 75 mg/ m\^2 as an IV infusion on Day 1 of each 3 week cycle plus adavosertib 50 mg orally BID for 2.5 days, starting concomitantly with the administration of cisplatin on Day 1 and then at 12 hour intervals on Days 1-3 of each 3 week cycle. |
| adavosertib 100 mg BID x2.5 Multi Dose + Cisplatin 75 mg/ m^2 | EXPERIMENTAL | Participants received cisplatin 75 mg/ m\^2 as an IV infusion on Day 1 of each 3 week cycle plus adavosertib 100 mg orally BID for 2.5 days, starting concomitantly with the administration of cisplatin on Day 1 and then at 12 hour intervals on Days 1-3 of each 3 week cycle. |
| adavosertib 125 mg BID x2.5 Multi Dose + Cisplatin 75 mg/ m^2 | EXPERIMENTAL | Participants received cisplatin 75 mg/ m\^2 as an IV infusion on Day 1 of each 3 week cycle plus adavosertib 125 mg orally BID for 2.5 days, starting concomitantly with the administration of cisplatin on Day 1 and then at 12 hour intervals on Days 1-3 of each 3 week cycle. |
| adavosertib 150 mg BID x2.5 Multi Dose + Cisplatin 75 mg/ m^2 | EXPERIMENTAL | Participants received cisplatin 75 mg/ m\^2 as an IV infusion on Day 1 of each 3 week cycle plus adavosertib 150 mg orally BID for 2.5 days, starting concomitantly with the administration of cisplatin on Day 1 and then at 12 hour intervals on Days 1-3 of each 3 week cycle. |
| adavosertib 200 mg BID x2.5 Multi Dose + Cisplatin 75 mg/ m^2 | EXPERIMENTAL | Participants received cisplatin 75 mg/ m\^2 as an IV infusion on Day 1 of each 3 week cycle plus adavosertib 200 mg orally BID for 2.5 days, starting concomitantly with the administration of cisplatin on Day 1 and then at 12 hour intervals on Days 1-3 of each 3 week cycle. |
| adavosertib 250 mg BID x2.5 Multi Dose + Cisplatin 75 mg/ m^2 | EXPERIMENTAL | Participants received cisplatin 75 mg/ m\^2 as an IV infusion on Day 1 of each 3 week cycle plus adavosertib 250 mg orally BID for 2.5 days, starting concomitantly with the administration of cisplatin on Day 1 and then at 12 hour intervals on Days 1-3 of each 3 week cycle. |
| adavosertib 75 mg BID x2.5 Multi Dose + Carboplatin AUC 5 | EXPERIMENTAL | Participants received carboplatin AUC 5 as an IV infusion on Day 1 of each 3 week cycle plus adavosertib 75 mg orally BID for 2.5 days, starting concomitantly with the administration of carboplatin on Day 1 and then at 12 hour intervals on Days 1-3 of each 3 week cycle. |
| adavosertib 150 mg BID x 2.5 Multi Dose + Carboplatin AUC 5 | EXPERIMENTAL | Participants received carboplatin AUC 5 as an IV infusion on Day 1 of each 3 week cycle plus adavosertib 150 mg orally BID for 2.5 days, starting concomitantly with the administration of carboplatin on Day 1 and then at 12 hour intervals on Days 1-3 of each 3 week cycle. |
| adavosertib 225 mg BID x2.5 Multi Dose + Carboplatin AUC 5 | EXPERIMENTAL | Participants received carboplatin AUC 5 as an IV infusion on Day 1 of each 3 week cycle plus adavosertib 225 mg orally BID for 2.5 days, starting concomitantly with the administration of carboplatin on Day 1 and then at 12 hour intervals on Days 1-3 of each 3 week cycle. |
| adavosertib 325 mg BID x2.5 Multi Dose + Carboplatin AUC 5 | EXPERIMENTAL | Participants received carboplatin AUC 5 as an IV infusion on Day 1 of each 3 week cycle plus adavosertib 325 mg orally BID for 2.5 days, starting concomitantly with the administration of carboplatin on Day 1 and then at 12 hour intervals on Days 1-3 of each 3 week cycle. |
| Name | Type | Description |
|---|---|---|
| adavosertib | DRUG | Adavosertib capsules, orally, twice a day (BID) for a total of 5 doses starting on Day 1 of each 3-week cycle |
| Placebo | DRUG | placebo to adavosertib, capsule, orally, BID for a total of 5 doses, starting on Day 1 of each 3-week cycle |
| paclitaxel | DRUG | paclitaxel, intravenous (IV) infusion on Day 1 of each 3-week cycle |
| carboplatin | DRUG | carboplatin, IV infusion on Day 1 of each 3-week cycle |
| gemcitabine | DRUG | Gemcitabine administered at 1000 mg/m\^2 by IV infusion in a 28-day cycle. |
| cisplatin | DRUG | Cisplatin administered at 75 mg/m\^2 by IV infusion in a 21-day cycle. |
Inclusion Criteria: * Histologically confirmed non-low grade, non-borderline (low malignant potential) ovarian, fallopian tube, or primary peritoneal cancer which has progressed after paclitaxel / platinum-based therapy. * Platinum-sensitive disease. Radiological progression must have occurred 6 mo...
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Adavosertib is an investigational small molecule being studied in oncology for ovarian cancer and advanced solid tumors. It has been evaluated in platinum-sensitive ovarian tumors with the p53 gene mutation and in adults with advanced solid tumors. It is not an approved therapy and remains in clinical development.
Adavosertib targets WEE1, a kinase involved in cell cycle regulation. Adavosertib is a WEE1 inhibitor. By inhibiting WEE1, adavosertib interferes with the DNA damage response and cell cycle checkpoints, which is the basis for its study in combination with chemotherapy in ovarian cancer and solid tumors.
Adavosertib is being developed by Merck & Company, Inc., which trades under the ticker MRK. Merck is the sponsor of the clinical trials evaluating adavosertib in ovarian cancer and advanced solid tumors.
Adavosertib is in Phase 2 clinical development. It is an investigational agent and has not been approved by the FDA. The Phase 2 trial has been completed, and a Phase 1 dose escalation study has also been completed.
Adavosertib has been studied in two completed trials. NCT01357161 was a Phase 2 trial of adavosertib (MK-1775) with paclitaxel and carboplatin versus paclitaxel and carboplatin alone in platinum-sensitive ovarian tumors with the p53 gene mutation, enrolling 136 participants. NCT00648648 was a Phase 1 dose escalation study in advanced solid tumors, enrolling 206 participants.
Yes, adavosertib is also known as MK-1775. The clinical trials for adavosertib are titled with the MK-1775 designation, such as MK-1775-004 and MK-1775-001. Both names refer to the same investigational WEE1 inhibitor developed by Merck.