A Study of Adavosertib (MK-1775) in Combination With Paclitaxel and Carboplatin Versus Paclitaxel and Carboplatin Alone for Participants With Platinum-Sensitive Ovarian Tumors With the P53 Gene Mutation (MK-1775-004)

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.

Time frame: During Cycle 1 of Part 1 (first 21 days)

Population: All participants who received ≥1 dose of study treatment during Cycle 1 of Part 1 open-label period and were evaluable at the time of the interim analysis. One participant took a prohibited medication during Part 1 and was considered unevaluable. Two participants enrolled into Part 1 after the interim analysis database lock and were not included.

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.

Time frame: Up to 57 months

Population: Intent to Treat (ITT) Population: All randomized participants in Part 2

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.

Time frame: Part 1: Day 1 through Post Study (286 days total). Part 2: Day 1 through Post Study (479 days total)

Population: Part 1: All participants who received at least one dose of study treatment during the open-label period.~Part 2: All randomized participants who received at least one dose of study treatment. 2 participants were randomized to the Part 2 placebo arm but were not treated.

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.

Time frame: Part 1: Day 1 through Post Study (286 days total). Part 2: Day 1 through Post Study (479 days total)

Population: Part 1: All participants who received at least one dose of study treatment during the open-label period.~Part 2: All randomized participants who received at least one dose of study treatment. 2 participants were randomized to the Part 2 placebo arm but were not treated.

ORR was defined as the percentage of participants whose best response was confirmed partial response (PR) or complete response (CR) based both on imaging per RECIST 1.1 and on serum marker CA-125 level according to GCIC criteria. CR was defined by RECIST 1.1 as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have had reduction in short axis to \<10 mm. PR was defined by RECIST 1.1 as at least a 30% decrease in the sum of the diameters (SOD) of target lesions, taking as reference the baseline SOD. A response according to CA-125 had occurred if there was ≥50% reduction in CA-125 levels from a pretreatment sample. The response must have been confirmed and maintained for at least 28 days. Participants could be evaluated according to CA-125 only if they had a pretreatment sample that was ≥2 times the upper limit of normal and within 2 weeks prior to starting treatment. Only evaluable Part 1 participants were included in this analysis.

Time frame: Up to 57 months

Population: All participants receiving MK-1775 (225 mg) during Part 1 and evaluable at the time of the interim analysis. One participant took a prohibited medication during Part 1 and was considered unevaluable. Two participants enrolled into Part 1 after the interim analysis database lock and were not included.

OS was defined as the time from randomization to death due to any cause, reported in months. Participants without documented death at the time of analysis were censored at the date last known to be alive. For this endpoint, all randomized participants in Part 2 were analyzed. Per protocol, Part 1 participants were not evaluated for OS.

Time frame: Up to 57 months

Population: ITT Population: All randomized participants in Part 2

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 RECIST 1.1 criteria. According to RECIST 1.1, progressive disease was the appearance of one or more new lesions, OR a ≥20% increase in the sum of target lesion diameters (SOD) taking as reference the nadir (smallest SOD recorded since treatment started). PFS was analyzed for all randomized participants in Part 2 using the Kaplan-Meier method and median PFS was reported in weeks. Per protocol, Part 1 participants were not included in this analysis.

Time frame: Up to 57 months

Population: ITT Population: All randomized participants in Part 2

ORR defined as the percentage of participants with best response of confirmed PR or CR based both on imaging per enhanced RECIST 1.1 and on serum marker CA-125 level according to GCIC criteria. CR defined by enhanced RECIST 1.1 as disappearance of all target lesions. Any pathological lymph nodes (target or non-target) must have had reduction in short axis to \<10 mm. PR was defined by enhanced RECIST 1.1 as ≥30% decrease in SOV of target lesions, taking as reference baseline SOV. Response according to CA-125 had occurred if there was ≥50% reduction in CA-125 levels from pretreatment sample. Response must have been confirmed and maintained for ≥28 days. Participants could be evaluated according to CA-125 only if they had a pretreatment sample that was ≥2 times the upper limit of normal and within 2 weeks prior to starting treatment. All randomized participants in Part 2 were analyzed. Per protocol, Part 1 participants were not included in this analysis.

Time frame: Up to 57 months

Population: ITT Population: All randomized participants in Part 2