Trial Outcomes & Findings for 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) (NCT NCT01357161)

Last Updated: 2023-09-21

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

136 participants

Primary outcome timeframe

Up to 57 months

Results posted on

2023-09-21

Participant Flow

Fifteen participants were enrolled in Part 1 and 121 participants were enrolled in Part 2 (n=136 total).

Participant milestones

Participant milestones
Measure	Part 1: MK-1775 225 mg + Paclitaxel +Carboplatin During the open-label run-in, participants received 225 mg MK-1775 twice daily (BID) starting on Day 1 of Cycle 1 (cycle=21 days) for a total of 5 doses. Participants received MK-1775 in combination with paclitaxel (175 mg/m\^2) and carboplatin (area under the curve \[AUC\] 5).	Part 2: MK-1775 225 mg + Paclitaxel +Carboplatin During Part 2, participants received 225 mg MK-1775 BID starting on Day 1 of each 21 day cycle for a total of 5 doses. Participants received MK-1775 in combination with paclitaxel (175 mg/m\^2) and carboplatin (AUC 5).	Part 2: Placebo + Paclitaxel +Carboplatin During Part 2, participants received matched placebo to MK-1775 BID starting on Day 1 of each 21 day cycle for a total of 5 doses. Participants received placebo in combination with paclitaxel (175 mg/m\^2) and carboplatin (AUC 5).
Part 1 (Open Label Run-in) STARTED	15	0	0
Part 1 (Open Label Run-in) COMPLETED	0	0	0
Part 1 (Open Label Run-in) NOT COMPLETED	15	0	0
Part 2 (Double-Blind Comparison) STARTED	0	59	62
Part 2 (Double-Blind Comparison) Treated	0	59	60
Part 2 (Double-Blind Comparison) COMPLETED	0	0	0
Part 2 (Double-Blind Comparison) NOT COMPLETED	0	59	62

Reasons for withdrawal

Reasons for withdrawal
Measure	Part 1: MK-1775 225 mg + Paclitaxel +Carboplatin During the open-label run-in, participants received 225 mg MK-1775 twice daily (BID) starting on Day 1 of Cycle 1 (cycle=21 days) for a total of 5 doses. Participants received MK-1775 in combination with paclitaxel (175 mg/m\^2) and carboplatin (area under the curve \[AUC\] 5).	Part 2: MK-1775 225 mg + Paclitaxel +Carboplatin During Part 2, participants received 225 mg MK-1775 BID starting on Day 1 of each 21 day cycle for a total of 5 doses. Participants received MK-1775 in combination with paclitaxel (175 mg/m\^2) and carboplatin (AUC 5).	Part 2: Placebo + Paclitaxel +Carboplatin During Part 2, participants received matched placebo to MK-1775 BID starting on Day 1 of each 21 day cycle for a total of 5 doses. Participants received placebo in combination with paclitaxel (175 mg/m\^2) and carboplatin (AUC 5).
Part 1 (Open Label Run-in) Death	5	0	0
Part 1 (Open Label Run-in) Lost to Follow-up	3	0	0
Part 1 (Open Label Run-in) Physician Decision	1	0	0
Part 1 (Open Label Run-in) Study Terminated By Sponsor	5	0	0
Part 1 (Open Label Run-in) Withdrawal by Subject	1	0	0
Part 2 (Double-Blind Comparison) Death	0	22	19
Part 2 (Double-Blind Comparison) Lost to Follow-up	0	1	6
Part 2 (Double-Blind Comparison) Physician Decision	0	1	4
Part 2 (Double-Blind Comparison) Progressive Disease	0	1	3
Part 2 (Double-Blind Comparison) Study Terminated By Sponsor	0	29	26
Part 2 (Double-Blind Comparison) Withdrawal by Subject	0	5	4

Baseline Characteristics

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)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Part 1: MK-1775 225 mg + Paclitaxel +Carboplatin n=15 Participants During the open-label run-in, participants received 225 mg MK-1775 twice daily (BID) starting on Day 1 of Cycle 1 (cycle=21 days) for a total of 5 doses. Participants received MK-1775 in combination with paclitaxel (175 mg/m\^2) and carboplatin (area under the curve \[AUC\] 5).	Part 2: MK-1775 225 mg + Paclitaxel +Carboplatin n=59 Participants During Part 2, participants received 225 mg MK-1775 BID starting on Day 1 of each 21 day cycle for a total of 5 doses. Participants received MK-1775 in combination with paclitaxel (175 mg/m\^2) and carboplatin (AUC 5).	Part 2: Placebo + Paclitaxel +Carboplatin n=62 Participants During Part 2, participants received matched placebo to MK-1775 BID starting on Day 1 of each 21 day cycle for a total of 5 doses. Participants received placebo in combination with paclitaxel (175 mg/m\^2) and carboplatin (AUC 5).	Total n=136 Participants Total of all reporting groups
Age, Continuous	58.2 years STANDARD_DEVIATION 9.9 • n=5 Participants	58.3 years STANDARD_DEVIATION 10.1 • n=7 Participants	60.4 years STANDARD_DEVIATION 9.8 • n=5 Participants	59.3 years STANDARD_DEVIATION 9.9 • n=4 Participants
Sex: Female, Male Female	15 Participants n=5 Participants	59 Participants n=7 Participants	62 Participants n=5 Participants	136 Participants n=4 Participants
Sex: Female, Male Male	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants

PRIMARY outcome

Timeframe: Up to 57 months

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

Outcome measures

Outcome measures
Measure	Part 1: MK-1775 225 mg + Paclitaxel +Carboplatin During the open-label run-in, participants received 225 mg MK-1775 twice daily (BID) starting on Day 1 of Cycle 1 (cycle=21 days) for a total of 5 doses. Participants received MK-1775 in combination with paclitaxel (175 mg/m\^2) and carboplatin (area under the curve \[AUC\] 5).	Part 2: MK-1775 225 mg + Paclitaxel +Carboplatin n=59 Participants During Part 2, participants received 225 mg MK-1775 BID starting on Day 1 of each 21 day cycle for a total of 5 doses. Participants received MK-1775 in combination with paclitaxel (175 mg/m\^2) and carboplatin (AUC 5).	Part 2: Placebo + Paclitaxel +Carboplatin n=62 Participants During Part 2, participants received matched placebo to MK-1775 BID starting on Day 1 of each 21 day cycle for a total of 5 doses. Participants received placebo in combination with paclitaxel (175 mg/m\^2) and carboplatin (AUC 5).
Part 2: Median Progression-free Survival (PFS) in Weeks Based on Enhanced Response Evaluation Criteria In Solid Tumors Version 1.1 (Enhanced RECIST 1.1) by Independent Radiology Review	—	34.14 weeks Interval 29.86 to 43.14	31.86 weeks Interval 24.43 to 35.57

PRIMARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Part 1: MK-1775 225 mg + Paclitaxel +Carboplatin n=12 Participants During the open-label run-in, participants received 225 mg MK-1775 twice daily (BID) starting on Day 1 of Cycle 1 (cycle=21 days) for a total of 5 doses. Participants received MK-1775 in combination with paclitaxel (175 mg/m\^2) and carboplatin (area under the curve \[AUC\] 5).	Part 2: MK-1775 225 mg + Paclitaxel +Carboplatin During Part 2, participants received 225 mg MK-1775 BID starting on Day 1 of each 21 day cycle for a total of 5 doses. Participants received MK-1775 in combination with paclitaxel (175 mg/m\^2) and carboplatin (AUC 5).	Part 2: Placebo + Paclitaxel +Carboplatin During Part 2, participants received matched placebo to MK-1775 BID starting on Day 1 of each 21 day cycle for a total of 5 doses. Participants received placebo in combination with paclitaxel (175 mg/m\^2) and carboplatin (AUC 5).
Part 1: Number of Participants With a Dose Limiting Toxicity (DLT) Total	3 participants	—	—
Part 1: Number of Participants With a Dose Limiting Toxicity (DLT) Febrile neutropenia	1 participants	—	—
Part 1: Number of Participants With a Dose Limiting Toxicity (DLT) Thrombocytopenia	1 participants	—	—
Part 1: Number of Participants With a Dose Limiting Toxicity (DLT) Neutropenia	1 participants	—	—

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Part 1: MK-1775 225 mg + Paclitaxel +Carboplatin n=15 Participants During the open-label run-in, participants received 225 mg MK-1775 twice daily (BID) starting on Day 1 of Cycle 1 (cycle=21 days) for a total of 5 doses. Participants received MK-1775 in combination with paclitaxel (175 mg/m\^2) and carboplatin (area under the curve \[AUC\] 5).	Part 2: MK-1775 225 mg + Paclitaxel +Carboplatin n=59 Participants During Part 2, participants received 225 mg MK-1775 BID starting on Day 1 of each 21 day cycle for a total of 5 doses. Participants received MK-1775 in combination with paclitaxel (175 mg/m\^2) and carboplatin (AUC 5).	Part 2: Placebo + Paclitaxel +Carboplatin n=60 Participants During Part 2, participants received matched placebo to MK-1775 BID starting on Day 1 of each 21 day cycle for a total of 5 doses. Participants received placebo in combination with paclitaxel (175 mg/m\^2) and carboplatin (AUC 5).
Parts 1 and 2: Percentage of Participants That Experienced an Adverse Event (AE)	100.0 percentage of participants	100.0 percentage of participants	96.7 percentage of participants

PRIMARY outcome

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

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.

Outcome measures

Outcome measures
Measure	Part 1: MK-1775 225 mg + Paclitaxel +Carboplatin n=15 Participants During the open-label run-in, participants received 225 mg MK-1775 twice daily (BID) starting on Day 1 of Cycle 1 (cycle=21 days) for a total of 5 doses. Participants received MK-1775 in combination with paclitaxel (175 mg/m\^2) and carboplatin (area under the curve \[AUC\] 5).	Part 2: MK-1775 225 mg + Paclitaxel +Carboplatin n=59 Participants During Part 2, participants received 225 mg MK-1775 BID starting on Day 1 of each 21 day cycle for a total of 5 doses. Participants received MK-1775 in combination with paclitaxel (175 mg/m\^2) and carboplatin (AUC 5).	Part 2: Placebo + Paclitaxel +Carboplatin n=60 Participants During Part 2, participants received matched placebo to MK-1775 BID starting on Day 1 of each 21 day cycle for a total of 5 doses. Participants received placebo in combination with paclitaxel (175 mg/m\^2) and carboplatin (AUC 5).
Parts 1 and 2: Percentage of Participants That Discontinued Study Treatment Due to an AE	20.0 percentage of participants	20.3 percentage of participants	21.7 percentage of participants

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Part 1: MK-1775 225 mg + Paclitaxel +Carboplatin n=12 Participants During the open-label run-in, participants received 225 mg MK-1775 twice daily (BID) starting on Day 1 of Cycle 1 (cycle=21 days) for a total of 5 doses. Participants received MK-1775 in combination with paclitaxel (175 mg/m\^2) and carboplatin (area under the curve \[AUC\] 5).	Part 2: MK-1775 225 mg + Paclitaxel +Carboplatin During Part 2, participants received 225 mg MK-1775 BID starting on Day 1 of each 21 day cycle for a total of 5 doses. Participants received MK-1775 in combination with paclitaxel (175 mg/m\^2) and carboplatin (AUC 5).	Part 2: Placebo + Paclitaxel +Carboplatin During Part 2, participants received matched placebo to MK-1775 BID starting on Day 1 of each 21 day cycle for a total of 5 doses. Participants received placebo in combination with paclitaxel (175 mg/m\^2) and carboplatin (AUC 5).
Part 1: Objective Response Rate (ORR) Per Gynecological Cancer Intergroup (GCIG) Criteria Based on Both RECIST 1.1 and Cancer Antigen 125 (CA-125) Level by Independent Radiology Review	75.00 percentage of participants Interval 42.814 to 94.514	—	—

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Part 1: MK-1775 225 mg + Paclitaxel +Carboplatin During the open-label run-in, participants received 225 mg MK-1775 twice daily (BID) starting on Day 1 of Cycle 1 (cycle=21 days) for a total of 5 doses. Participants received MK-1775 in combination with paclitaxel (175 mg/m\^2) and carboplatin (area under the curve \[AUC\] 5).	Part 2: MK-1775 225 mg + Paclitaxel +Carboplatin n=59 Participants During Part 2, participants received 225 mg MK-1775 BID starting on Day 1 of each 21 day cycle for a total of 5 doses. Participants received MK-1775 in combination with paclitaxel (175 mg/m\^2) and carboplatin (AUC 5).	Part 2: Placebo + Paclitaxel +Carboplatin n=62 Participants During Part 2, participants received matched placebo to MK-1775 BID starting on Day 1 of each 21 day cycle for a total of 5 doses. Participants received placebo in combination with paclitaxel (175 mg/m\^2) and carboplatin (AUC 5).
Part 2: Median PFS in Weeks Based on RECIST 1.1 by Independent Radiology Review	—	42.86 weeks Interval 35.0 to 48.86	34.86 weeks Interval 30.43 to 36.86

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Part 1: MK-1775 225 mg + Paclitaxel +Carboplatin During the open-label run-in, participants received 225 mg MK-1775 twice daily (BID) starting on Day 1 of Cycle 1 (cycle=21 days) for a total of 5 doses. Participants received MK-1775 in combination with paclitaxel (175 mg/m\^2) and carboplatin (area under the curve \[AUC\] 5).	Part 2: MK-1775 225 mg + Paclitaxel +Carboplatin n=59 Participants During Part 2, participants received 225 mg MK-1775 BID starting on Day 1 of each 21 day cycle for a total of 5 doses. Participants received MK-1775 in combination with paclitaxel (175 mg/m\^2) and carboplatin (AUC 5).	Part 2: Placebo + Paclitaxel +Carboplatin n=62 Participants During Part 2, participants received matched placebo to MK-1775 BID starting on Day 1 of each 21 day cycle for a total of 5 doses. Participants received placebo in combination with paclitaxel (175 mg/m\^2) and carboplatin (AUC 5).
Part 2: ORR Per GCIG Criteria Based on Both Enhanced RECIST 1.1 and CA125 Level by Independent Radiology Review	—	74.58 percentage of participants Interval 61.6 to 85.0	69.35 percentage of participants Interval 56.3 to 80.4

SECONDARY outcome

Timeframe: Up to 57 months

Population: ITT Population: All randomized participants in Part 2

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.

Outcome measures

Outcome measures
Measure	Part 1: MK-1775 225 mg + Paclitaxel +Carboplatin During the open-label run-in, participants received 225 mg MK-1775 twice daily (BID) starting on Day 1 of Cycle 1 (cycle=21 days) for a total of 5 doses. Participants received MK-1775 in combination with paclitaxel (175 mg/m\^2) and carboplatin (area under the curve \[AUC\] 5).	Part 2: MK-1775 225 mg + Paclitaxel +Carboplatin n=59 Participants During Part 2, participants received 225 mg MK-1775 BID starting on Day 1 of each 21 day cycle for a total of 5 doses. Participants received MK-1775 in combination with paclitaxel (175 mg/m\^2) and carboplatin (AUC 5).	Part 2: Placebo + Paclitaxel +Carboplatin n=62 Participants During Part 2, participants received matched placebo to MK-1775 BID starting on Day 1 of each 21 day cycle for a total of 5 doses. Participants received placebo in combination with paclitaxel (175 mg/m\^2) and carboplatin (AUC 5).
Part 2: Median Overall Survival (OS) in Months	—	NA months Interval 20.34 to Median OS could not be calculated due to small percentage of death events observed by time of cut-off analysis date	NA months Median OS could not be calculated due to small percentage of death events observed by time of cut-off analysis date

Adverse Events

Part 1: MK-1775 225 mg + Paclitaxel +Carboplatin

Serious events: 9 serious events

Other events: 15 other events

Deaths: 0 deaths

Part 2: MK-1775 225 mg + Paclitaxel +Carboplatin

Serious events: 24 serious events

Other events: 59 other events

Deaths: 0 deaths

Part 2: Placebo + Paclitaxel +Carboplatin

Serious events: 12 serious events

Other events: 57 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Senior Vice President, Global Clinical Development

Merck Sharp & Dohme Corp.

Phone: 1-800-672-6372

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The SPONSOR must have the opportunity to review all proposed abstracts, manuscripts, or presentations regarding this study 60 days prior to submission for publication/presentation. Any information identified by the SPONSOR as confidential must be deleted prior to submission. SPONSOR review can be expedited to meet publication timelines.
Publication restrictions are in place

Restriction type: OTHER