A Dose Escalation Study of Adavosertib (MK-1775) in Combination With Either Gemcitabine, Cisplatin, or Carboplatin in Adults With Advanced Solid Tumors (MK-1775-001)

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.

Time frame: At 0-4 hours, 4-8 hours, and 12-24 hours post Day 1 dose of monotherapy

Population: All treated Part 1 participants with available urine sample data.

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.

Time frame: Part 1: Up to 14 days, Part 2: Up to 28 days

Population: All participants who received at least one dose of study treatment and were evaluable for DLT.

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.

Time frame: Baseline, 8 hours after first MK-1775 dose

Population: Participants in Parts 1, 2-A, and 2-B/3 with ≥1 dose treatment and evaluable CDC2 data at 8 hours post dosing. Per protocol the MK-1775 QD x2.5 Multi Dose + Gemcitabine groups, MK-1775 150, 200, and 250 mg BID x 2.5 Multi Dose + cisplatin 75 mg/m\^2 groups, and MK-1775 325 mg BID x 2.5 Multi Dose + carboplatin AUC 5 group did not have data reported

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.

Time frame: Baseline, 24 hours after first MK-1775 dose

Population: All participants in the Part 2-B/3 MK-1775 QD x2 Multi Dose plus Gemcitabine treatment groups who received at least one dose of study treatment and had evaluable CDC2 data at 24 hours post dosing. Per protocol, the Part 1, Part 2-A, and Part 2-B/3 MK-1775 BID treatment groups did not have data reported for this time point.

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.

Time frame: Baseline, 48 hours after first MK-1775 dose

Population: All participants in 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 325 mg BID x2.5 Multi Dose + carboplatin group who received ≥1 dose of study treatment and had evaluable CDC2 data at 48 hours post dose. Per protocol, Part 1, Part 2-A, and remaining Part 2-B/3 groups did not have data reported.

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.

Time frame: 8 hours after MK-1775 dose

Population: All treated participants with available C8hr data.

Best overall response achieved by a participant. Starting at Day 1, participants in Part 2 were evaluated for tumor response every 6-8 weeks until discontinuation from study treatment according to RECIST criteria; which are based on radiographic imaging. Recorded responses were either confirmed by Central Review or unconfirmed (Investigator assessment only), and included complete response (CR; defined as disappearance of all target lesions), partial response (PR; at least a 30% decrease in the sum of the longest diameter \[LD\] of target lesions, taking as reference the baseline sum LD), stable disease (SD; neither sufficient shrinkage to qualify for PR nor sufficient growth to qualify for PD, taking as reference the smallest sum LD since the treatment started), or progressive disease (PD; ≥20% increase in sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started, or the appearance of one or more new lesions).

Time frame: From Day 1 up through discontinuation of study treatment (up to ~11.2 months)

Population: All treated participants in Part 2 with measurable disease at baseline per RECIST criteria. Participants who were originally treated in Part 1 and continued in Part 2 were included in their respective Part 2 arms. Participants who could not be evaluated after treatment are categorized as not evaluable (NE).