Study of Safety and Pharmacokinetics of MK-8242 in Participants With Advanced Solid Tumors (P07650)

Study Overview
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Brief Summary
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This study is being done to evaluate the safety and pharmacokinetic profile of MK-8242 and its active metabolite (M16) in participants with advanced solid tumors. In Part 1 of the study, the study drug dose will be escalated to determine the maximum tolerated dose (MTD). In Part 2 of the study, the MTD will be confirmed and the recommended Phase 2 dose (RPTD) established; the effect of MK-8242 on liposarcoma and other tumor types will also be evaluated.

Detailed Description
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Participants are considered to have completed the study after Cycle 12. Amendment 4 (14 April 2015) was done to allow participants on active treatment at the time the study was closed to enrollment to continue study treatment beyond Cycle 12 if deriving clinical benefit, at the Investigator's discretion.

Official Title
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A Phase I Study to Evaluate the Safety and Tolerability and Pharmacokinetic/Pharmacodynamics of MK-8242 in Patients With Advanced Solid Tumors

Conditions
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Solid Tumors

Intervention / Treatment
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* Drug: MK-8242


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Histologically confirmed advanced solid tumor for which there are no effective standard therapy options Willing to provide tumor tissue for p53 wild type gene analysis Eastern Cooperative Oncology Group (ECOG) performance status of ≤1 Adequate organ function Female participants and male participants and their partners who are of childbearing potential must agree to abstain from sexual intercourse or to use an acceptable method of contraception during the study and for 90 days following the last dose of study drug At least one measurable lesion In Part 2, participants with liposarcoma must have a confirmed well-differentiated or de-differentiated histology Exclusion criteria: Known treated or untreated leptomeningeal metastases, or metastatic central nervous system disease History of recent myocardial infarction (within the past year); or with unstable or uncontrolled angina, New York Heart Association (NYHA) Class III or IV congestive heart failure, uncontrolled hypertension, clinically significant cardiac dysrhythmia or clinically significant electrocardiogram (ECG) abnormality Uncontrolled active infection on optimal systemic treatment Clinically significant hepatitis or hepatitis C antibody positive, hepatitis B surface antigen positive, or human immunodeficiency virus (HIV) seropositive Persistent, unresolved common terminology criteria for adverse events (CTCAE v4.0) ≥Grade 2 drug-related toxicity associated with previous treatment except for alopecia Radiation therapy or other loco-regional therapy within 2 weeks prior to study Use of moderate and strong cytochrome P450 inhibitors or inducers within 1 week prior to study Chemotherapy or any investigational drug(s) within 4 weeks prior to study Known hypersensitivity to MK-8242 or its components Nursing, pregnant, or intention to become pregnant during the study Initiating bisphosphonate therapy or adjusting the bisphosphonate dose or regimen within 30 days of Cycle 1 Day 1

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MK-8242 60 mg BID<br>In Cycle 1, participants received MK-8242 60 mg administered orally (PO) twice a day (BID) on Days 1-6 and PO once daily (QD) in the morning on Day 7 of the 21-day cycle to accommodate pharmacokinetic (PK) sampling. In Cycle 2 and subsequent cycles, participants received MK-8242 60 mg PO BID on Days 1-7 of each 21-day cycle. | Drug: MK-8242<br>* 10 mg, 100 mg and 150 mg capsules<br>* Other names: SCH 900242;|
| Experimental: MK-8242 120 mg BID<br>In Cycle 1, participants received MK-8242 120 mg administered PO BID on Days 1-6 and PO QD in the morning on Day 7 of the 21-day cycle to accommodate PK sampling. In Cycle 2 and subsequent cycles, participants received MK-8242 120 mg PO BID on Days 1-7 of each 21-day cycle. | Drug: MK-8242<br>* 10 mg, 100 mg and 150 mg capsules<br>* Other names: SCH 900242;|
| Experimental: MK-8242 170 mg BID<br>In Cycle 1, participants received MK-8242 170 mg administered PO BID on Days 1-6 and PO QD in the morning on Day 7 of the 21-day cycle to accommodate PK sampling. In Cycle 2 and subsequent cycles, participants received MK-8242 170 mg PO BID on Days 1-7 of each 21-day cycle. | Drug: MK-8242<br>* 10 mg, 100 mg and 150 mg capsules<br>* Other names: SCH 900242;|
| Experimental: MK-8242 250 mg BID<br>In Cycle 1, participants received MK-8242 250 mg administered PO BID on Days 1-6 and PO QD in the morning on Day 7 of the 21-day cycle to accommodate PK sampling. In Cycle 2 and subsequent cycles, participants received MK-8242 250 mg PO BID on Days 1-7 of each 21-day cycle. | Drug: MK-8242<br>* 10 mg, 100 mg and 150 mg capsules<br>* Other names: SCH 900242;|
| Experimental: MK-8242 300 mg BID<br>In Cycle 1, participants received MK-8242 300 mg administered PO BID on Days 1-6 and PO QD in the morning on Day 7 of the 21-day cycle to accommodate PK sampling. In Cycle 2 and subsequent cycles, participants received MK-8242 300 mg PO BID on Days 1-7 of each 21-day cycle. | Drug: MK-8242<br>* 10 mg, 100 mg and 150 mg capsules<br>* Other names: SCH 900242;|
| Experimental: MK-8242 350 mg BID<br>In Cycle 1, participants received MK-8242 350 mg administered PO BID on Days 1-6 and PO QD in the morning on Day 7 of the 21-day cycle to accommodate PK sampling. In Cycle 2 and subsequent cycles, participants received MK-8242 350 mg PO BID on Days 1-7 of each 21-day cycle. | Drug: MK-8242<br>* 10 mg, 100 mg and 150 mg capsules<br>* Other names: SCH 900242;|
| Experimental: MK-8242 400 mg BID<br>In Cycle 1, participants received MK-8242 400 mg administered PO BID on Days 1-6 and PO QD in the morning on Day 7 of the 21-day cycle to accommodate PK sampling. In Cycle 2 and subsequent cycles, participants received MK-8242 400 mg PO BID on Days 1-7 of each 21-day cycle. | Drug: MK-8242<br>* 10 mg, 100 mg and 150 mg capsules<br>* Other names: SCH 900242;|
| Experimental: MK-8242 500 mg BID<br>In Cycle 1, participants received MK-8242 500 mg administered PO BID on Days 1-6 and PO QD in the morning on Day 7 of the 21-day cycle to accommodate PK sampling. In Cycle 2 and subsequent cycles, participants received MK-8242 500 mg PO BID on Days 1-7 of each 21-day cycle. | Drug: MK-8242<br>* 10 mg, 100 mg and 150 mg capsules<br>* Other names: SCH 900242;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Dose Limiting Toxicities (DLTs) | DLT was defined as: any drug-related hematologic toxicity ≥ Grade 3 lasting ≥1 week, ≥ Grade 3 thrombocytopenia with bleeding, ≥ Grade 3 neutropenia with infection OR non-hematologic DLTs that were any Grade 3, 4, or 5 toxicity with the following exceptions/clarifications: 1) Grade 3 nausea, vomiting, diarrhea, and dehydration were excluded from the determination of DLT if, in the opinion of the investigator and sponsor, they occurred in a setting of inadequate treatment, 2) Grade 3 nausea, vomiting, diarrhea, and dehydration were each considered a DLT if they persisted despite 72 hours of maximal supportive care measures or 3) Any abnormal non-hematological laboratory value ≥ Grade 3 (that is not attributable to any other causes) was considered a DLT only if medical intervention was required to treat the participant, the abnormality led to hospitalization, or the abnormality persisted for ≥1 week. | Cycle 1 (21 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Observed Plasma Concentration (Cmax) of MK-8242 | PK plasma samples were to be collected at the following time points: 0, 0.5, 1, 2, 4, 6, 8,and 12 hours after the first dose on Day 1; and 0, 0.5, 1, 2, 4, 6, 8, 12, 24 (Day 8) and 48 (Day 9) hours post-dose on Day 7. | Cycle 1, Day 1 pre-dose and through 24 hours post dose; Cycle 1 Day 7 pre-dose and through 48 hours post dose | 
| Time to Maximum Plasma Concentration (Tmax) of MK-8242 | PK plasma samples were to be collected at the following time points: 0, 0.5, 1, 2, 4, 6, 8 and 12 hours after the first dose on Day 1; and 0, 0.5, 1, 2, 4, 6, 8, 12, 24 (Day 8) and 48 (Day 9) hours post-dose on Day 7. | Cycle 1, Day 1 pre-dose and through 12 hours postdose; Cycle 1 Day 7 pre-dose and through 48 hours post dose | 
| Area Under the Concentration Time Curve From Hour 0 to Hour 12 (AUC0-12) for MK-8242 | PK plasma samples were to be collected at the following time points: 0, 0.5, 1, 2, 4, 6, 8 and 12 hours after the first dose on Day 1; and 0, 0.5, 1, 2, 4, 6, 8, 12, 24 (Day 8) and 48 (Day 9) hours post-dose on Day 7. | Cycle 1, Day 1 and Day 7, Hour 0 through Hour 12 | 
| AUC at Time of Last Sample (AUClast) for MK-8242 | PK plasma samples were to be collected at the following time points: 0, 0.5, 1, 2, 4, 6, 8 and 12 hours after the first dose on Day 1; and 0, 0.5, 1, 2, 4, 6, 8, 12, 24 (Day 8) and 48 (Day 9) hours post-dose on Day 7. | Cycle 1, Day 1 pre-dose and through 12 hours post dose; Cycle 1 Day 7 pre-dose and through 48 hours post dose |