Participants receive 30 mg oral MK-2206 every other day (QOD) in repeating 4-week treatment cycles.

Participants receive 60 mg oral MK-2206 QOD in repeating 4-week treatment cycles.

Participants receive 75 mg oral MK-2206 QOD in repeating 4-week treatment cycles.

Participants receive 90 mg oral MK-2206 QOD in repeating 4-week treatment cycles.

Participants receive 90 mg oral MK-2206 every week (QW) in repeating 4-week treatment cycles.

Participants receive 135 mg oral MK-2206 QW in repeating 4-week treatment cycles.

Participants receive 200 mg oral MK-2206 QW in repeating 4-week treatment cycles.

Participants receive 300 mg oral MK-2206 QW in repeating 4-week treatment cycles.

Participants receive 250 mg oral MK-2206 QW in repeating 4-week treatment cycles.

Participants receive 150 mg oral MK-2206 QW in repeating 4-week treatment cycles.

MK-2206 administered as an oral formulation in rising dose levels on a QOD schedule (30 mg, 60 mg, 75 mg, and 90 mg) or QW schedule (90 mg, 135 mg, 200 mg, 250 mg, and 300 mg) in repeating 4 week cycles, depending upon allocation.

MK-2206

Medical Monitor

The primary purpose of this study is to investigate the Dose Limiting Toxicities (DLTs), pharmacokinetics (PK), and pharmacodynamics (PD) of MK-2206 administered orally to participants with advanced solid tumors. The preliminary efficacy of MK-2206 will also be investigated.

Dose Escalation Study With MK-2206 in Patients With Locally Advanced or Metastatic Solid Tumors (MK-2206-002)

A Phase I Dose Escalation Study of Oral MK-2206 in Patients With Locally Advanced or Metastatic Solid Tumors

http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf

DLT was any drug-related AE, regardless of grade, leading to a dose modification of MK-2206. Dose-limiting hematologic and nonhematologic toxicities were defined differently and were based on events occurring during the first cycle of study drug administration. Hematologic DLT defined as any Grade (Gr) 4 or greater hematologic toxicity except neutropenia described as follows: Neutropenia that was Gr 4 lasting for ≥7 days, or Gr 3/Gr 4 with fever \>38.5°C and/or infection requiring antibiotic or anti-fungal treatment considered DLT. Gr 4 thrombocytopenia (≤25.0 x 10\^9/L) was also considered DLT. Non-hematologic DLTs were defined as any Gr 3, 4, or 5 nonhematologic toxicity, with the specific exceptions of: Gr 3 nausea, vomiting, diarrhea, or dehydration occurring with inadequate supportive care and lasting \<48 hours; alopecia; inadequately treated hypersensitivity reactions; and Gr 3 elevated transaminases of ≤1 week in duration. A participant could have more than one DLT.

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 product, 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 pre-existing condition which was temporally associated with the use of the SPONSOR's product, was also an AE. The number of participants that experienced one or more AEs was reported for each dose level group.

Blood samples were collected for PK analyses during the first cycle of therapy. Samples were centrifuged, plasma was withdrawn and plasma concentrations were analyzed by high performance liquid chromatography with tandem mass spectroscopy. AUC 0-48hr was calculated for Day 1 and the last day of treatment in Cycle 1 (Day 27) and reported for all dose levels receiving MK-2206 orally QOD (30, 60, 75, and 90 mg QOD).

Blood samples were collected for PK analyses during the first cycle of therapy. Samples were centrifuged, plasma was withdrawn and plasma concentrations were analyzed by high performance liquid chromatography with tandem mass spectroscopy. Cmax was calculated for Day 1 and the last day of treatment in Cycle 1 (Day 27) and reported for all dose levels receiving MK-2206 orally QOD (30, 60, 75, and 90 mg QOD).

Blood samples were collected for PK analyses during the first cycle of therapy. Samples were centrifuged, plasma was withdrawn and plasma concentrations were analyzed by high performance liquid chromatography with tandem mass spectroscopy. C48hr was calculated for Day 1 and the last day of treatment in Cycle 1 (Day 27) and reported for all dose levels receiving MK-2206 orally QOD (30, 60, 75, and 90 mg QOD).

Blood samples were collected for PK analyses during the first cycle of therapy. Samples were centrifuged, plasma was withdrawn and plasma concentrations were analyzed by high performance liquid chromatography with tandem mass spectroscopy. Tmax was calculated for Day 1 and the last day of treatment in Cycle 1 and reported for all dose levels receiving MK-2206 orally QOD (30, 60, 75, and 90 mg QOD).

Blood samples were collected for PK analyses on Day 27 of the first cycle of therapy. Samples were centrifuged, plasma was withdrawn and plasma concentrations were analyzed by high performance liquid chromatography with tandem mass spectroscopy. t½ (Harmonic mean ± pseudo SD) was calculated and reported for all dose levels receiving MK-2206 orally QOD (30, 60, 75, and 90 mg QOD).

Blood samples were collected for PK analyses during the first cycle of therapy. Samples were centrifuged, plasma was withdrawn and plasma concentrations were analyzed by high performance liquid chromatography with tandem mass spectroscopy. AUC 0-168 was calculated for Day 1 and the last day of treatment in Cycle 1 and reported for all dose levels receiving MK-2206 orally QW (90, 135, 200, 300, 250, and 150 mg QW).

Blood samples were collected for PK analyses during the first cycle of therapy. Samples were centrifuged, plasma was withdrawn and plasma concentrations were analyzed by high performance liquid chromatography with tandem mass spectroscopy. Cmax was calculated for Day 1 and the last day of treatment in Cycle 1 and reported for all dose levels receiving MK-2206 orally QW (90, 135, 200, 300, 250, and 150 mg QW).

Blood samples were collected for PK analyses during the first cycle of therapy. Samples were centrifuged, plasma was withdrawn and plasma concentrations were analyzed by high performance liquid chromatography with tandem mass spectroscopy. C48hr was calculated for Day 1 and the last day of treatment in Cycle 1 and reported for all dose levels receiving MK-2206 orally QW (90, 135, 200, 300, 250, and 150 mg QW).

Blood samples were collected for PK analyses during the first cycle of therapy. Samples were centrifuged, plasma was withdrawn and plasma concentrations were analyzed by high performance liquid chromatography with tandem mass spectroscopy. Tmax was calculated for Day 1 and the last day of treatment in Cycle 1 and reported for all dose levels receiving MK-2206 orally QW (90, 135, 200, 300, 250, and 150 mg QW).

Blood samples were collected for PK analyses during the first cycle of therapy. Samples were centrifuged, plasma was withdrawn and plasma concentrations were analyzed by high performance liquid chromatography with tandem mass spectroscopy. t½ (Harmonic mean ± pseudo SD) was calculated for the last day of treatment in Cycle 1 and reported for all dose levels receiving MK-2206 orally QW (90, 135, 200, 300, 250, and 150 mg QW).

To determine the inhibition of pAkt by MK-2206 in participants treated at the MTD, levels of Akt phosphorylated at the serine 473 residue (pAkt Ser473 Akt) were measured in snap-frozen tumors collected at baseline and Day 15 of Cycle 1 using a MesoScale enzyme-linked immunosorbent assay (ELISA). Per protocol, pAkt levels were determined only for the MK-2206 MTD (60 mg QOD) group.

Overall tumor response was assessed during the study by diagnostic anatomic imaging using RECIST. The number of participants with a confirmed Complete Response (CR: Disappearance of all target lesions) as per RECIST was reported for each dose level group.

Merck Sharp & Dohme LLC

APaT population: All participants who received at least one dose of study treatment.

MK-2206 30 mg QOD

MK-2206 60 mg QOD

MK-2206 75 mg QOD

MK-2206 90 mg QOD

MK-2206 90 mg QW

MK-2206 135 mg QW

MK-2206 200 mg QW

MK-2206 300 mg QW

MK-2206 250 mg QW

MK-2206 150 mg QW

Total

Age, Continuous

Sex: Female, Male

Senior Vice President, Global Clinical Development

Hyperglycaemia

Rash

Rash macular

Stomatitis

Diarrhoea

Pruritis

Rash generalized

Dermatitis acneiform

Total number of participants with DLTs

The All Participants as Treated (APaT) population: All participants who received at least one dose of study treatment.

Number of Participants With Dose Limiting Toxicities (DLTs)

Number of Participants With One or More Adverse Events (AE)

The Last Day (Day 27)/Day 1 AUC 0-48 hr Geometric Mean Ratio (GMR) was calculated as follows: Last Day (Day 27) AUC 0-48hr Geometric Mean (GM) ÷ Day 1 AUC 0-48hr GM.

AUC 0-48hr GMR for last dose (Day 27) calculated using only data from participants who completed cycle one dosing as scheduled and had sufficient data for calculation.

The Last Day (Day 27)/Day 1 AUC 0-48 hr GMR was calculated as follows: Last Day (Day 27) AUC 0-48hr GM ÷ Day 1 AUC 0-48hr GM.

AUC 0-48hr GMR for last dose (Day 27) calculated using only data from participants who completed cycle one dosing as scheduled and had sufficient data for calculation.

Day 1

Last Day (Day 27)

All participants who received MK-2206 orally QOD during Cycle 1 (30, 60, 75, and 90 mg QOD) and had available PK data. Data for the MK-2206 QW dose groups (90, 135, 200, 300, 250, and 150 mg QW) are reported separately.

Area Under the Concentration-time Curve of MK-2206 From Time 0 to 48 Hours (AUC0-48hr) in Participants Receiving Multiple QOD Dosing

The Last Day (Day 27)/Day 1 Cmax GMR was calculated as follows: Last Day (Day 27) Cmax GM ÷ Day 1 Cmax GM.

Cmax GMR for last dose (Day 27) calculated using only data from participants who completed cycle one dosing as scheduled and had sufficient data for calculation.

Maximum Concentration (Cmax) of MK-2206 in Participants Receiving Multiple QOD Dosing

The Last Day (Day 27)/Day 1 C48hr GMR was calculated as follows: Last Day (Day 27) C48hr GM ÷ Day 1 C48hr GM.

C48hr GMR for last dose (Day 27) calculated using only data from participants who completed cycle one dosing as scheduled and had sufficient data for calculation.

Concentration of MK-2206 After 48 Hours (C48hr) in Participants Receiving Multiple QOD Dosing

Time to Maximum Concentration (Tmax) of MK-2206 in Participants Receiving Multiple QOD Dosing

All participants who received MK-2206 orally QOD on Day 27 of Cycle 1 (30, 60, 75, and 90 mg QOD) and had available PK data. Data for the MK-2206 QW dose groups (90, 135, 200, 300, 250, and 150 mg QW) are reported separately.

Apparent Terminal Half-life (t½) of MK-2206 in Participants Receiving Multiple QOD Dosing

The Last Day/Day 1 AUC 0-168 hr GMR was calculated as follows: Last Day AUC 0-168hr GM ÷ Day 1 AUC 0-48hr GM.

Last Day (Day 22)

All participants who received MK-2206 orally QW during Cycle 1 (90, 135, 200, 300, 250, and 150 mg QW) and had available PK data. Data for the MK-2206 QOD dose groups (30, 60, 75, and 90 mg QOD) are reported separately.

AUC0-168hr in Participants Receiving Multiple QW Dosing

The Last Day/Day 1 Cmax GMR was calculated as follows: Last Day Cmax GM ÷ Day 1 Cmax GM.

Cmax of MK-2206 in Participants Receiving Multiple QW Dosing

The Last Day/Day 1 C48hr GMR was calculated as follows: Last Day C48hr GM ÷ Day 1 C48hr GM.

C48hr of MK-2206 in Participants Receiving Multiple QW Dosing

Tmax of MK-2206 in Participants Receiving Multiple QW Dosing

All participants who received MK-2206 orally QW on Day 22 of Cycle 1 (90, 135, 200, 300, 250, and 150 mg QW) and had available PK data. Data for the MK-2206 QOD dose groups (30, 60, 75, and 90 mg QOD) are reported separately.

t½ of MK-2206 in Participants Receiving Multiple QW Dosing

pAkt Geometric Mean Ratio (GMR)

= Day 15 Geometric Mean (GM) ÷ Baseline GM

Baseline

Cycle 1 Day 15

Participants treated at the MTD (60 mg QOD) dose level with measurable disease at baseline per RECIST and paired tumor samples at baseline and C1D15. Per protocol, no other dose level groups were analyzed.

Phosphorylated Protein Kinase B (pAkt) Level on Cycle 1 Day 15 (C1D15) After Treatment With MK-2206 at the Maximum Tolerated Dose (MTD)

All participants with measurable disease at baseline per RECIST.

Spots Global Cancer Trial Database for Dose Escalation Study With MK-2206 in Patients With Locally Advanced or Metastatic Solid Tumors (MK-2206-002)

Trial Identification

Conditions

Interventions

Study Description

Keywords

Eligibility

Locations

Contact Details

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