Cancer, Locally Advanced Tumors, Metastatic Solid Tumors, Neoplasms
Conditions
Brief summary
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.
Interventions
DRUGMK-2206
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.
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Participant must have confirmed locally advanced or metastatic solid tumors that have failed to respond to standard therapy, have gotten worse or have come back after existing therapy * Has normal organ function; is no greater than 2 on the ECOG Performance Scale * Has a negative blood or urine pregnancy test within 72 hours of receiving the first dose of study drug if participant is female * Is able to swallow capsules and has no surgical or bodily condition that will prevent the patient from swallowing and absorbing oral medications on an ongoing basis
Exclusion criteria
* Participant has had chemotherapy, radiotherapy, biological therapy or surgery within 4 weeks of starting the study and has not recovered from adverse events caused by the treatment * Is currently participating or has participated in a study with an investigational compound or device within 30 days * Has a primary central nervous system tumor * Has a history or current evidence of heart disease, slow heart rate or untreated high blood pressure * Is a known diabetic who is taking insulin or oral antidiabetic therapy * Is pregnant or breastfeeding or planning to become pregnant during the study * Is HIV-positive * Has known history of Hepatitis B or C or active Hepatitis A * Is receiving treatment with oral corticosteroids
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| t½ of MK-2206 in Participants Receiving Multiple QW Dosing | Day 22: predose and 2, 4, 6, 10, 24, 48, 96 hours, and 168 hours after MK-2206 dosing | 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). |
| C48hr of MK-2206 in Participants Receiving Multiple QW Dosing | Days 1 and 22: predose and 48 hours after MK-2206 dosing | 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). |
| Tmax of MK-2206 in Participants Receiving Multiple QW Dosing | Days 1 and 22: predose and 2, 4, 6, 10, 24, 48, 96 hours, and 168 hours after MK-2206 dosing | 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). |
| Number of Participants With Dose Limiting Toxicities (DLTs) | Day 1 to Day 28 (Cycle 1) | 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. |
| Number of Participants With One or More Adverse Events (AE) | Up to 269 days | 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. |
| Area Under the Concentration-time Curve of MK-2206 From Time 0 to 48 Hours (AUC0-48hr) in Participants Receiving Multiple QOD Dosing | Days 1 and 27: predose and 0.5, 1, 2, 3, 4, 6, 10, 24, and 48 hours after MK-2206 dosing | 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). |
| Maximum Concentration (Cmax) of MK-2206 in Participants Receiving Multiple QOD Dosing | Days 1 and 27: predose and 0.5, 1, 2, 3, 4, 6, 10, 24, and 48 hours after MK-2206 dosing | 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). |
| Concentration of MK-2206 After 48 Hours (C48hr) in Participants Receiving Multiple QOD Dosing | Days 1 and 27: predose and 48 hours after MK-2206 dosing. | 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). |
| Time to Maximum Concentration (Tmax) of MK-2206 in Participants Receiving Multiple QOD Dosing | Days 1 and 27: predose and 0.5, 1, 2, 3, 4, 6, 10, 24, and 48 hours after MK-2206 dosing | 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). |
| Apparent Terminal Half-life (t½) of MK-2206 in Participants Receiving Multiple QOD Dosing | Day 27: predose and 0.5, 1, 2, 3, 4, 6, 10, 24, and 48 hours after MK-2206 dosing. | 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). |
| AUC0-168hr in Participants Receiving Multiple QW Dosing | Days 1 and 22: predose and 2, 4, 6, 10, 24, 48, 96 hours, and 168 hours after MK-2206 dosing | 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). |
| Cmax of MK-2206 in Participants Receiving Multiple QW Dosing | Days 1 and 22: predose and 2, 4, 6, 10, 24, 48, 96 hours, and 168 hours after MK-2206 dosing | 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Confirmed Response as Per Response Evaluation Criteria in Solid Tumors (RECIST) | From Cycle 1 Day 1 through the End of Study Visit (up to 6 months) | 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. |
| Phosphorylated Protein Kinase B (pAkt) Level on Cycle 1 Day 15 (C1D15) After Treatment With MK-2206 at the Maximum Tolerated Dose (MTD) | Baseline, Cycle 1 Day 15 | 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. |
Participant flow
Pre-assignment details
A total of 104 participants were enrolled and received treatment in this study.
Participants by arm
| Arm | Count |
|---|---|
| MK-2206 30 mg QOD Participants receive 30 mg oral MK-2206 every other day (QOD) in repeating 4-week treatment cycles. | 3 |
| MK-2206 60 mg QOD Participants receive 60 mg oral MK-2206 QOD in repeating 4-week treatment cycles. | 58 |
| MK-2206 75 mg QOD Participants receive 75 mg oral MK-2206 QOD in repeating 4-week treatment cycles. | 3 |
| MK-2206 90 mg QOD Participants receive 90 mg oral MK-2206 QOD in repeating 4-week treatment cycles. | 7 |
| MK-2206 90 mg QW Participants receive 90 mg oral MK-2206 every week (QW) in repeating 4-week treatment cycles. | 3 |
| MK-2206 135 mg QW Participants receive 135 mg oral MK-2206 QW in repeating 4-week treatment cycles. | 5 |
| MK-2206 200 mg QW Participants receive 200 mg oral MK-2206 QW in repeating 4-week treatment cycles. | 17 |
| MK-2206 300 mg QW Participants receive 300 mg oral MK-2206 QW in repeating 4-week treatment cycles. | 3 |
| MK-2206 250 mg QW Participants receive 250 mg oral MK-2206 QW in repeating 4-week treatment cycles. | 3 |
| MK-2206 150 mg QW Participants receive 150 mg oral MK-2206 QW in repeating 4-week treatment cycles. | 2 |
| Total | 104 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 7 | 0 | 3 | 1 | 1 | 5 | 1 | 0 | 1 |
| Overall Study | Physician Decision | 1 | 9 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Progressive Disease | 2 | 41 | 3 | 2 | 2 | 4 | 11 | 2 | 2 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 0 | 1 | 0 | 0 | 1 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | 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 | 60.3 Years STANDARD_DEVIATION 9.5 | 58.2 Years STANDARD_DEVIATION 11.4 | 62.3 Years STANDARD_DEVIATION 7.6 | 58.0 Years STANDARD_DEVIATION 13.1 | 59.0 Years STANDARD_DEVIATION 8.2 | 53.8 Years STANDARD_DEVIATION 8.8 | 57.9 Years STANDARD_DEVIATION 13.3 | 58.7 Years STANDARD_DEVIATION 8.4 | 57.0 Years STANDARD_DEVIATION 5.6 | 56.0 Years STANDARD_DEVIATION 18.4 | 58.1 Years STANDARD_DEVIATION 11.1 |
| Sex: Female, Male Female | 2 Participants | 28 Participants | 0 Participants | 4 Participants | 0 Participants | 4 Participants | 7 Participants | 2 Participants | 1 Participants | 1 Participants | 49 Participants |
| Sex: Female, Male Male | 1 Participants | 30 Participants | 3 Participants | 3 Participants | 3 Participants | 1 Participants | 10 Participants | 1 Participants | 2 Participants | 1 Participants | 55 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 5 / 58 | 0 / 3 | 0 / 7 | 0 / 3 | 2 / 5 | 3 / 17 | 0 / 3 | 0 / 3 | 1 / 2 |
| other Total, other adverse events | 3 / 3 | 56 / 58 | 3 / 3 | 7 / 7 | 3 / 3 | 4 / 5 | 16 / 17 | 3 / 3 | 3 / 3 | 2 / 2 |
| serious Total, serious adverse events | 1 / 3 | 21 / 58 | 0 / 3 | 5 / 7 | 0 / 3 | 3 / 5 | 8 / 17 | 2 / 3 | 0 / 3 | 2 / 2 |
Outcome results
Primary
Apparent Terminal Half-life (t½) of MK-2206 in Participants Receiving Multiple QOD Dosing
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).
Time frame: Day 27: predose and 0.5, 1, 2, 3, 4, 6, 10, 24, and 48 hours after MK-2206 dosing.
Population: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MK-2206 30 mg QOD | Apparent Terminal Half-life (t½) of MK-2206 in Participants Receiving Multiple QOD Dosing | 62.7 hour | Standard Deviation 15.1 |
| MK-2206 60 mg QOD | Apparent Terminal Half-life (t½) of MK-2206 in Participants Receiving Multiple QOD Dosing | 66.3 hour | Standard Deviation 17 |
| MK-2206 75 mg QOD | Apparent Terminal Half-life (t½) of MK-2206 in Participants Receiving Multiple QOD Dosing | 66.2 hour | Standard Deviation 4.9 |
| MK-2206 90 mg QOD | Apparent Terminal Half-life (t½) of MK-2206 in Participants Receiving Multiple QOD Dosing | 65.6 hour | Standard Deviation 0 |
Primary
Area Under the Concentration-time Curve of MK-2206 From Time 0 to 48 Hours (AUC0-48hr) in Participants Receiving Multiple QOD Dosing
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).
Time frame: Days 1 and 27: predose and 0.5, 1, 2, 3, 4, 6, 10, 24, and 48 hours after MK-2206 dosing
Population: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MK-2206 30 mg QOD | Area Under the Concentration-time Curve of MK-2206 From Time 0 to 48 Hours (AUC0-48hr) in Participants Receiving Multiple QOD Dosing | Day 1 | 916 nM•hr | Standard Deviation 395 |
| MK-2206 30 mg QOD | Area Under the Concentration-time Curve of MK-2206 From Time 0 to 48 Hours (AUC0-48hr) in Participants Receiving Multiple QOD Dosing | Last Day (Day 27) | NA nM•hr | — |
| MK-2206 60 mg QOD | Area Under the Concentration-time Curve of MK-2206 From Time 0 to 48 Hours (AUC0-48hr) in Participants Receiving Multiple QOD Dosing | Last Day (Day 27) | 6160 nM•hr | Standard Deviation 2690 |
| MK-2206 60 mg QOD | Area Under the Concentration-time Curve of MK-2206 From Time 0 to 48 Hours (AUC0-48hr) in Participants Receiving Multiple QOD Dosing | Day 1 | 1950 nM•hr | Standard Deviation 832 |
| MK-2206 75 mg QOD | Area Under the Concentration-time Curve of MK-2206 From Time 0 to 48 Hours (AUC0-48hr) in Participants Receiving Multiple QOD Dosing | Day 1 | 2110 nM•hr | Standard Deviation 782 |
| MK-2206 75 mg QOD | Area Under the Concentration-time Curve of MK-2206 From Time 0 to 48 Hours (AUC0-48hr) in Participants Receiving Multiple QOD Dosing | Last Day (Day 27) | NA nM•hr | — |
| MK-2206 90 mg QOD | Area Under the Concentration-time Curve of MK-2206 From Time 0 to 48 Hours (AUC0-48hr) in Participants Receiving Multiple QOD Dosing | Day 1 | 3950 nM•hr | Standard Deviation 1920 |
| MK-2206 90 mg QOD | Area Under the Concentration-time Curve of MK-2206 From Time 0 to 48 Hours (AUC0-48hr) in Participants Receiving Multiple QOD Dosing | Last Day (Day 27) | 7970 nM•hr | Standard Deviation 5990 |
Comparison: 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.
Comparison: 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.
Primary
AUC0-168hr in Participants Receiving Multiple QW Dosing
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).
Time frame: Days 1 and 22: predose and 2, 4, 6, 10, 24, 48, 96 hours, and 168 hours after MK-2206 dosing
Population: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MK-2206 90 mg QW | AUC0-168hr in Participants Receiving Multiple QW Dosing | Last Day (Day 22) | 10600 nM•hr | Standard Deviation 7520 |
| MK-2206 90 mg QW | AUC0-168hr in Participants Receiving Multiple QW Dosing | Day 1 | 6510 nM•hr | Standard Deviation 3810 |
| MK-2206 135 mg QW | AUC0-168hr in Participants Receiving Multiple QW Dosing | Last Day (Day 22) | 20700 nM•hr | Standard Deviation 8780 |
| MK-2206 135 mg QW | AUC0-168hr in Participants Receiving Multiple QW Dosing | Day 1 | 12000 nM•hr | Standard Deviation 4610 |
| MK-2206 200 mg QW | AUC0-168hr in Participants Receiving Multiple QW Dosing | Last Day (Day 22) | 23500 nM•hr | Standard Deviation 14700 |
| MK-2206 200 mg QW | AUC0-168hr in Participants Receiving Multiple QW Dosing | Day 1 | 16400 nM•hr | Standard Deviation 5470 |
| MK-2206 300 mg QW | AUC0-168hr in Participants Receiving Multiple QW Dosing | Day 1 | 27700 nM•hr | Standard Deviation 3320 |
| MK-2206 250 mg QW | AUC0-168hr in Participants Receiving Multiple QW Dosing | Day 1 | 14000 nM•hr | Standard Deviation 2950 |
| MK-2206 250 mg QW | AUC0-168hr in Participants Receiving Multiple QW Dosing | Last Day (Day 22) | 10700 nM•hr | — |
| MK-2206 150 mg QW | AUC0-168hr in Participants Receiving Multiple QW Dosing | Last Day (Day 22) | 22600 nM•hr | Standard Deviation 0 |
| MK-2206 150 mg QW | AUC0-168hr in Participants Receiving Multiple QW Dosing | Day 1 | 20700 nM•hr | Standard Deviation 0 |
Comparison: 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.
Comparison: 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.
Primary
C48hr of MK-2206 in Participants Receiving Multiple QW Dosing
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).
Time frame: Days 1 and 22: predose and 48 hours after MK-2206 dosing
Population: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MK-2206 90 mg QW | C48hr of MK-2206 in Participants Receiving Multiple QW Dosing | Last Day (Day 22) | 79.3 nM | Standard Deviation 33.7 |
| MK-2206 90 mg QW | C48hr of MK-2206 in Participants Receiving Multiple QW Dosing | Day 1 | 50.9 nM | Standard Deviation 38.2 |
| MK-2206 135 mg QW | C48hr of MK-2206 in Participants Receiving Multiple QW Dosing | Last Day (Day 22) | 158 nM | Standard Deviation 59.2 |
| MK-2206 135 mg QW | C48hr of MK-2206 in Participants Receiving Multiple QW Dosing | Day 1 | 90.3 nM | Standard Deviation 25.1 |
| MK-2206 200 mg QW | C48hr of MK-2206 in Participants Receiving Multiple QW Dosing | Last Day (Day 22) | 187 nM | Standard Deviation 113 |
| MK-2206 200 mg QW | C48hr of MK-2206 in Participants Receiving Multiple QW Dosing | Day 1 | 121 nM | Standard Deviation 47.4 |
| MK-2206 300 mg QW | C48hr of MK-2206 in Participants Receiving Multiple QW Dosing | Day 1 | 253 nM | Standard Deviation 0 |
| MK-2206 250 mg QW | C48hr of MK-2206 in Participants Receiving Multiple QW Dosing | Day 1 | 103 nM | Standard Deviation 19.6 |
| MK-2206 250 mg QW | C48hr of MK-2206 in Participants Receiving Multiple QW Dosing | Last Day (Day 22) | 74.8 nM | Standard Deviation 0 |
| MK-2206 150 mg QW | C48hr of MK-2206 in Participants Receiving Multiple QW Dosing | Last Day (Day 22) | 185 nM | Standard Deviation 0 |
| MK-2206 150 mg QW | C48hr of MK-2206 in Participants Receiving Multiple QW Dosing | Day 1 | 155 nM | Standard Deviation 0 |
Comparison: The Last Day/Day 1 C48hr GMR was calculated as follows: Last Day C48hr GM ÷ Day 1 C48hr GM.
Comparison: The Last Day/Day 1 C48hr GMR was calculated as follows: Last Day C48hr GM ÷ Day 1 C48hr GM.
Comparison: The Last Day/Day 1 C48hr GMR was calculated as follows: Last Day C48hr GM ÷ Day 1 C48hr GM.
Primary
Cmax of MK-2206 in Participants Receiving Multiple QW Dosing
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).
Time frame: Days 1 and 22: predose and 2, 4, 6, 10, 24, 48, 96 hours, and 168 hours after MK-2206 dosing
Population: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MK-2206 90 mg QW | Cmax of MK-2206 in Participants Receiving Multiple QW Dosing | Last Day (Day 22) | 153 nM | Standard Deviation 98 |
| MK-2206 90 mg QW | Cmax of MK-2206 in Participants Receiving Multiple QW Dosing | Day 1 | 81.7 nM | Standard Deviation 42.4 |
| MK-2206 135 mg QW | Cmax of MK-2206 in Participants Receiving Multiple QW Dosing | Last Day (Day 22) | 352 nM | Standard Deviation 210 |
| MK-2206 135 mg QW | Cmax of MK-2206 in Participants Receiving Multiple QW Dosing | Day 1 | 199 nM | Standard Deviation 98.9 |
| MK-2206 200 mg QW | Cmax of MK-2206 in Participants Receiving Multiple QW Dosing | Last Day (Day 22) | 345 nM | Standard Deviation 199 |
| MK-2206 200 mg QW | Cmax of MK-2206 in Participants Receiving Multiple QW Dosing | Day 1 | 264 nM | Standard Deviation 75.8 |
| MK-2206 300 mg QW | Cmax of MK-2206 in Participants Receiving Multiple QW Dosing | Day 1 | 466 nM | Standard Deviation 123 |
| MK-2206 250 mg QW | Cmax of MK-2206 in Participants Receiving Multiple QW Dosing | Day 1 | 231 nM | Standard Deviation 39.1 |
| MK-2206 250 mg QW | Cmax of MK-2206 in Participants Receiving Multiple QW Dosing | Last Day (Day 22) | 169 nM | — |
| MK-2206 150 mg QW | Cmax of MK-2206 in Participants Receiving Multiple QW Dosing | Last Day (Day 22) | 346 nM | — |
| MK-2206 150 mg QW | Cmax of MK-2206 in Participants Receiving Multiple QW Dosing | Day 1 | 337 nM | Standard Deviation 0 |
Comparison: The Last Day/Day 1 Cmax GMR was calculated as follows: Last Day Cmax GM ÷ Day 1 Cmax GM.
Comparison: The Last Day/Day 1 Cmax GMR was calculated as follows: Last Day Cmax GM ÷ Day 1 Cmax GM.
Primary
Concentration of MK-2206 After 48 Hours (C48hr) in Participants Receiving Multiple QOD Dosing
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).
Time frame: Days 1 and 27: predose and 48 hours after MK-2206 dosing.
Population: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MK-2206 30 mg QOD | Concentration of MK-2206 After 48 Hours (C48hr) in Participants Receiving Multiple QOD Dosing | Day 1 | 14.1 nM | Standard Deviation 5.38 |
| MK-2206 30 mg QOD | Concentration of MK-2206 After 48 Hours (C48hr) in Participants Receiving Multiple QOD Dosing | Last Day (Day 27) | 67.9 nM | — |
| MK-2206 60 mg QOD | Concentration of MK-2206 After 48 Hours (C48hr) in Participants Receiving Multiple QOD Dosing | Last Day (Day 27) | 100 nM | Standard Deviation 45.6 |
| MK-2206 60 mg QOD | Concentration of MK-2206 After 48 Hours (C48hr) in Participants Receiving Multiple QOD Dosing | Day 1 | 30.9 nM | Standard Deviation 14.4 |
| MK-2206 75 mg QOD | Concentration of MK-2206 After 48 Hours (C48hr) in Participants Receiving Multiple QOD Dosing | Day 1 | 30.6 nM | Standard Deviation 12 |
| MK-2206 75 mg QOD | Concentration of MK-2206 After 48 Hours (C48hr) in Participants Receiving Multiple QOD Dosing | Last Day (Day 27) | 110 nM | — |
| MK-2206 90 mg QOD | Concentration of MK-2206 After 48 Hours (C48hr) in Participants Receiving Multiple QOD Dosing | Day 1 | 64.1 nM | Standard Deviation 28 |
| MK-2206 90 mg QOD | Concentration of MK-2206 After 48 Hours (C48hr) in Participants Receiving Multiple QOD Dosing | Last Day (Day 27) | 134 nM | Standard Deviation 112 |
Comparison: 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.
Comparison: 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.
Primary
Maximum Concentration (Cmax) of MK-2206 in Participants Receiving Multiple QOD Dosing
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).
Time frame: Days 1 and 27: predose and 0.5, 1, 2, 3, 4, 6, 10, 24, and 48 hours after MK-2206 dosing
Population: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MK-2206 30 mg QOD | Maximum Concentration (Cmax) of MK-2206 in Participants Receiving Multiple QOD Dosing | Day 1 | 33.7 nM | Standard Deviation 15.8 |
| MK-2206 30 mg QOD | Maximum Concentration (Cmax) of MK-2206 in Participants Receiving Multiple QOD Dosing | Last Day (Day 27) | NA nM | — |
| MK-2206 60 mg QOD | Maximum Concentration (Cmax) of MK-2206 in Participants Receiving Multiple QOD Dosing | Last Day (Day 27) | 176 nM | Standard Deviation 77.9 |
| MK-2206 60 mg QOD | Maximum Concentration (Cmax) of MK-2206 in Participants Receiving Multiple QOD Dosing | Day 1 | 71.6 nM | Standard Deviation 36.3 |
| MK-2206 75 mg QOD | Maximum Concentration (Cmax) of MK-2206 in Participants Receiving Multiple QOD Dosing | Day 1 | 102 nM | Standard Deviation 79.9 |
| MK-2206 75 mg QOD | Maximum Concentration (Cmax) of MK-2206 in Participants Receiving Multiple QOD Dosing | Last Day (Day 27) | NA nM | — |
| MK-2206 90 mg QOD | Maximum Concentration (Cmax) of MK-2206 in Participants Receiving Multiple QOD Dosing | Day 1 | 132 nM | Standard Deviation 76.5 |
| MK-2206 90 mg QOD | Maximum Concentration (Cmax) of MK-2206 in Participants Receiving Multiple QOD Dosing | Last Day (Day 27) | 232 nM | Standard Deviation 148 |
Comparison: 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.
Comparison: 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.
Primary
Number of Participants With Dose Limiting Toxicities (DLTs)
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.
Time frame: Day 1 to Day 28 (Cycle 1)
Population: The All Participants as Treated (APaT) population: All participants who received at least one dose of study treatment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| MK-2206 30 mg QOD | Number of Participants With Dose Limiting Toxicities (DLTs) | Pruritis | 0 Participants |
| MK-2206 30 mg QOD | Number of Participants With Dose Limiting Toxicities (DLTs) | Diarrhoea | 0 Participants |
| MK-2206 30 mg QOD | Number of Participants With Dose Limiting Toxicities (DLTs) | Hyperglycaemia | 0 Participants |
| MK-2206 30 mg QOD | Number of Participants With Dose Limiting Toxicities (DLTs) | Total number of participants with DLTs | 0 Participants |
| MK-2206 30 mg QOD | Number of Participants With Dose Limiting Toxicities (DLTs) | Rash | 0 Participants |
| MK-2206 30 mg QOD | Number of Participants With Dose Limiting Toxicities (DLTs) | Dermatitis acneiform | 0 Participants |
| MK-2206 30 mg QOD | Number of Participants With Dose Limiting Toxicities (DLTs) | Rash macular | 0 Participants |
| MK-2206 30 mg QOD | Number of Participants With Dose Limiting Toxicities (DLTs) | Rash generalized | 0 Participants |
| MK-2206 30 mg QOD | Number of Participants With Dose Limiting Toxicities (DLTs) | Stomatitis | 0 Participants |
| MK-2206 60 mg QOD | Number of Participants With Dose Limiting Toxicities (DLTs) | Total number of participants with DLTs | 8 Participants |
| MK-2206 60 mg QOD | Number of Participants With Dose Limiting Toxicities (DLTs) | Rash | 5 Participants |
| MK-2206 60 mg QOD | Number of Participants With Dose Limiting Toxicities (DLTs) | Hyperglycaemia | 1 Participants |
| MK-2206 60 mg QOD | Number of Participants With Dose Limiting Toxicities (DLTs) | Dermatitis acneiform | 0 Participants |
| MK-2206 60 mg QOD | Number of Participants With Dose Limiting Toxicities (DLTs) | Stomatitis | 1 Participants |
| MK-2206 60 mg QOD | Number of Participants With Dose Limiting Toxicities (DLTs) | Rash macular | 2 Participants |
| MK-2206 60 mg QOD | Number of Participants With Dose Limiting Toxicities (DLTs) | Rash generalized | 0 Participants |
| MK-2206 60 mg QOD | Number of Participants With Dose Limiting Toxicities (DLTs) | Diarrhoea | 0 Participants |
| MK-2206 60 mg QOD | Number of Participants With Dose Limiting Toxicities (DLTs) | Pruritis | 0 Participants |
| MK-2206 75 mg QOD | Number of Participants With Dose Limiting Toxicities (DLTs) | Pruritis | 0 Participants |
| MK-2206 75 mg QOD | Number of Participants With Dose Limiting Toxicities (DLTs) | Rash macular | 0 Participants |
| MK-2206 75 mg QOD | Number of Participants With Dose Limiting Toxicities (DLTs) | Rash generalized | 0 Participants |
| MK-2206 75 mg QOD | Number of Participants With Dose Limiting Toxicities (DLTs) | Hyperglycaemia | 0 Participants |
| MK-2206 75 mg QOD | Number of Participants With Dose Limiting Toxicities (DLTs) | Rash | 2 Participants |
| MK-2206 75 mg QOD | Number of Participants With Dose Limiting Toxicities (DLTs) | Stomatitis | 0 Participants |
| MK-2206 75 mg QOD | Number of Participants With Dose Limiting Toxicities (DLTs) | Diarrhoea | 1 Participants |
| MK-2206 75 mg QOD | Number of Participants With Dose Limiting Toxicities (DLTs) | Dermatitis acneiform | 0 Participants |
| MK-2206 75 mg QOD | Number of Participants With Dose Limiting Toxicities (DLTs) | Total number of participants with DLTs | 3 Participants |
| MK-2206 90 mg QOD | Number of Participants With Dose Limiting Toxicities (DLTs) | Stomatitis | 0 Participants |
| MK-2206 90 mg QOD | Number of Participants With Dose Limiting Toxicities (DLTs) | Rash generalized | 1 Participants |
| MK-2206 90 mg QOD | Number of Participants With Dose Limiting Toxicities (DLTs) | Rash macular | 0 Participants |
| MK-2206 90 mg QOD | Number of Participants With Dose Limiting Toxicities (DLTs) | Total number of participants with DLTs | 4 Participants |
| MK-2206 90 mg QOD | Number of Participants With Dose Limiting Toxicities (DLTs) | Pruritis | 1 Participants |
| MK-2206 90 mg QOD | Number of Participants With Dose Limiting Toxicities (DLTs) | Dermatitis acneiform | 0 Participants |
| MK-2206 90 mg QOD | Number of Participants With Dose Limiting Toxicities (DLTs) | Hyperglycaemia | 0 Participants |
| MK-2206 90 mg QOD | Number of Participants With Dose Limiting Toxicities (DLTs) | Diarrhoea | 0 Participants |
| MK-2206 90 mg QOD | Number of Participants With Dose Limiting Toxicities (DLTs) | Rash | 3 Participants |
| MK-2206 90 mg QW | Number of Participants With Dose Limiting Toxicities (DLTs) | Diarrhoea | 0 Participants |
| MK-2206 90 mg QW | Number of Participants With Dose Limiting Toxicities (DLTs) | Hyperglycaemia | 0 Participants |
| MK-2206 90 mg QW | Number of Participants With Dose Limiting Toxicities (DLTs) | Rash | 0 Participants |
| MK-2206 90 mg QW | Number of Participants With Dose Limiting Toxicities (DLTs) | Rash macular | 0 Participants |
| MK-2206 90 mg QW | Number of Participants With Dose Limiting Toxicities (DLTs) | Stomatitis | 0 Participants |
| MK-2206 90 mg QW | Number of Participants With Dose Limiting Toxicities (DLTs) | Pruritis | 0 Participants |
| MK-2206 90 mg QW | Number of Participants With Dose Limiting Toxicities (DLTs) | Rash generalized | 0 Participants |
| MK-2206 90 mg QW | Number of Participants With Dose Limiting Toxicities (DLTs) | Dermatitis acneiform | 0 Participants |
| MK-2206 90 mg QW | Number of Participants With Dose Limiting Toxicities (DLTs) | Total number of participants with DLTs | 0 Participants |
| MK-2206 135 mg QW | Number of Participants With Dose Limiting Toxicities (DLTs) | Hyperglycaemia | 0 Participants |
| MK-2206 135 mg QW | Number of Participants With Dose Limiting Toxicities (DLTs) | Rash generalized | 0 Participants |
| MK-2206 135 mg QW | Number of Participants With Dose Limiting Toxicities (DLTs) | Pruritis | 0 Participants |
| MK-2206 135 mg QW | Number of Participants With Dose Limiting Toxicities (DLTs) | Total number of participants with DLTs | 0 Participants |
| MK-2206 135 mg QW | Number of Participants With Dose Limiting Toxicities (DLTs) | Diarrhoea | 0 Participants |
| MK-2206 135 mg QW | Number of Participants With Dose Limiting Toxicities (DLTs) | Dermatitis acneiform | 0 Participants |
| MK-2206 135 mg QW | Number of Participants With Dose Limiting Toxicities (DLTs) | Stomatitis | 0 Participants |
| MK-2206 135 mg QW | Number of Participants With Dose Limiting Toxicities (DLTs) | Rash macular | 0 Participants |
| MK-2206 135 mg QW | Number of Participants With Dose Limiting Toxicities (DLTs) | Rash | 0 Participants |
| MK-2206 200 mg QW | Number of Participants With Dose Limiting Toxicities (DLTs) | Diarrhoea | 0 Participants |
| MK-2206 200 mg QW | Number of Participants With Dose Limiting Toxicities (DLTs) | Rash generalized | 0 Participants |
| MK-2206 200 mg QW | Number of Participants With Dose Limiting Toxicities (DLTs) | Stomatitis | 0 Participants |
| MK-2206 200 mg QW | Number of Participants With Dose Limiting Toxicities (DLTs) | Hyperglycaemia | 0 Participants |
| MK-2206 200 mg QW | Number of Participants With Dose Limiting Toxicities (DLTs) | Dermatitis acneiform | 1 Participants |
| MK-2206 200 mg QW | Number of Participants With Dose Limiting Toxicities (DLTs) | Rash | 3 Participants |
| MK-2206 200 mg QW | Number of Participants With Dose Limiting Toxicities (DLTs) | Total number of participants with DLTs | 4 Participants |
| MK-2206 200 mg QW | Number of Participants With Dose Limiting Toxicities (DLTs) | Pruritis | 0 Participants |
| MK-2206 200 mg QW | Number of Participants With Dose Limiting Toxicities (DLTs) | Rash macular | 0 Participants |
| MK-2206 300 mg QW | Number of Participants With Dose Limiting Toxicities (DLTs) | Rash generalized | 1 Participants |
| MK-2206 300 mg QW | Number of Participants With Dose Limiting Toxicities (DLTs) | Diarrhoea | 0 Participants |
| MK-2206 300 mg QW | Number of Participants With Dose Limiting Toxicities (DLTs) | Rash macular | 0 Participants |
| MK-2206 300 mg QW | Number of Participants With Dose Limiting Toxicities (DLTs) | Pruritis | 0 Participants |
| MK-2206 300 mg QW | Number of Participants With Dose Limiting Toxicities (DLTs) | Total number of participants with DLTs | 3 Participants |
| MK-2206 300 mg QW | Number of Participants With Dose Limiting Toxicities (DLTs) | Rash | 2 Participants |
| MK-2206 300 mg QW | Number of Participants With Dose Limiting Toxicities (DLTs) | Dermatitis acneiform | 0 Participants |
| MK-2206 300 mg QW | Number of Participants With Dose Limiting Toxicities (DLTs) | Hyperglycaemia | 0 Participants |
| MK-2206 300 mg QW | Number of Participants With Dose Limiting Toxicities (DLTs) | Stomatitis | 0 Participants |
| MK-2206 250 mg QW | Number of Participants With Dose Limiting Toxicities (DLTs) | Rash | 2 Participants |
| MK-2206 250 mg QW | Number of Participants With Dose Limiting Toxicities (DLTs) | Total number of participants with DLTs | 2 Participants |
| MK-2206 250 mg QW | Number of Participants With Dose Limiting Toxicities (DLTs) | Rash macular | 0 Participants |
| MK-2206 250 mg QW | Number of Participants With Dose Limiting Toxicities (DLTs) | Stomatitis | 0 Participants |
| MK-2206 250 mg QW | Number of Participants With Dose Limiting Toxicities (DLTs) | Dermatitis acneiform | 0 Participants |
| MK-2206 250 mg QW | Number of Participants With Dose Limiting Toxicities (DLTs) | Hyperglycaemia | 0 Participants |
| MK-2206 250 mg QW | Number of Participants With Dose Limiting Toxicities (DLTs) | Pruritis | 0 Participants |
| MK-2206 250 mg QW | Number of Participants With Dose Limiting Toxicities (DLTs) | Diarrhoea | 0 Participants |
| MK-2206 250 mg QW | Number of Participants With Dose Limiting Toxicities (DLTs) | Rash generalized | 0 Participants |
| MK-2206 150 mg QW | Number of Participants With Dose Limiting Toxicities (DLTs) | Rash generalized | 0 Participants |
| MK-2206 150 mg QW | Number of Participants With Dose Limiting Toxicities (DLTs) | Hyperglycaemia | 0 Participants |
| MK-2206 150 mg QW | Number of Participants With Dose Limiting Toxicities (DLTs) | Rash macular | 0 Participants |
| MK-2206 150 mg QW | Number of Participants With Dose Limiting Toxicities (DLTs) | Pruritis | 0 Participants |
| MK-2206 150 mg QW | Number of Participants With Dose Limiting Toxicities (DLTs) | Diarrhoea | 0 Participants |
| MK-2206 150 mg QW | Number of Participants With Dose Limiting Toxicities (DLTs) | Total number of participants with DLTs | 1 Participants |
| MK-2206 150 mg QW | Number of Participants With Dose Limiting Toxicities (DLTs) | Stomatitis | 0 Participants |
| MK-2206 150 mg QW | Number of Participants With Dose Limiting Toxicities (DLTs) | Dermatitis acneiform | 0 Participants |
| MK-2206 150 mg QW | Number of Participants With Dose Limiting Toxicities (DLTs) | Rash | 1 Participants |
Primary
Number of Participants With One or More Adverse Events (AE)
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.
Time frame: Up to 269 days
Population: APaT population: All participants who received at least one dose of study treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| MK-2206 30 mg QOD | Number of Participants With One or More Adverse Events (AE) | 3 Participants |
| MK-2206 60 mg QOD | Number of Participants With One or More Adverse Events (AE) | 58 Participants |
| MK-2206 75 mg QOD | Number of Participants With One or More Adverse Events (AE) | 3 Participants |
| MK-2206 90 mg QOD | Number of Participants With One or More Adverse Events (AE) | 7 Participants |
| MK-2206 90 mg QW | Number of Participants With One or More Adverse Events (AE) | 3 Participants |
| MK-2206 135 mg QW | Number of Participants With One or More Adverse Events (AE) | 5 Participants |
| MK-2206 200 mg QW | Number of Participants With One or More Adverse Events (AE) | 17 Participants |
| MK-2206 300 mg QW | Number of Participants With One or More Adverse Events (AE) | 3 Participants |
| MK-2206 250 mg QW | Number of Participants With One or More Adverse Events (AE) | 3 Participants |
| MK-2206 150 mg QW | Number of Participants With One or More Adverse Events (AE) | 2 Participants |
Primary
t½ of MK-2206 in Participants Receiving Multiple QW Dosing
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).
Time frame: Day 22: predose and 2, 4, 6, 10, 24, 48, 96 hours, and 168 hours after MK-2206 dosing
Population: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MK-2206 90 mg QW | t½ of MK-2206 in Participants Receiving Multiple QW Dosing | 71.6 hour | Standard Deviation 12.2 |
| MK-2206 135 mg QW | t½ of MK-2206 in Participants Receiving Multiple QW Dosing | 88.9 hour | Standard Deviation 26.9 |
| MK-2206 200 mg QW | t½ of MK-2206 in Participants Receiving Multiple QW Dosing | 75.1 hour | Standard Deviation 14.7 |
| MK-2206 250 mg QW | t½ of MK-2206 in Participants Receiving Multiple QW Dosing | 53.7 hour | Standard Deviation 0 |
| MK-2206 150 mg QW | t½ of MK-2206 in Participants Receiving Multiple QW Dosing | 64.4 hour | Standard Deviation 0 |
Primary
Time to Maximum Concentration (Tmax) of MK-2206 in Participants Receiving Multiple QOD Dosing
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).
Time frame: Days 1 and 27: predose and 0.5, 1, 2, 3, 4, 6, 10, 24, and 48 hours after MK-2206 dosing
Population: 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.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| MK-2206 30 mg QOD | Time to Maximum Concentration (Tmax) of MK-2206 in Participants Receiving Multiple QOD Dosing | Day 1 | 6.0 hour |
| MK-2206 30 mg QOD | Time to Maximum Concentration (Tmax) of MK-2206 in Participants Receiving Multiple QOD Dosing | Last Day (Day 27) | 4.0 hour |
| MK-2206 60 mg QOD | Time to Maximum Concentration (Tmax) of MK-2206 in Participants Receiving Multiple QOD Dosing | Last Day (Day 27) | 6.0 hour |
| MK-2206 60 mg QOD | Time to Maximum Concentration (Tmax) of MK-2206 in Participants Receiving Multiple QOD Dosing | Day 1 | 4.0 hour |
| MK-2206 75 mg QOD | Time to Maximum Concentration (Tmax) of MK-2206 in Participants Receiving Multiple QOD Dosing | Day 1 | 6.0 hour |
| MK-2206 75 mg QOD | Time to Maximum Concentration (Tmax) of MK-2206 in Participants Receiving Multiple QOD Dosing | Last Day (Day 27) | 10.0 hour |
| MK-2206 90 mg QOD | Time to Maximum Concentration (Tmax) of MK-2206 in Participants Receiving Multiple QOD Dosing | Day 1 | 6.0 hour |
| MK-2206 90 mg QOD | Time to Maximum Concentration (Tmax) of MK-2206 in Participants Receiving Multiple QOD Dosing | Last Day (Day 27) | 5.0 hour |
Primary
Tmax of MK-2206 in Participants Receiving Multiple QW Dosing
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).
Time frame: Days 1 and 22: predose and 2, 4, 6, 10, 24, 48, 96 hours, and 168 hours after MK-2206 dosing
Population: 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.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| MK-2206 90 mg QW | Tmax of MK-2206 in Participants Receiving Multiple QW Dosing | Last Day (Day 22) | 4.0 hour |
| MK-2206 90 mg QW | Tmax of MK-2206 in Participants Receiving Multiple QW Dosing | Day 1 | 6.0 hour |
| MK-2206 135 mg QW | Tmax of MK-2206 in Participants Receiving Multiple QW Dosing | Last Day (Day 22) | 5.0 hour |
| MK-2206 135 mg QW | Tmax of MK-2206 in Participants Receiving Multiple QW Dosing | Day 1 | 4.0 hour |
| MK-2206 200 mg QW | Tmax of MK-2206 in Participants Receiving Multiple QW Dosing | Last Day (Day 22) | 6.0 hour |
| MK-2206 200 mg QW | Tmax of MK-2206 in Participants Receiving Multiple QW Dosing | Day 1 | 6.0 hour |
| MK-2206 300 mg QW | Tmax of MK-2206 in Participants Receiving Multiple QW Dosing | Day 1 | 4.0 hour |
| MK-2206 250 mg QW | Tmax of MK-2206 in Participants Receiving Multiple QW Dosing | Day 1 | 6.0 hour |
| MK-2206 250 mg QW | Tmax of MK-2206 in Participants Receiving Multiple QW Dosing | Last Day (Day 22) | 4.0 hour |
| MK-2206 150 mg QW | Tmax of MK-2206 in Participants Receiving Multiple QW Dosing | Last Day (Day 22) | 4.0 hour |
| MK-2206 150 mg QW | Tmax of MK-2206 in Participants Receiving Multiple QW Dosing | Day 1 | 7.0 hour |
Secondary
Number of Participants With Confirmed Response as Per Response Evaluation Criteria in Solid Tumors (RECIST)
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.
Time frame: From Cycle 1 Day 1 through the End of Study Visit (up to 6 months)
Population: All participants with measurable disease at baseline per RECIST.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| MK-2206 30 mg QOD | Number of Participants With Confirmed Response as Per Response Evaluation Criteria in Solid Tumors (RECIST) | 0 Participants |
| MK-2206 60 mg QOD | Number of Participants With Confirmed Response as Per Response Evaluation Criteria in Solid Tumors (RECIST) | 0 Participants |
| MK-2206 75 mg QOD | Number of Participants With Confirmed Response as Per Response Evaluation Criteria in Solid Tumors (RECIST) | 0 Participants |
| MK-2206 90 mg QOD | Number of Participants With Confirmed Response as Per Response Evaluation Criteria in Solid Tumors (RECIST) | 0 Participants |
| MK-2206 90 mg QW | Number of Participants With Confirmed Response as Per Response Evaluation Criteria in Solid Tumors (RECIST) | 0 Participants |
| MK-2206 135 mg QW | Number of Participants With Confirmed Response as Per Response Evaluation Criteria in Solid Tumors (RECIST) | 0 Participants |
| MK-2206 200 mg QW | Number of Participants With Confirmed Response as Per Response Evaluation Criteria in Solid Tumors (RECIST) | 0 Participants |
| MK-2206 300 mg QW | Number of Participants With Confirmed Response as Per Response Evaluation Criteria in Solid Tumors (RECIST) | 0 Participants |
| MK-2206 250 mg QW | Number of Participants With Confirmed Response as Per Response Evaluation Criteria in Solid Tumors (RECIST) | 0 Participants |
| MK-2206 150 mg QW | Number of Participants With Confirmed Response as Per Response Evaluation Criteria in Solid Tumors (RECIST) | 0 Participants |
Secondary
Phosphorylated Protein Kinase B (pAkt) Level on Cycle 1 Day 15 (C1D15) After Treatment With MK-2206 at the Maximum Tolerated Dose (MTD)
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.
Time frame: Baseline, Cycle 1 Day 15
Population: 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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| MK-2206 60 mg QOD | Phosphorylated Protein Kinase B (pAkt) Level on Cycle 1 Day 15 (C1D15) After Treatment With MK-2206 at the Maximum Tolerated Dose (MTD) | Baseline | 2.15 pAkt lysate units/mg protein |
| MK-2206 60 mg QOD | Phosphorylated Protein Kinase B (pAkt) Level on Cycle 1 Day 15 (C1D15) After Treatment With MK-2206 at the Maximum Tolerated Dose (MTD) | Cycle 1 Day 15 | 0.29 pAkt lysate units/mg protein |
Comparison: pAkt Geometric Mean Ratio (GMR)~= Day 15 Geometric Mean (GM) ÷ Baseline GM95% CI: [0.051, 0.347]