A Study of MK-2206 in Combination With Trastuzumab and Lapatinib for the Treatment of HER2+ Solid Tumors (MK-2206-015)

The maximum tolerated dose (MTD) of MK-2206 in combination with trastuzumab (Part 1) was assessed for both QOD and QW dosing schedules. To calculate MTD, a dose-response curve for the rate of patients in each treatment combination arm experiencing a DLT in Cycle 1 will be estimated using the pooling-of-adjacent-violators algorithm, with this dose-response curve used to determine the MTD. The MTD is defined as the dose at which the percentage of patients experiencing a DLT is the closest to 25% or 30% in Part 1 and Part 2, respectively. As the study was terminated prior to Part 2 enrollment, the MTD of MK-2206 in combination with trastuzumab/lapatinib could not be determined.

Time frame: Up to 3 weeks (up to day 21 of cycle 1)

Population: All participants in Part 1 receiving ≥1 dose of study medication (i.e. all participants as treated), categorized by QOD or QW dosing of MK-2206. Due to trial termination, participants were not enrolled in Part 2; MTD could not be calculated for Part 2.

The number of participants discontinuing study drug due to an AE was assessed. An AE is 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. Further, 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, is also an AE.

Time frame: Up to 32 weeks

Population: All participants in Part 1 receiving ≥1 dose of study medication (i.e. all participants as treated). Due to trial termination, participants were not enrolled in Part 2; Part 2-specific arms are not included for analysis.

The number of participants experiencing an adverse event (AE) was assessed. An AE is 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. Further, 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, is also an AE.

Time frame: Up to 36 weeks (up to 4 weeks following cessation of study treatment)

Population: All participants in Part 1 receiving ≥1 dose of study medication (i.e. all participants as treated). Due to trial termination, participants were not enrolled in Part 2; Part 2-specific arms are not included for analysis.

A DLT is a drug-related AE not related to disease progression or intercurrent illnesses. Toxicities are graded in severity according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCICTCAE) version 3.0. The following are considered DLTs: A.) Hematologic \[grade 4 neutropenia (≥5 days); grade 3/4 neutropenia; grade 4 thrombocytopenia.\] B.) Non-Hematologic \[any grade ≥3 non-hematologic toxicity except: grade 3 nausea, vomiting, diarrhea, or dehydration; asthenia; hypersensitivity; grade 3 elevated transaminases (1 week).\] C.) Additional \[any drug-related AE leading to MK-2206 dose modification; grade ≥2 drug-related AE causing drug interruption (≥8 days); any drug-related AE causing drug interruption (≥15 days); grade ≥3 glucose intolerance with grade ≥2 hyperglycemia; fasting glucose \>250 mg/dL (≥2 days); grade ≥3 electrolyte abnormality; lactoacidosis or ketoacidosis; non-fasting grade 4 hyperglycemia; increased QTc interval; significant bradycardia.\].

Time frame: Up to 3 weeks (up to day 21 of cycle 1)

Population: All participants in Part 1 receiving ≥1 dose of study drug were included: 1) if experiencing a DLT in cycle 1; or 2) if not experiencing a DLT in cycle 1, received 90% of planned doses and completed all safety evaluations by ≤20 days after first dose of MK-2206. Trial terminated before Part 2 enrollment; Part 2-specific arms excluded.

The recommended phase 2 dose (RP2D) of MK-2206 in combination with trastuzumab (Part 1) was assessed. Data from Part 1 informing the determination of the MTD (i.e. DLTs in cycle 1), along with safety and tolerability data, and the pharmacokinetic profile was used to determine the RP2D for both the QOD and QW dosing of MK-2206 in combination with trastuzumab. As the study was terminated prior to Part 2 enrollment, the RP2D of MK-2206 in combination with trastuzumab/lapatinib could not be determined.

Time frame: Up to 36 weeks (up to 4 weeks following cessation of study treatment)

Population: All participants in Part 1 receiving ≥1 dose of study medication (i.e. all participants as treated), categorized by QOD or QW dosing of MK-2206. Due to trial termination, participants were not enrolled in Part 2; RP2D could not be calculated for Part 2.