Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Breast Neoplasms

Antineoplastic Agents

All Drugs and Chemicals

Amino Acids

Trastuzumab

Lapatinib

Antineoplastic Agents, Immunological

Tyrosine Kinase Inhibitors

Protein Kinase Inhibitors

Enzyme Inhibitors

Tyrosine

Participants in Part 1 (Pt. 1) receive MK-2206 45 mg every other day (QOD), taken orally. In combination with MK-2206, trastuzumab is administered by intravenous (IV) infusion at an initial dose of 8 mg/kg (loading dose) followed by 6 mg/kg every 3 weeks (q3wk).

Participants in Pt. 1 receive MK-2206 60 mg QOD, taken orally. In combination with MK-2206, trastuzumab is administered by IV infusion at an initial dose of 8 mg/kg (loading dose) followed by 6 mg/kg q3wk.

Participants in Pt. 1 receive MK-2206 135 mg once weekly (QW), taken orally. In combination with MK-2206, trastuzumab is administered by IV infusion at an initial dose of 8 mg/kg (loading dose) followed by 6 mg/kg q3wk.

Participants in Pt. 1 receive MK-2206 200 mg QW, taken orally. In combination with MK-2206, trastuzumab is administered by IV infusion at an initial dose of 8 mg/kg (loading dose) followed by 6 mg/kg q3wk.

Participants in Part 2 (Pt. 2) receive MK-2206 (dosed either QOD or QW) taken orally at the maximum tolerated dose defined in Part 1 (Pt. 1 MTD). MK-2206 is administered in combination with trastuzumab (IV infusion at an initial dose of 8 mg/kg (loading dose) followed by 6 mg/kg q3wk) as well as lapatinib 500 mg taken orally once daily (QD).

Participants in Pt. 2 receive MK-2206 (dosed either QOD or QW) taken orally at the Pt. 1 MTD. MK-2206 is administered in combination with trastuzumab (IV infusion at an initial dose of 8 mg/kg (loading dose) followed by 6 mg/kg q3wk) as well as lapatinib 750 mg taken orally QD.

Participants in Part 2 (Pt. 2) receive MK-2206 (dosed either QOD or QW) taken orally at the Pt. 1 MTD. MK-2206 is administered in combination with trastuzumab (IV infusion at an initial dose of 8 mg/kg (loading dose) followed by 6 mg/kg q3wk) as well as lapatinib 1000 mg taken orally QD.

\[Part 1\]: MK-2206 tablets will be given starting at a dose of 45 mg QOD and escalated to 60 mg QOD if tolerated, OR starting at a dose of 135 mg QW and escalated to 200 mg QW if tolerated. Dose reduction to 30mg QOD or 90 mg QW may be permitted. The dose of MK2206 will be increased or decreased as required to find the maximum tolerated dose (MTD) of MK2206 for both the QOD and QW dosing schedules in combination with trastuzumab. \[Part 2\] The Part 2 dosing level and schedule of MK2206 will be chosen from the MTD of either the QOD or QW dosing schedules depending on the toxicity profile and preliminary efficacy.

MK-2206

Trastuzumab will be administered as a 90-minute IV infusion at a loading dose of 8 mg/kg followed by 6 mg/kg q3wk.

Lapatinib tablets will be administered orally QD in doses of 500 mg, 750 mg, or 1000 mg.

Medical Director

This study will assess the safety, tolerability, and the maximum tolerated dose (MTD) of MK-2206 in combination with both trastuzumab and trastuzumab/lapatinib in participants with human epidermal growth factor receptor 2 positive (HER2+) breast cancer and other solid tumors. The primary hypothesis of this study is that the combination of oral MK-2206 with trastuzumab or with trastuzumab/lapatinib will be well tolerated in participants with advanced HER2+ solid tumors.

This study was divided into 2 parts. In Part 1, cohorts of 3 participants were to be enrolled sequentially on escalating doses of MK-2206 in combination with a fixed dose of trastuzumab. Barring dose-limiting toxicities (DLTs), additional participants were to be enrolled and dose-finding would proceed until an MTD was identified for MK-2206 when dosed either every other day (QOD) or once weekly (QW) in combination with trastuzumab. In Part 2, cohorts of 3 participants were to be enrolled sequentially on rising doses of lapatinib administered in combination with the MTD dose of MK-2206/trastuzumab established in Part 1. Barring DLTs, dose finding would proceed until an MTD of the 3-drug combination was identified.

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

A Phase I Investigation of the Combination of MK-2206, Trastuzumab and Lapatinib in HER2+ Solid Tumors

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.

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.

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 \[any drug-related AE leading to MK-2206 dose modification; grade ≥2 drug-related AE causing drug interruption (≥8 days); any drug-related AE causing drug interruption (≥15 days); grade ≥3 glucose intolerance with grade ≥2 hyperglycemia; fasting glucose \>250 mg/dL (≥2 days); grade ≥3 electrolyte abnormality; lactoacidosis or ketoacidosis; non-fasting grade 4 hyperglycemia; increased QTc interval; significant bradycardia.\].

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.

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.

Merck Sharp & Dohme LLC

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; AEs were not collected for Part 2-specific arms.

Participants in Pt. 1 receive MK-2206 45 mg QOD, taken orally. In combination with MK-2206, trastuzumab is administered by IV infusion at an initial dose of 8 mg/kg (loading dose) followed by 6 mg/kg q3wk.

Pt. 1: MK-2206 45mg, QOD + Trastuzumab

Pt. 1: MK-2206 60mg, QOD + Trastuzumab

Participants in Pt. 1 receive MK-2206 135 mg QW, taken orally. In combination with MK-2206, trastuzumab is administered by IV infusion at an initial dose of 8 mg/kg (loading dose) followed by 6 mg/kg q3wk.

Pt. 1: MK-2206 135mg, QW + Trastuzumab

Pt. 1: MK-2206 200mg, QW + Trastuzumab

Total

Age, Continuous

Sex: Female, Male

The analysis population includes all participants receiving ≥1 dose of study treatment.

Senior Vice President, Global Clinical Development

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.

Number of Participants Experiencing ≥1 Adverse Event

Number of Participants Discontinuing Study Drug Due to an Adverse Event

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.

Number of Participants Experiencing ≥1 Dose-Limiting Toxicity (DLT) in Cycle 1

Participants in Pt. 1 receive MK-2206 (at 45 or 60 mg) QOD, taken orally. In combination with MK-2206, trastuzumab is administered by IV infusion at an initial dose of 8 mg/kg (loading dose) followed by 6 mg/kg q3wk.

Pt. 1: MK-2206 (QOD Dosing) + Trastuzumab

Participants in Pt. 1 receive MK-2206 (135 or 200 mg) QW, taken orally. In combination with MK-2206, trastuzumab is administered by IV infusion at an initial dose of 8 mg/kg (loading dose) followed by 6 mg/kg q3wk.

Pt. 1: MK-2206 (QW Dosing) + Trastuzumab

Participants in Pt. 2 receive MK-2206 (dosed either QOD or QW) taken orally at the Pt. 1 MTD. MK-2206 is administered in combination with trastuzumab (IV infusion at an initial dose of 8 mg/kg (loading dose) followed by 6 mg/kg q3wk) as well as lapatinib at 500, 750, or 1000 mg taken orally QD.

Pt. 2: MK-2206 (Pt.1 MTD) + Trastuzumab + Lapatinib

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.

Maximum Tolerated Dose of MK-2206 in Combination With Trastuzumab (Part 1) and With Trastuzumab/Lapatinib (Part 2)

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.

Recommended Phase 2 Dose of MK-2206 in Combination With Trastuzumab (Part 1) and With Trastuzumab/Lapatinib (Part 2)

Pt. 2: MK-2206 (Pt.1 MTD) + Trastuzumab + Lapatinib 500mg, QD

Pt. 2: MK-2206 (Pt.1 MTD) + Trastuzumab + Lapatinib 750mg, QD

Participants in Pt. 2 receive MK-2206 (dosed either QOD or QW) taken orally at the Pt. 1 MTD. MK-2206 is administered in combination with trastuzumab (IV infusion at an initial dose of 8 mg/kg (loading dose) followed by 6 mg/kg q3wk) as well as lapatinib 1000 mg taken orally QD.

Spots Global Cancer Trial Database for documented to be her2+