Clinical trial NCT00963547: A Study of MK-2206 in Combination With Trastuzumab and Lapatinib for the Treatment of HER2+ Solid Tumors (MK-2206-015)
Official title: A Phase I Investigation of the Combination of MK-2206, Trastuzumab and Lapatinib in HER2+ Solid Tumors
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Advanced Solid Tumors
Breast Cancer
Keywords: Documented to be HER2+
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
First posted: 2009-08-21
Enrollment: 33
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

* Have a histologically or cytologically-confirmed locally advanced or metastatic HER2+ solid tumor.
* Have performance status ≤1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale.
* Have adequate organ function.
* Female participants have a negative pregnancy test 72 hours prior to receiving the first dose of study medication.
* Have completed any major surgery for a minimum of 28 days prior to enrollment in this study.
* Able to swallow tablets and has no surgical or anatomical condition that will preclude the patient from swallowing or absorbing oral medications on an ongoing basis.

Exclusion Criteria:

* Had chemotherapy, radiotherapy or biological therapy within 4 weeks of screening. Participants receiving trastuzumab and/or lapatinib prior to screening must be off both medications for 1 week prior to first dose of MK-2206 if trastuzumab had been administered at 2 mg/kg weekly and 3 weeks if trastuzumab had been administered at 6 mg/kg weekly.
* Currently participating or has participated in a study with an investigational compound or device within 30 days, or 5x half-life from prior agents, whichever is longer, of Day 1 of this study
* Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis.
* Has a primary CNS tumor.
* Has known hypersensitivity to the components of study drugs or its analogs.
* Has a history or evidence of heart disease.
* Has uncontrolled hypertension or diabetes.
* Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
* Is pregnant or breastfeeding or is expecting to conceive or father children during the study.
* Is HIV positive.
* Has symptomatic ascites or pleural effusion.
* Is receiving treatment with oral corticosteroids for reason other than CNS metastasis.

Primary outcomes:
measure: Number of Participants Experiencing ≥1 Adverse Event
timeFrame: Up to 36 weeks (up to 4 weeks following cessation of study treatment)
measure: Number of Participants Discontinuing Study Drug Due to an Adverse Event
timeFrame: Up to 32 weeks
measure: Number of Participants Experiencing ≥1 Dose-Limiting Toxicity (DLT) in Cycle 1
timeFrame: Up to 3 weeks (up to day 21 of cycle 1)
measure: Maximum Tolerated Dose of MK-2206 in Combination With Trastuzumab (Part 1) and With Trastuzumab/Lapatinib (Part 2)
timeFrame: Up to 3 weeks (up to day 21 of cycle 1)
measure: Recommended Phase 2 Dose of MK-2206 in Combination With Trastuzumab (Part 1) and With Trastuzumab/Lapatinib (Part 2)
timeFrame: Up to 36 weeks (up to 4 weeks following cessation of study treatment)
Secondary outcomes:
Other outcomes:
Locations:
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: Hudis C, Swanton C, Janjigian YY, Lee R, Sutherland S, Lehman R, Chandarlapaty S, Hamilton N, Gajria D, Knowles J, Shah J, Shannon K, Tetteh E, Sullivan DM, Moreno C, Yan L, Han HS. A phase 1 study evaluating the combination of an allosteric AKT inhibitor (MK-2206) and trastuzumab in patients with HER2-positive solid tumors. Breast Cancer Res. 2013 Nov 19;15(6):R110. doi: 10.1186/bcr3577.