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
4 other identifiers
interventional
33
0 countries
N/A
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.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P50-P75 for phase_1
Started Sep 2009
Typical duration for phase_1
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
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Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
August 19, 2009
CompletedFirst Posted
Study publicly available on registry
August 21, 2009
CompletedStudy Start
First participant enrolled
September 15, 2009
CompletedPrimary Completion
Last participant's last visit for primary outcome
August 9, 2011
CompletedStudy Completion
Last participant's last visit for all outcomes
December 22, 2011
CompletedResults Posted
Study results publicly available
October 31, 2018
CompletedJune 4, 2024
May 1, 2024
1.9 years
August 19, 2009
March 28, 2018
May 20, 2024
Conditions
Keywords
Outcome Measures
Primary Outcomes (5)
Number of Participants Experiencing ≥1 Adverse Event
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.
Up to 36 weeks (up to 4 weeks following cessation of study treatment)
Number of Participants Discontinuing Study Drug Due to an Adverse Event
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.
Up to 32 weeks
Number of Participants Experiencing ≥1 Dose-Limiting Toxicity (DLT) in Cycle 1
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 \[any drug-related AE leading to MK-2206 dose modification; grade ≥2 drug-related AE causing drug interruption (≥8 days); any drug-related AE causing drug interruption (≥15 days); grade ≥3 glucose intolerance with grade ≥2 hyperglycemia; fasting glucose \>250 mg/dL (≥2 days); grade ≥3 electrolyte abnormality; lactoacidosis or ketoacidosis; non-fasting grade 4 hyperglycemia; increased QTc interval; significant bradycardia.\].
Up to 3 weeks (up to day 21 of cycle 1)
Maximum Tolerated Dose of MK-2206 in Combination With Trastuzumab (Part 1) and With Trastuzumab/Lapatinib (Part 2)
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.
Up to 3 weeks (up to day 21 of cycle 1)
Recommended Phase 2 Dose of MK-2206 in Combination With Trastuzumab (Part 1) and With Trastuzumab/Lapatinib (Part 2)
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.
Up to 36 weeks (up to 4 weeks following cessation of study treatment)
Study Arms (7)
Pt. 1: MK-2206 45mg, QOD + Trastuzumab
EXPERIMENTALParticipants 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).
Pt. 1: MK-2206 60mg, QOD + Trastuzumab
EXPERIMENTALParticipants 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.
Pt. 1: MK-2206 135mg, QW + Trastuzumab
EXPERIMENTALParticipants 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.
Pt. 1: MK-2206 200mg, QW + Trastuzumab
EXPERIMENTALParticipants 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.
Pt. 2: MK-2206 (Pt.1 MTD) + Trastuzumab + Lapatinib 500mg, QD
EXPERIMENTALParticipants 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).
Pt. 2: MK-2206 (Pt.1 MTD) + Trastuzumab + Lapatinib 750mg, QD
EXPERIMENTALParticipants 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.
Pt. 2: MK-2206 (Pt.1 MTD) + Trastuzumab + Lapatinib 1000mg, QD
EXPERIMENTALParticipants 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.
Interventions
\[Part 1\]: 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.
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.
Eligibility Criteria
You may qualify if:
- 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.
You may not qualify if:
- 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.
Contact the study team to confirm eligibility.
Sponsors & Collaborators
Related Publications (1)
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.
PMID: 24252402RESULT
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Results Point of Contact
- Title
- Senior Vice President, Global Clinical Development
- Organization
- Merck Sharp & Dohme Corp.
Study Officials
- STUDY DIRECTOR
Medical Director
Merck Sharp & Dohme LLC
Publication Agreements
- PI is Sponsor Employee
- No
- Restriction Type
- OTHER
- Restrictive Agreement
- Yes
Study Design
- Study Type
- interventional
- Phase
- phase 1
- Allocation
- NON RANDOMIZED
- Masking
- NONE
- Purpose
- TREATMENT
- Intervention Model
- PARALLEL
- Sponsor Type
- INDUSTRY
- Responsible Party
- SPONSOR
Study Record Dates
First Submitted
August 19, 2009
First Posted
August 21, 2009
Study Start
September 15, 2009
Primary Completion
August 9, 2011
Study Completion
December 22, 2011
Last Updated
June 4, 2024
Results First Posted
October 31, 2018
Record last verified: 2024-05
Data Sharing
- IPD Sharing
- Will share
https://www.merck.com/clinical-trials/pdf/ProcedureAccessClinicalTrialData.pdf