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A Phase 1b Dose-Escalation Study of the AKT Inhibitor MK-2206 (NSC#749607) Plus Lapatinib (NSC#727989) Administered in Patients With HER2 Positive Metastatic Breast Cancer

Phase 1
18 Years
Open (Enrolling)
Estrogen Receptor-negative Breast Cancer, Estrogen Receptor-positive Breast Cancer, HER2-positive Breast Cancer, Progesterone Receptor-negative Breast Cancer, Progesterone Receptor-positive Breast Cancer, Recurrent Breast Cancer, Stage IV Breast Cancer

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Trial Information

A Phase 1b Dose-Escalation Study of the AKT Inhibitor MK-2206 (NSC#749607) Plus Lapatinib (NSC#727989) Administered in Patients With HER2 Positive Metastatic Breast Cancer


I. To determine the safety and tolerability of continuous daily administration of lapatinib
(lapatinib ditosylate) in combination with weekly administration of MK2206 (AKT inhibitor
MK2206) in patients with human epidermal growth factor receptor (HER)2-positive advanced
breast cancer.

II. To determine the dose-limiting toxicity (DLT) and identify the maximum-tolerated dose
(MTD) and/or recommended phase II dose (RP2D) for this administration schedule.


I. To determine the pharmacokinetics (PK) of MK2206 and lapatinib, each given alone and in
the combination.

II. To evaluate potential pharmacogenetic influence of the candidate drug-metabolizing
enzymes and transporters on the PK of MK2206 and lapatinib.

III. To evaluate the change in select breast cancer biomarkers in the
PTEN/PI3K/Akt-signaling pathways, (e.g., pPTEN, PTEN, pAkt, Akt, pGSK3-beta, GSK3-beta),
Wnt/beta-catenin pathway (e.g., activated beta-catenin (ABC), beta-catenin), and pHER2.

IV. To evaluate the change in breast cancer stem cell (BCSC) biomarkers, ALDH1 and
CD44+/CD24-, before and after 4 weeks of treatment with the combination of MK2206 and
lapatinib at the MTD. The percent change in BCSCs in tumor biopsies will also be evaluated.

V. To determine tumor response in patients with measurable disease as assessed by the
Response Evaluation Criteria in Solid Tumors (RECIST), and by percent change in BCSCs within
the tumor before vs after 4 weeks of treatment.

VI. To perform genomic profiling of the tumor cell and BCSC populations before and after
treatment with the combination of MK2206 and lapatinib at the MTD.

OUTLINE: This is a phase I, dose-escalation study followed by an expansion cohort study.

Patients receive lapatinib ditosylate orally (PO) once daily (QD) on days 1 and 15-28 of
course 1 and on days 1-28 of subsequent courses. Patients also receive AKT inhibitor MK2206
PO QD on days 8 and 15 of course 1 and on days 1, 8, 15, and 22 of subsequent courses.
Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study therapy, patients are followed up for 30 days.

Inclusion Criteria:

- Patients must be women with histologically or cytologically confirmed Her2 positive
(3+ by immunohistochemistry [IHC] or fluorescence in situ hybridization [FISH] ratio
>= 2.0) advanced breast cancer that is metastatic or unresectable and for which
standard curative or palliative measures do not exist or are no longer effective

- Patients must have estrogen receptor (ER) and progesterone receptor (PR) negative
metastatic breast cancer or have had progressive disease following at least 1 prior
hormonal therapy for ER or PR positive metastatic breast cancer

- Patients enrolled in the expansion cohort at the MTD dose of MK-2206/lapatinib
combination must agree to undergo two biopsies for research purposes (Note: we will
only biopsy the MTD cohort and their tumor must be accessible for biopsy)

- Patients with brain metastases will be eligible if the brain mets have been stable
for at least one month and the patients are steroid-independent

- Patients must have measurable disease, defined as at least one lesion that can be
accurately measured in at least one dimension (longest diameter to be recorded for
non-nodal lesions and short axis for nodal lesions) as >= 20 mm with conventional
techniques or as >= 10 mm with spiral CT scan; patients with skin-only disease not
measurable by RECIST are eligible but must have disease for which unilateral
dimensions can be measured and must have monthly photographs with measurements

- Patients must have Eastern Cooperative Oncology Group (ECOG) performance status =< 2
(Karnofsky >= 60%; Merck & Co. suggest ECOG performance status of 0-1 for trials with
MK-2206, but inclusion of performance status 2 patients is at the discretion of

- Leukocytes >= 3,000/mcL

- Absolute neutrophil count >= 1,500/mcL

- Platelets >= 100,000/mcL

- Total bilirubin within normal institutional limits

- Magnesium within normal institutional limits

- Potassium within normal institutional limits

- Aspartate amniotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvate transaminase [SGPT])
=< 2.5 X institutional upper limit of normal

- Creatinine =< 1.2 X institutional upper limit of normal OR creatinine clearance >= 60
mL/min/1.73 m^2 for patients with creatinine levels above institutional norm

- Lapatinib has been reported to decrease left ventricle ejection fraction (LVEF);
patients with preexisting cardiac conditions, including uncontrolled or symptomatic
angina, arrhythmias, or congestive heart failure will not be eligible; normal LVEF
will be confirmed before starting lapatinib, and evaluations (echocardiogram
[ECHO]/multi gated acquisition scan [MUGA]) continued every 3 cycles during
treatment; repeat LVEF determination will be performed for any signs or symptoms
suggestive of congestive heart failure

- Patients must have developed progressive disease following at least 1 prior systemic
therapy for metastatic breast cancer

- Prior chemotherapy is allowed; patients must not have received chemotherapy for 3
weeks prior to the initiation of study treatment and must have recovered to =< CTCAE
grade 1 toxicities related to prior chemotherapy; patients must not have had
nitrosoureas or mitomycin C for 6 weeks prior to the initiation of study treatment;
patients who have alopecia (any grade) or residual drug-induced neuropathy of =<
grade 2 will be eligible if it has been stable, and not worsening, for at least 30
days; patients who have prior treatment with an AKT inhibitor will be excluded from
participating in this study; patients are eligible if they had prior therapy with
lapatinib UNLESS they are to be enrolled in the expansion cohort at the MTD dose of
MK-2206/lapatinib; patients in the expansion cohort at the MTD dose of
MK-2206/lapatinib who had prior treatment with lapatinib will be EXCLUDED

- Prior radiation therapy is allowed; however, any radiation therapy must have occurred
greater than 3 weeks from the planned initiation of study treatment and any
radiation-induced toxicity must have recovered to =< Grade 1 at the time of
initiation of study treatment; patients who have received prior radiation to 50% or
more of their total marrow volume will be excluded

- Prior experimental (non-Food and Drug Administration [FDA] approved) therapies and
immunotherapies are allowed; patients must not have received these therapies for 30
days or five half lives of the drug (whichever is less) prior to the initiation of
study treatment and must have full recovery from any acute effects of these
therapies; prior therapy with TDM-1 or anti-Her2 monoclonal antibodies (i.e.
trastuzumab, pertuzumab) is allowed

- Patients must not have received allogeneic stem cell transplant

- Patients must not have co-morbid condition(s) that, at the opinion of the
investigator, prevent safe treatment

- Patients must not be pregnant or nursing

- Patients who are human immunodeficiency virus positive (HIV+) are eligible if they
have adequate CD4 counts (CD4 cell count of >= 350 cells/mm^3) and are not undergoing
highly active antiretroviral therapy (HAART); patients must not have a history of
hepatitis B+ or hepatitis C+ (active or previous treatment)

- Life expectancy of greater than 12 weeks

- Women of child-bearing potential must agree to use two forms of contraception
(hormonal or barrier method of birth control; abstinence) prior to study entry and
for the duration of study participation; should a woman become pregnant or suspect
she is pregnant while she or her partner is participating in this study, the patient
should inform the treating physician immediately

- Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

- Patients who have had chemotherapy or radiotherapy within 3 weeks (4 weeks for those
who received radiation therapy of > 5% of their total marrow volume; 6 weeks for
nitrosoureas or mitomycin C) prior to entering the study; or those who have not
recovered to =< CTCAE grade 1 toxicities related to prior therapy are not eligible to
participate in this study with the exception of grade 2 peripheral neuropathy if it
has been stable, and not worsening, for at least 30 days

- Patients may not have received any other investigational agents or immunotherapies
within the preceding 30 days or five half lives of the drug (whichever is less)

- Patients must not have received prior treatment with either an AKT inhibitor or
lapatinib with the exception of patients who have been administered an AKT inhibitor
or lapatinib as part of a single or extremely limited dosing study, such as a phase 0

- Patients must not receive any other anti-cancer therapy (cytotoxic, biologic,
radiation, or hormonal other than for replacement) while on this study except for
medications that are prescribed for supportive care but may potentially have an
anti-cancer effect (i.e. megestrol acetate, bisphosphonates); these medications must
have been started 1 month prior to enrollment on this study; erythropoietin (Epo) and
darbepoetin (Darbepo) are allowed

- Patients may not be receiving any other investigational agents

- Any patient requiring chronic maintenance of white blood cell counts or granulocyte
counts through the use of growth factor support (e.g. Neulasta, Neupogen)

- Patients with a prior history of seizures

- Patients with known brain metastases are excluded from this clinical trial if the
mets have been stable for less than one month and/or if they are on active steroid

- Patients with a history of allergic reactions attributed to compounds of similar
chemical or biologic composition to MK-2206, lapatinib, or other agents used in study

- Preclinical studies demonstrated the potential of MK-2206 for induction of
hyperglycemia in all preclinical species tested; patients with diabetes or at risk
for hyperglycemia are not to be excluded from trials with MK-2206, but the
hyperglycemia should be well controlled on oral agents before the patient enters the

- Preclinical studies indicated transient changes in QTc interval during MK-2206
treatment; prolongation of QTc interval is potentially a safety concern while on
MK-2206 therapy; patients with baseline QTcF > 450 msec (male) or QTcF >470 msec
(female) will be excluded from entry on study; a list of medications that may cause
QTc interval prolongation are listed, and should be avoided by patients entering on

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements

- Pregnant women are excluded from this study because MK-2206 is an agent with the
potential for teratogenic or abortifacient effects; because there is an unknown but
potential risk for adverse events in nursing infants secondary to treatment of the
mother with MK-2206, breastfeeding should be discontinued if the mother is treated
with MK-2206; these potential risks may also apply to other agents used in this study

- HIV-positive patients on combination antiretroviral therapy are ineligible because of
the potential for pharmacokinetic interactions with MK-2206; in addition, these
patients are at increased risk of lethal infections when treated with
marrow-suppressive therapy

- Patients with malabsorption syndrome or other condition that would interfere with
intestinal absorption; patients must be able to swallow tablets

- Patients enrolled on the MTD cohort who do not have accessible tumor or who refuse
serial biopsies

- Due to a high incidence of bradycardia observed in early trials of MK-2206, patients
with significant bundle branch block, or bradycardia related to cardiac disease,
should be excluded from the trial

Type of Study:


Study Design:

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Identification of maximum tolerated dose determined by dose-limiting toxicity and adverse events and the associated NCI CTCAE grade of continuous daily administration of lapatinib ditosylate in combination with weekly administration of MK-2206

Outcome Time Frame:

28 days

Safety Issue:


Principal Investigator

Patricia LoRusso

Investigator Role:

Principal Investigator

Investigator Affiliation:

Barbara Ann Karmanos Cancer Institute


United States: Food and Drug Administration

Study ID:




Start Date:

January 2011

Completion Date:

Related Keywords:

  • Estrogen Receptor-negative Breast Cancer
  • Estrogen Receptor-positive Breast Cancer
  • HER2-positive Breast Cancer
  • Progesterone Receptor-negative Breast Cancer
  • Progesterone Receptor-positive Breast Cancer
  • Recurrent Breast Cancer
  • Stage IV Breast Cancer
  • Breast Neoplasms



Translational Genomics Research Institute Phoenix, Arizona  
Barbara Ann Karmanos Cancer Institute Detroit, Michigan  48201
Vanderbilt-Ingram Cancer Center Nashville, Tennessee  37232-6838
Dana-Farber Cancer Institute Boston, Massachusetts  02115
University of Michigan University Hospital Ann Arbor, Michigan  48109