Lapatinib Ditosylate and MK2206 in Treating Women With Metastatic Breast Cancer
Status: Recruiting
Phase: Phase 1
Diagnosis: Breast: Metastatic
NCT ID: NCT01281163
(View complete trial on ClinicalTrials.gov)
DFCI Protocol ID: 11-106
RATIONALE: Lapatinib ditosylate and MK2206 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. PURPOSE: This phase I clinical trial is study the side effects and the best dose of lapatinib ditosylate and MK2206 in treating women with metastatic breast cancer.
Conducting Institutions:
Dana-Farber Cancer Institute, Brigham and Women's Hospital
Overall PI:
Sara Tolaney, MD,
Dana-Farber Cancer Institute
Site-responsible Investigators:
Contacts:
Dana-Farber Cancer Institute:
Breast Cancer Nursing Team, 617-632-3478
Eligibility Criteria
DISEASE CHARACTERISTICS:
- Histologically or cytologically confirmed HER2-positive (3+ by IHC or 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
- Must have estrogen-receptor (ER) and progesterone-receptor (PR)-negative metastatic
breast cancer OR must have 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 MK2206/lapatinib
combination must agree to undergo serial biopsies for research purposes
- Tumor must be accessible for biopsy
- 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 by conventional techniques or as ≥ 10 mm by
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 available
- Patients with brain metastases are eligible if the brain metastases have been stable
for at least one month and the patients are steroid-independent
PATIENT CHARACTERISTICS:
- Menopausal status not specified
- ECOG performance status (PS) 0-2 (Karnofsky PS 60-100%)
- Life expectancy > 12 weeks
- WBC ≥ 3,000/mm³
- ANC ≥ 1,500/mm³
- Platelet count ≥ 100,000/mm³
- Total bilirubin normal
- Magnesium normal
- Potassium normal
- AST/ALT ≤ 2.5 times upper limit of normal (ULN)
- Creatinine ≤ 1.2 times ULN OR creatinine clearance ≥ 60 mL/min
- Not pregnant or nursing
- Negative pregnancy test
- Women of child-bearing potential must agree to use two forms of contraception
(hormonal, barrier method of birth control, or abstinence) prior to study entry, for
the duration of study participation, and for 3 months after the last dose of study
therapy
- Able to swallow tablets
- No preexisting cardiac conditions, including uncontrolled or symptomatic angina,
arrhythmias, or congestive heart failure
- Patients with residual drug-induced peripheral neuropathy ≤ grade 2 eligible provided
that it has been stable and not worsening for at least 30 days
- Patients who are HIV-positive are eligible if CD4 count ≥ 350 cells/mm³ and they are
not undergoing HAART anti-retroviral therapy
- No co-morbid condition(s) that, at the opinion of the investigator, prevent safe
treatment
- No history of hepatitis B or C positivity (active or previous therapy)
- No requirement for chronic maintenance of white blood cell counts or granulocyte
counts through the use of growth factor support (e.g., Neulasta®, Neupogen®)
- No history of seizures
- No history of allergic reactions attributed to compounds of similar chemical or
biologic composition to MK2206, lapatinib, or other agents used in study
- Diabetes or risk for hyperglycemia that has been well controlled on oral agents
before entering the trial allowed
- No baseline QTcF > 450 msec (male) or QTcF > 470 msec (female)
- No 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
- No malabsorption syndrome or other condition that would interfere with intestinal
absorption
- No significant bundle branch block or bradycardia related to cardiac disease
PRIOR CONCURRENT THERAPY:
- See Disease Characteristics
- More than 3 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin C)
or radiotherapy and recovered to CTCAE ≤ grade 1 toxicities
- No prior radiotherapy to ≥ 50% of total marrow volume
- More than 30 days or five half lives (whichever is less) since prior experimental and
immunotherapies and fully recovered from any acute effects of these therapies
- No prior lapatinib ditosylate or an AKT inhibitor
- Patients who have received an AKT inhibitor or lapatinib as part of a single or
extremely limited dosing study, such as a phase 0 study, are allowed
- Prior TDM-1 or anti-HER2 monoclonal antibody (i.e., trastuzumab, pertuzumab) allowed
- No prior allogeneic stem cell transplantation
- No concurrent HAART anti-retroviral therapy for HIV-positive patients
- No concurrent medications that may cause QTc interval prolongation
- No other concurrent anti-cancer therapy (cytotoxic, biologic, radiation, or hormonal
other than for replacement) except for medications that are prescribed for supportive
care but may potentially have an anti-cancer effect (i.e., megestrol acetate or
bisphosphonates) that were started within a month prior to enrollment into study
- Concurrent erythropoietin and darbepoetin allowed
- No other concurrent investigational agents