Breast Cancer
Conditions
Keywords
MK-0752, Tamoxifen, Letroxole
Brief summary
The purpose of this research project is to study the effect of a research (investigational) drug, MK-0752 combined with either tamoxifen or letrozole on breast cancer cells. Tamoxifen and letrozole are standard hormone treatments used to treat breast cancers that are positive for the estrogen receptor. However, over time the breast cancer cells can become resistant to tamoxifen and letrozole. MK-0752 is in a class of drugs called gamma secretase inhibitors. Gamma secretase inhibitors may play a role in reversing the resistance to drugs such as tamoxifen and letrozole.
Detailed description
OBJECTIVES To evaluate the safety and tolerability of the gamma-secretase inhibitor MK-0752 in the pre-surgical setting in patients with early stage, estrogen receptor (ER) positive breast cancer, in combination with tamoxifen or an aromatase inhibitor (AI). To establish the feasibility and success of multi-laboratory collaborations in evaluating clinical specimens and biomarker testing. To provide preliminary data on the impact of MK-0752 on a panel of biomarkers involved in the notch signaling pathway.
Interventions
DRUGMK-0752
Women who are post menopausal will receive letrozole 2.5 mg by mouth one time per day for 24 days. Women who are pre menopausal, or who have a contraindication to letrozole will receive tamoxifen 20 mg orally one time per day for a period of 24 days. Starting on day 15 of this 24 day period all patients will receive the oral gamma-secretase inhibitor drug MK-0752 at a dose of 350 mg for three days on, then off four days, then three days on, for a total of 6 doses over a period of 10 days.
Sponsors
Merck Sharp & Dohme LLC
Loyola University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients must have histologically or cytologically confirmed early stage, ER-positive (Allred score ≥3), invasive breast cancer that is not either locally advanced by criteria other than size or inflammatory, and is not metastatic. - Patients must be candidates for surgical removal of the tumor by lumpectomy or mastectomy. * Patients must not have bilateral tumors. Tumor must be amenable to core biopsy in midstudy. * Patients must be \>18 years of age. * Patients must have a performance status ≤1 by Zubrod criteria. * Patients must have a life expectancy of greater than three months. * Patients must have normal organ and marrow function within 28 days of registration as defined below: * absolute neutrophil count \>1,500/μL * platelets \>100,000/μL * total bilirubin ≤1.5 x the institutional upper limit of normal * AST(SGOT)/ALT(SGPT) \<2 X institutional upper limit of normal * creatinine within normal institutional limits OR * creatinine clearance \>60 mL/min/1.73 m2 for patients with creatinine levels above institutional normal * Women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. A negative serum pregnancy test must be obtained within 72 hours of receiving the first dose of the hormonal therapy as well as within 72 hours of the first dose of the MK-0752 GSI medication for women of child-bearing potential. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.
Exclusion criteria
* Patients may not have received any prior chemotherapy or endocrine therapy (tamoxifen, raloxifene, or an aromatase inhibitor) and may not have received prior therapy with a gamma-secretase inhibitor or other investigational agents. - Patients may not have received previous radiation therapy. * Patients may not be currently participating or have participated in a study with an investigational compound or device within 30 days. * Patients must not have known brain or CNS disease, evidence of brain or CNS metastases, or carcinomatous meningitis. * Patients must not have an 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. * Patients may not have known hypersensitivity to the components of MK-0752 or it analogs. * Patients will be excluded if there is a known history of human immunodeficiency (HIV) virus infection, or a known history of hepatitis B or C infection. * Patients must not have a previous history of inflammatory bowel disease or uncontrolled irritable bowel syndrome. * Patients must not have a history of greater than one basal cell carcinoma of the skin within the past five years or a history of Gorlin syndrome.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Experiencing at Least One Adverse Event | 30 days | The number of participants experiencing at least one adverse event during the 24-day observation period and initial post-operative visit. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| MK-0752 Oral gamma-secretase inhibitor drug MK-0752, 350 mg for three days, four days off, then three days on, over a period of 10 days
MK-0752: Women who are post menopausal will receive letrozole 2.5 mg by mouth one time per day for 24 days. Women who are pre menopausal, or who have a contraindication to letrozole will receive tamoxifen 20 mg orally one time per day for a period of 24 days. Starting on day 15 of this 24 day period all patients will receive the oral gamma-secretase inhibitor drug MK-0752 at a dose of 350 mg for three days on, then off four days, then three days on, for a total of 6 doses over a period of 10 days. | 20 |
| Total | 20 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Withdrawal by Subject | 2 |
Baseline characteristics
| Characteristic | MK-0752 |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 5 Participants |
| Age, Categorical Between 18 and 65 years | 15 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 17 Participants |
| Region of Enrollment United States | 20 Participants |
| Sex: Female, Male Female | 20 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 20 |
| other Total, other adverse events | 15 / 20 |
| serious Total, serious adverse events | 0 / 20 |
Outcome results
Primary
Number of Participants Experiencing at Least One Adverse Event
The number of participants experiencing at least one adverse event during the 24-day observation period and initial post-operative visit.
Time frame: 30 days
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| MK-0752 | Number of Participants Experiencing at Least One Adverse Event | At least one adverse event | 15 Participants |
| MK-0752 | Number of Participants Experiencing at Least One Adverse Event | No Adverse Events | 5 Participants |