Phase II Short-term Adjuvant Therapy and Biomarker Studies With Targeted Agents in Women With Estrogen Receptor Negative Breast Cancer

Overall Response Rate (ORR)

Change in Ki-67 in Breast Tissue of High-Risk Women

ORR defined as percentage of participants achieving disappearance of atypia in random periareolar fine needle aspiration (RPFNA), change from baseline to 6 months.

Primary endpoint is the change in Ki-67 before and after 3 months of dasatinib treatment in breast tissue of high-risk women.
Ki-67 is measured as a continuous variable and a one-way ANOVA followed by Dunnett's multiple comparison test comparing the change of Ki-67 of each of the three treated groups with control.
The purpose of this study is to determine the minimum biological effective dose, which is defined as the lowest dose where the change of Ki-67 is significantly different from that in the control group.

Baseline to 6 months post Metformin

3 months

SINGLE_GROUP

PARALLEL

300

66

Metformin

Dasatinib

Metformin 850 mg orally twice a day for 6 months.

Participants take no drug, or the study drug dasatinib at a dose of 40, or 80 mg daily for 3 months (+/- 7 days) and at the end of the 3 months (+/- 7 days) will undergo a repeat FNA and blood collection for the same marker analyses.

Drug: Metformin

Drug: Dasatinib

Placebo

No Dasatinib

PLACEBO_COMPARATOR

NO_INTERVENTION

Placebo orally twice a day for 6 months.

No treatment control group.

Metformin

Dasatinib

850 mg by mouth twice a day for 6 months.

<p>Group 1: 40 mg by mouth once a day.</p><p>Group 2: 80 mg by mouth once a day.</p><p>Group 3: No drug.</p>

Metformin

Dasatinib

<p>Inclusion Criteria:</p><ol><li>Histological confirmation of estrogen receptor (ER) negative breast carcinoma, stage I, II, or III</li><li>Completed all adjuvant therapy including (if indicated) endocrine, trastuzumab, radiation therapy</li><li>Contralateral atypia on random periareolar fine needle aspiration (RPFNA) at least 90 days after completion of adjuvant treatment for breast cancer.</li><li>At least 18 years of age.</li><li>Provided written informed consent.</li><li>Adequate bone marrow function (within last 3 months) Hemoglobin &gt;&#x2F;= 9 gm&#x2F;dL.
• Absolute granulocyte count 1,500&#x2F;mm^3 (1.5 * 10^9&#x2F;L).
• Platelets 75,000&#x2F;mm^3 (100 * 10^9&#x2F;L).</li><li>Normal mammogram within 12 months prior to study entry</li><li>Female: A female is eligible to enter and participate in the study if she is of: a. Non-childbearing potential (i.e., women with functioning ovaries who have a current documented tubal ligation or hysterectomy, or women who are post-menopausal); or b.
Childbearing potential (i.e., women with functioning ovaries and no documented impairment of oviductal or uterine function that would cause sterility.
This category includes women with oligomenorrhoea (severe), women who are perimenopausal, and young women who have begun to menstruate), has a negative serum pregnancy test at screening, and agrees to one of the following where considered acceptable to the local IRB&#x2F;IEC: • Double-barrier contraception (condom with spermicidal jelly, foam suppository, or film; diaphragm with spermicide; or male condom and diaphragm).
• Abstinence from sexual intercourse from 2 weeks prior to administration of the investigational product, throughout the active study treatment period.</li><li>(Continued from above) • Male partner who is sterile prior to the female subject&#x27;s entry into the study and is the sole sexual partner for that female subject.
• Any intrauterine device (IUD).
• Barrier methods including diaphragm or condom with a spermicide.</li><li>Able to swallow and retain oral medication.</li><li>ECOG (Eastern Cooperative Oncology Group) performance status 0 to 2.</li><li>Serum creatinine &lt; 1.4 mg&#x2F;dL or calculated creatinine clearance (CrCl) &gt;&#x2F;= 60 mL&#x2F;min ( within last 3 months)</li><li>Aspartate and alanine transaminase (AST or ALT) &lt;&#x2F;= 3 times the upper limit of the reference range (within last 3 months).</li><li>Has a left ventricular ejection fraction (LVEF) &gt;&#x2F;= 50%, or &gt;&#x2F;= lower limit of normal for the institution, based on echocardiogram (ECHO) or multi-gated angiogram (MUGA) (within last 3 months).</li><li>Normal Hgb A1c</li><li>Total bilirubin &lt;&#x2F;= 3.0 mg&#x2F;dL (within last 3 months)</li></ol><p>Exclusion Criteria:</p><ol><li>Heart failure defined as New York Heart Association (NYHA) class III or IV functional status</li><li>Has evidence of recurrent or metastatic (Stage IV) breast cancer.</li><li>Is a pregnant or lactating female.</li><li>Has a known immediate or delayed hypersensitivity reaction or idiosyncrasy to Metformin</li><li>Has received treatment with any investigational drug in the previous 4 weeks.</li><li>Has received chemotherapy, immunotherapy, biologic therapy or endocrine therapy within the past 12 weeks.</li><li>Contraindication to random periareolar fine needle aspiration (RPFNA) including breast implant(s), bilateral radiation, anticoagulation.</li><li>Unwillingness to undergo RPFNA.</li><li>RPFNA that does not demonstrate atypia.</li><li>Is considered medically unfit for the study by the investigator as a result of the medical interview, physical exam, or screening investigations.</li><li>Is currently receiving oral steroid treatment (inhaled steroids are permitted)</li><li>Oral estrogen, progesterone, testosteron therapy within last 3 months.</li><li>Excessive alcohol intake as determined by the treating physician</li><li>Known vitamin B12 deficiency</li><li>Concomitant medications including metformin, sulfonylurea, thiazolidinedione, insulin</li></ol>

<p>Inclusion Criteria:</p><ol><li>Histological confirmation of ER negative breast carcinoma, stage I, II, or III</li><li>Completed all adjuvant therapy including (if indicated) endocrine, trastuzumab, radiation therapy</li><li>At least 18 years of age.</li><li>Provided written informed consent.</li><li>Adequate bone marrow function: Hemoglobin &gt;&#x2F;= 9 gm&#x2F;dL.
• Absolute granulocyte count &gt;&#x2F;= 1,500&#x2F;mm^3 (1.5 x 10^9&#x2F;L).
• Platelets &gt;&#x2F;= 75,000&#x2F;mm^3 (100 x 10^9&#x2F;L).</li><li>Normal mammogram of unaffected breast within 12 months prior to study entry.</li><li>Female: A female is eligible to enter and participate in the study if she is of: a. Non-childbearing potential (i.e., women with functioning ovaries who have a current documented tubal ligation or hysterectomy, or women who are post-menopausal); or b.
Childbearing potential (i.e., women with functioning ovaries and no documented impairment of oviductal or uterine function that would cause sterility.
This category includes women with oligomenorrhoea (severe), women who are perimenopausal, and young women who have begun to menstruate), has a negative serum pregnancy test at screening, and agrees to one of the following where considered acceptable to the local IRB&#x2F;IEC: • Double-barrier contraception (condom with spermicidal jelly, foam suppository, or film; diaphragm with spermicide; or male condom and diaphragm).
• Abstinence from sexual intercourse from 2 weeks prior to administration of the investigational product, throughout the active study treatment period.</li><li>(Continued from above) • Male partner who is sterile prior to the female subject&#x27;s entry into the study and is the sole sexual partner for that female subject.
• Any intrauterine device (IUD).
• Barrier methods including diaphragm or condom with a spermicide.</li><li>Able to swallow and retain oral medication.</li><li>ECOG (Eastern Cooperative Oncology Group) performance status 0 to 2.</li><li>Serum creatinine &lt; 1.4 mg&#x2F;dL or calculated creatinine clearance (CrCl) &gt;&#x2F;= 60 mL&#x2F;min</li><li>Aspartate and alanine transaminase (AST or ALT) &lt;&#x2F;= 2 times the upper limit of the reference range.</li><li>Patients must have a baseline ECG with QTc within the normal range within 28 days prior to registration.</li><li>Total bilirubin &lt;&#x2F;= 1.5 times the upper limit of the reference range</li></ol><p>Exclusion Criteria:</p><ol><li>Uncontrolled angina, congestive heart failure, MI (within last 6 months), congenital long QT syndrome, history of clinically significant ventricular arrhythmia, prolonged QTc interval on pre-entry EKG (greater than normal range)</li><li>Has evidence of recurrent or metastatic (Stage IV) breast cancer.</li><li>Is a pregnant or lactating female.</li><li>Has a known immediate or delayed hypersensitivity reaction or idiosyncrasy to dasatinib</li><li>Has received treatment with any investigational drug in the previous 4 weeks.</li><li>Has received chemotherapy, immunotherapy, biologic therapy or endocrine therapy within the past 12 weeks.</li><li>Contraindication to RPFNA including breast implant(s), bilateral radiation, anticoagulation.</li><li>Unwillingness to undergo RPFNA.</li><li>Is considered medically unfit for the study by the investigator as a result of the medical interview, physical exam, or screening investigations.</li><li>Is currently receiving oral steroid treatment (inhaled steroids are permitted)</li><li>Oral estrogen, progesterone, testosterone therapy within last 3 months.</li><li>Concurrent medical condition that would increase drug toxicity: Pleural or pericardial effusion, coagulation or platelet function disorder, ongoing or recent (less than 3 months gastrointestinal bleeding)</li><li>Hypokalemia or hypomagnesemia if it cannot be corrected</li><li>Concomitant Medications, consider the following prohibitions (Drugs must be discontinued for 7 days prior to starting protocol therapy): Drugs that are generally accepted to have a risk of causing Torsades de Pointes including : quinidine, procainamide, disopyramide, amiodarone, sotalol, ibutilide, dofetilide erythromycins, clarithromycin, chlorpromazine, haloperidol, mesoridazine, thioridazine, pimozide, cisapride, bepridil, droperidol, methadone, arsenic, chloroquine, domperidone, halofantrine, levomethadyl, pentamidine, sparfloxacin, lidoflazine.
The concomitant use of H2 blockers or proton pump inhibitors with dasatinib is not recommended.
The use of antacids should be considered in place of H2 blockers or proton pump inhibitors in patients receiving dasatinib therapy.
Patient agrees to discontinue St. Johns Wort while receiving dasatinib therapy</li><li>Patient may not be receiving any prohibited CYP3A4 inhibitors</li></ol>

2013-01

2013-05

2017-01

2017-05

2012-09

2013-01

2012-09-05

2013-01-25

2012-09-06

2013-01-28

<p>The goal of this clinical research study is to learn if metformin can help prevent breast cancer from developing in the unaffected breast.</p><p>Metformin was designed to treat patients with diabetes.
It may be able to block mammalian target of rapamycin (mTOR) and slow the start and growth of tumors.</p>

<p>The goal of this clinical research study is to learn if dasatinib can help prevent breast cancer from developing in the unaffected breast.</p><p>Dasatinib is designed to decrease the activity of one or more proteins that are responsible for the uncontrolled growth of tumor cells.</p>

<p>Study Drug Administration:</p><p>If you are found to be eligible to take part in this study, you will be randomly assigned (as in the flip of a coin) to 1 of 2 study groups:</p><ul><li>If you are in Group 1, you will take metformin 2 times a day by mouth with water.</li><li>If you are in Group 2, you will not receive metformin.</li></ul><p>You will be given a study drug diary to complete.
In the diary, you will record when you take the study drug.</p><p>Study Visits:</p><p>At Months 2, 4, and 5, you will be called by a nurse and asked about any drugs you are taking and side effects you may be having.
You will also be asked to review your drug diary.
This call will take about 20 minutes</p><p>At Month 3:</p><ul><li>Blood (about 2 tablespoons) will be drawn for routine tests.</li><li>You will be asked about any drugs you may be taking and side effects you may be having.</li><li>Your drug diary will be reviewed.</li></ul><p>At Month 6 (or if you leave the study early):</p><ul><li>You will have a fine needle aspirate (FNA) of the breast for biomarker testing.
Biomarkers are found in the blood&#x2F;tissue and may be related to your reaction to the study drug.</li><li>Blood (about 2-3 tablespoons) will be drawn for biomarker testing.</li><li>You will be asked about any drugs you may be taking and side effects you may be having.</li><li>Your drug diary will be reviewed.</li></ul><p>Length of Study:</p><p>You may remain on study for up to 6 months.
You will no longer be able to take the study drug if the disease gets worse, if intolerable side effects occur, or if you are unable to follow study directions.</p><p>This is an investigational study.
Metformin is FDA approved and commercially available for diabetes control.
Its use in breast cancer patients in investigational.</p><p>Up to 100 patients will take part in this multicenter study.
Up to 75 will be enrolled at MD Anderson.</p>

<p>Study Drug Administration:</p><p>If you are found to be eligible to take part in this study, you will be randomly assigned (as in the flip of a coin) to 1 of 3 study groups:</p><ul><li>If you are in Group 1, you will take dasatinib 40mg once a day by mouth with water.</li><li>If you are in Group 2, you will take dasatinib 80mg once a day by mouth with water.</li><li>If you are in Group 3, you will not receive dasatinib.</li></ul><p>You will be given a study drug diary to complete.
In the diary, you will record when you take the study drug.</p><p>Study Visits:</p><p>At Month 1:</p><ul><li>Blood (about 2 tablespoons) will be drawn for routine tests.</li><li>You will be asked about any drugs you may be taking and side effects you may be having.</li><li>Your drug diary will be reviewed.</li><li>At Month 2 you will be called by a nurse and asked about any drugs you are taking and side effects you may be having.
You will also be asked to review your drug diary.
This call will take about 20 minutes</li></ul><p>At Month 3 (or if you leave the study early):</p><ul><li>You will have a fine needle aspirate (FNA) of the breast for biomarker testing.
Biomarkers are found in the blood&#x2F;tissue and may be related to your reaction to the study drug.</li><li>Blood (about 2-3 tablespoons) will be drawn for biomarker testing.</li><li>You will be asked about any drugs you may be taking and side effects you may be having.</li><li>Your drug diary will be reviewed.</li></ul><p>Length of Study:</p><p>You may remain on study for up to 3 months.
You will no longer be able to take the study drug if the disease gets worse, if intolerable side effects occur, or if you are unable to follow study directions.</p><p>This is an investigational study.
Dasatinib is FDA approved and commercially available for the treatment of leukemia.
Its use in breast cancer patients in investigational.</p><p>Up to 66 patients will take part in this multicenter study.
Up to 60 will be enrolled at MD Anderson.</p>

Mammalian target of rapamycin

Biomarker studies

mTOR

Ki-67

Metformin

Dasatinib

Placebo

BMS-354825

Sugar pill

Sprycel