UMCC 9901: Phase II Study of Tailored-Dose Docetaxel + Trastuzumab in Her-2 Positive Metastatic Breast Cancer
UMCC 9901: Phase II Study of Tailored-Dose Docetaxel + Trastuzumab in Her-2 Positive Metastatic Breast Cancer
This is a research study which aims to improve the way that doctors determine the dose of
 chemotherapy given to patients. Right now, chemotherapy is determined by a patient's height
 and weight. However, some patients metabolize chemotherapy faster or slower than the average
 person because of a different level of drug metabolizing enzyme in the liver. Therefore, some
 patients are either given too small or too large a dose of chemotherapy because the amount of
 enzyme is not taken into account. This research study will examine the use of a simple test,
 call the Erythromycin Breath Test(ERMBT) to determine the amount of enzyme which can
 metabolize the chemotherapy drug docetaxel (Taxotere). The dose of docetaxel will be tailored
 to the amount of enzyme which is available to metabolize the drug for each patient. The drug,
 docetaxel, is combined with another drug, trastuzumab (Herceptin), because at this time this
 combination appears to be promising in metastatic breast cancer research.
This is a research study which aims to improve the way that doctors determine the dose of
 chemotherapy given to patients. Right now, chemotherapy is determined by a patient's height
 and weight. However, some patients metabolize chemotherapy faster or slower than the average
 person because of a different level of drug metabolizing enzyme in the liver. Therefore, some
 patients are either given too small or too large a dose of chemotherapy because the amount of
 enzyme is not taken into account. This research study will examine the use of a simple test,
 call the Erythromycin Breath Test(ERMBT) to determine the amount of enzyme which can
 metabolize the chemotherapy drug docetaxel (Taxotere). The dose of docetaxel will be tailored
 to the amount of enzyme which is available to metabolize the drug for each patient. The drug,
 docetaxel, is combined with another drug, trastuzumab (Herceptin), because at this time this
 combination appears to be promising in metastatic breast cancer research.-Patients
 participating in this study will have biopsy proven, measurable metastatic breast cancer.

 During the study:

 -  Patients will receive tailored-dose docetaxel and Trastuzumab for their breast cancer.

 -  There are no sex or age restrictions although the patients in this disease category are
 reflective of an adult female population.

 Approximately 30 subjects will be recruited at this site.

 Diagnosis and Staging • All patients will have primary tumor measurements by physical exam
 and/or radiographic studies (CT, MRI, bone scan).

 Erythromycin Breath Test*

 • The ERMBT will be administered in the outpatient setting, prior to the first cycle of
 docetaxel. Twenty minutes after the injection of a trace amount of (14C N-methyl)
 erythromycin, (This test assesses the activity of the cytochrome P450 enzyme which is largely
 responsible for the metabolism of the chemotherapeutic agent docetaxel.)patients will exhale
 through a tube creating bubbles in a solution of hyamine hydroxide, ethanol, and a blue
 indicator until 2 mmol of carbon dioxide has been trapped and the blue color vanishes.

 Chemotherapy Regimen

 Premedications

 -  Dexamethasone 8 mg po bid for three days, beginning the day prior to docetaxel
 administration.

 -  Diphenhydramine 50 mg IVPB

 -  Granisetron 2 mg po 30 minutes pre-docetaxel

 Chemotherapy

 -  Docetaxel, tailored dose, to be infused over 1 hour on day 1 every 3 weeks for the
 duration of study.

 -  Starting dose of docetaxel to be determined by the ERMBT and serum albumin according to
 formula as stated in protocol (page 11).

 -  Trastuzumab, 4 mg/kg to be infused over 90 minutes on day 2 (after pharmacokinetic
 sampling).

 -  Beginning week 2, trastuzumab will be given at a dose of 2 mg/kg weekly throughout
 duration of study. (After the first dose of docetaxel, future doses may be given on the
 same day as docetaxel).

 Suggested post-chemotherapy antiemetics:

 -  Compazine 10 mg po q 6 hours prn nausea/vomiting Pharmacokinetic Analysis

 -  All patients will have pharmacokinetic determination with blood drawn for
 pharmacokinetic analysis over a 24 hour period after the first docetaxel treatment. Time
 points include time 0, 15 minutes, 45 minutes, 180 minutes (3 hours), 390 minutes (6.5
 hours), and 1440 minutes (24 hours).

 DEXA Scan*

 -  DEXA scan will be performed during the patient's stay in the Clinical Research Center,
 on the Lunar DPXL Bone Densitometer. This is a very simple and noninvasive test which
 uses x-rays and a computer program to analyze the ratio of 38 keV to 70 keV attenuation.
 The program then calculates Fat and Lean values for the arms, legs, abdomen, ribs, and
 the total body. This is the same test that is in widespread clinical use for the
 evaluation of osteoporosis. During the DEXA scan, patients will be exposed to a trace
 amount of radiation which is equal to about 2% of the yearly background dose, or less.

 *The amount of radiation to be administered by the erythromycin breath test and DEXA
 scan is not medically significant.

 -  Patients will receive 2 cycles of docetaxel/trastuzumab and be re-evaluated for response
 (ever 6 weeks, or later if dosage delays caused lengthening of cycle).

 -  Responding and stable patients will continue to receive docetaxel therapy, with
 evaluations every 2 cycles (every 6 weeks, or later if dosage delays caused lengthening
 of cycle).

 -  Continued treatment beyond 8 cycles will be at the discretion of the patient's primary
 oncologist.
Inclusion Criteria:

 -  Patients with biopsy proven, measurable metastatic breast cancer. Patients with
 bone-only, and/or effusion-only disease are excluded.

 -  HER-2 neu positive by standard immunohistochemical criteria (2+ positivity).

 -  No prior chemotherapy for distant metastatic disease.

 -  Prior paclitaxel in the adjuvant setting is allowed.

 -  Karnofsky performance status equal to 70 or greater.

 -  ANC > 1500, Hgb > 10, plt > 100.

 -  Patients with some degree of hepatic dysfunction and renal dysfunction are encouraged,
 in order to evaluate the ability of the ERMBT in tailoring dose in these patient
 populations.

 Exclusion Criteria:

 -  Age less than 18 years.

 -  Allergy to erythromycin.

 -  Previous treatment with docetaxel. Prior paclitaxel is allowed.

 -  Grade > 2 peripheral neuropathy.

 -  No confounding factors present to provide misinterpretation of data (i.e., concurrent
 malignancy).

 -  Patients who are pregnant or nursing will not be eligible for this protocol. Women of
 childbearing age who are not practicing reliable birth control must have a documented
 negative serum HCG.

 -  Patients who require concurrent treatment with drugs which are known to induce or
 inhibit CYP3A activity will be ineligible for the trial. This list includes the drugs
 midazolam, anti-mycotic agents (ketoconazole and related compounds), macrolide
 antibiotics (erythromycin and related compounds), nifedipine, anti-seizure drugs, and
 rifampin (induction).