Phase I/II Study of MK-0752 Followed by Docetaxel in Advanced or Metastatic Breast Cancer

• Dose Limiting Toxicity (DLT) [ Time Frame: first 21 days ] [ Designated as safety issue: Yes ]

  The number of DLTs experienced by participants within the first 21 days.

  DLTs were defined as toxicities possibly, probably, or definitely related to the study drug observed during the first 2 cycles (first 42 days) as follows:

  1. Non-hematologic toxicity Grade ≥3 by the NCI CTCAE version 3.0.
  2. ANC<1000 for more than 7 days despite use of pegfilgrastim.
  3. Platelet count <25,000 for more than 7 days, or associated with bleeding, or less than 10,000 at any time.
• Maximum Tolerated Dose (MTD) [ Time Frame: Up to 3 years ] [ Designated as safety issue: Yes ]
  The Maximum Tolerated Dose (MTD) for MK-0752 will be determined. Dose levels were: Level 1: 300 mg MK-0752 by mouth days 1-3; Level 2: 450 mg MK-0752 by mouth days 1-3; Level 3: 600 mg MK-0752 by mouth days 1-3; Level 4: 800 mg MK-0752 by mouth days 1-3.

New and better therapies for locally advanced and metastatic breast cancer are needed because, even if standard treatment is successful in shrinking the cancer, there is still a high chance that the cancer will recur. Recent research suggests that breast tumors have a small number of cells in them that are "breast cancer stem cells", which are very resistant to standard treatment. It is thought that the reason that many patients cannot be cured of their breast cancers is that the stem cells are unable to be killed and remain in the body after standard treatment. Laboratory research has shown that a new drug, MK-0752, can target stem cells and prevent tumor recurrences when the drug is combined with docetaxel, a chemotherapy drug commonly used to treat breast cancer.

We know that MK-0752 is safe when given by itself to people. We do not know if treatment with MK-0752 and docetaxel combined is safe or if it will kill "breast cancer stem cells" in people with breast cancer. This clinical trial is being done to determine the safety of several doses of MK-0752 in combination with docetaxel. Preliminary data about the effectiveness of MK-0752 in combination with docetaxel will be collected. Also, tumor biopsy samples will be taken from some patients who have tumors that can be easily biopsied. The samples will be used to perform research tests to help determine if the "breast cancer stem cells" are being killed by the drug combination.

Purpose—Accumulating evidence supports the existence of breast cancer stem cells (BCSCs), which are characterized by their capacity to self-renew and divide indefinitely, and resistance to conventional therapies. The Notch pathway is important for stem cell renewal, and is a potential target for BCSC-directed therapy. Experimental Design—Using human breast tumorgraft studies, we evaluated the impact of gamma secretase inhibitors (GSI) on the BCSC population and the efficacy of combining GSI with docetaxel treatment. The mouse experimental therapy paralleled a concurrent clinical trial in advanced breast cancer patients, designed to determine the maximally tolerated dose of the GSI, MK-0752, administered sequentially with docetaxel, and to evaluate BCSC markers in serial tumor biopsies.

Inclusion Criteria:

• Men or women with metastatic (Stage IV) breast cancer, or with locally advanced breast cancer (Stages IIIA > 10 cm, or Stages IIIB and IIIC) that did not respond to first-line anthracycline-based chemotherapy, for whom docetaxel is a recommended therapy
• Presence of measurable or evaluable disease
• Adequate organ function
• Ability to swallow intact study drug capsules
• Zubrod Performance Status of 0-1 with at least a 3 month life expectancy
• Appropriate time must have elapsed since prior anti-neoplastic therapy with resolution of acute toxicity

Exclusion Criteria:

• Concurrent treatment with hormonal therapy intended to treat cancer
• Radiotherapy within 7 days prior to first dose
• Symptomatic central nervous system, and/or epidural metastases or symptomatic carcinomatous meningitis or with radiation treatment completed within the past 8 weeks
• Serious comorbid illness which will limit the ability of the patient to safely receive anticancer treatment
• Patients who are pregnant or nursing
• Confounding factors present to provide misinterpretation of data (i.e., concurrent malignancy)

• Baylor College of Medicine
• Ohio State University
• Dana-Farber Cancer Institute
• Weill Medical College of Cornell University
• Merck Sharp & Dohme Corp.