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

This study has been completed.
Sponsor:
Collaborators:
Baylor College of Medicine
Ohio State University
Dana-Farber Cancer Institute
Weill Medical College of Cornell University
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
Ann Schott, MD, University of Michigan Cancer Center
ClinicalTrials.gov Identifier:
NCT00645333
First received: March 24, 2008
Last updated: February 24, 2014
Last verified: February 2014
  Purpose

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.


Condition Intervention Phase
Metastatic Breast Cancer
Drug: MK-0752, Docetaxel, Pegfilgrastim
Phase 1
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase I/II Trial of MK-0752 Followed by Docetaxel in Locally Advanced or Metastatic Breast Cancer: A Study by the Stem Cell Clinical Consortium

Resource links provided by NLM:


Further study details as provided by University of Michigan Cancer Center:

Primary Outcome Measures:
  • 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.


Enrollment: 30
Study Start Date: March 2008
Study Completion Date: October 2012
Primary Completion Date: January 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: MK-0752, Docetaxel, Pegfilgrastim
MK-0752, Docetaxel, Pegfilgrastim in combination with escalating doses of MK-0752
Drug: MK-0752, Docetaxel, Pegfilgrastim
MK-0752 in escalating doses of 300, 450, 600, and 800 mg given orally on days 1-3, followed by docetaxel 80 mg/m2 day 8 and pegfilgrastim 6 mg SQ on day 9
Other Names:
  • Taxotere
  • Neulasta

Detailed Description:

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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)
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00645333

Locations
United States, Massachusetts
Dana Farber Cancer Institute
Boston, Massachusetts, United States, 02115
United States, Michigan
University of Michigan Cancer Center
Ann Arbor, Michigan, United States, 48109
United States, Texas
Baylor College of Medicine
Houston, Texas, United States, 77030
Sponsors and Collaborators
University of Michigan Cancer Center
Baylor College of Medicine
Ohio State University
Dana-Farber Cancer Institute
Weill Medical College of Cornell University
Merck Sharp & Dohme Corp.
Investigators
Principal Investigator: Anne Schott, MD The University of Michigan Comprehensive Cancer Center
  More Information

Publications:
Responsible Party: Ann Schott, MD, Principal Investigator, University of Michigan Cancer Center
ClinicalTrials.gov Identifier: NCT00645333     History of Changes
Other Study ID Numbers: UMCC 2006.119
Study First Received: March 24, 2008
Results First Received: August 9, 2013
Last Updated: February 24, 2014
Health Authority: United States: Institutional Review Board
United States: Food and Drug Administration

Keywords provided by University of Michigan Cancer Center:
breast cancer
Phase I clinical trial
cancer stem cells
agents with other mechanisms of action
Notch inhibitors

Additional relevant MeSH terms:
Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Docetaxel
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on August 20, 2014