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

Tracking Information
First Submitted Date ICMJE	March 24, 2008
First Posted Date ICMJE	March 27, 2008
Results First Submitted Date	August 9, 2013
Results First Posted Date	April 4, 2014
Last Update Posted Date	April 4, 2014
Study Start Date ICMJE	March 2008
Actual Primary Completion Date	January 2010 (Final data collection date for primary outcome measure)
Current Primary Outcome Measures ICMJE; (submitted: February 24, 2014)	Dose Limiting Toxicity (DLT) [ Time Frame: first 21 days ]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: Non-hematologic toxicity Grade ≥3 by the NCI CTCAE version 3.0. ANC<1000 for more than 7 days despite use of pegfilgrastim. 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 ]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.
Original Primary Outcome Measures ICMJE; (submitted: March 26, 2008)	Dose Limiting Toxicity (DLT) [ Time Frame: first 21 days ]
Change History	Complete list of historical versions of study NCT00645333 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures ICMJE	Not Provided
Original Secondary Outcome Measures ICMJE; (submitted: March 26, 2008)	measurability of lesions, objective status at each evaluation,best response, performance status, CTC response [ Time Frame: course of study ]
Current Other Outcome Measures ICMJE	Not Provided
Original Other Outcome Measures ICMJE	Not Provided
Descriptive Information
Brief Title ICMJE	Phase I/II Study of MK-0752 Followed by Docetaxel in Advanced or Metastatic Breast Cancer
Official Title ICMJE	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
Brief Summary	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.
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.
Study Type ICMJE	Interventional
Study Phase	Phase 1; Phase 2
Study Design ICMJE	Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
Condition ICMJE	Metastatic Breast Cancer
Intervention ICMJE	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
Study Arms	Experimental: MK-0752, Docetaxel, Pegfilgrastim; MK-0752, Docetaxel, Pegfilgrastim in combination with escalating doses of MK-0752; Intervention: Drug: MK-0752, Docetaxel, Pegfilgrastim
Publications *	Schott AF, Landis MD, Dontu G, Griffith KA, Layman RM, Krop I, Paskett LA, Wong H, Dobrolecki LE, Lewis MT, Froehlich AM, Paranilam J, Hayes DF, Wicha MS, Chang JC. Preclinical and clinical studies of gamma secretase inhibitors with docetaxel on human breast tumors. Clin Cancer Res. 2013 Mar 15;19(6):1512-24. doi: 10.1158/1078-0432.CCR-11-3326. Epub 2013 Jan 22.
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status ICMJE	Completed
Actual Enrollment ICMJE; (submitted: March 26, 2008)	30
Original Estimated Enrollment ICMJE	Same as current
Actual Study Completion Date	October 2012
Actual Primary Completion Date	January 2010 (Final data collection date for primary outcome measure)
Eligibility Criteria ICMJE	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)
Sex/Gender	Sexes Eligible for Study: All
Ages	18 Years and older (Adult, Senior)
Accepts Healthy Volunteers	No
Contacts ICMJE	Contact information is only displayed when the study is recruiting subjects
Listed Location Countries ICMJE	United States
Removed Location Countries
Administrative Information
NCT Number ICMJE	NCT00645333
Other Study ID Numbers ICMJE	UMCC 2006.119
Has Data Monitoring Committee	Yes
U.S. FDA-regulated Product	Not Provided
IPD Sharing Statement	Not Provided
Responsible Party	Ann Schott, MD, University of Michigan Cancer Center
Study Sponsor ICMJE	University of Michigan Cancer Center
Collaborators ICMJE	Baylor College of Medicine; Ohio State University; Dana-Farber Cancer Institute; Weill Medical College of Cornell University; Merck Sharp & Dohme Corp.
Investigators ICMJE	Principal Investigator: Anne Schott, MD The University of Michigan Comprehensive Cancer Center
PRS Account	University of Michigan Cancer Center
Verification Date	February 2014
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP