MK2206 in Treating Patients With Stage I, Stage II, or Stage III Breast Cancer
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Purpose
This phase II trial is studying how well MK2206 works in treating patients with stage I, stage II, or stage III breast cancer. MK2206 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth
| Condition | Intervention | Phase |
|---|---|---|
|
Estrogen Receptor-negative Breast Cancer Estrogen Receptor-positive Breast Cancer HER2-negative Breast Cancer HER2-positive Breast Cancer Progesterone Receptor-negative Breast Cancer Progesterone Receptor-positive Breast Cancer Stage IB Breast Cancer Stage II Breast Cancer Stage IIIA Breast Cancer Stage IIIB Breast Cancer Stage IIIC Breast Cancer Triple-negative Breast Cancer |
Drug: Akt inhibitor MK2206 Procedure: therapeutic conventional surgery Genetic: microarray analysis Genetic: mutation analysis Genetic: western blotting Other: immunohistochemistry staining method Other: diagnostic laboratory biomarker analysis Other: pharmacological study Procedure: neoadjuvant therapy |
Phase 2 |
| Study Type: | Interventional |
| Study Design: | Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Treatment |
| Official Title: | Pre-surgical Evaluation of MK-2206 in Patients With Operable Invasive Breast Cancer |
- Change in phospho-Akt (Ser473) levels [ Time Frame: Baseline and day 0 ] [ Designated as safety issue: No ]A Wilcoxon signed-rank matched-pairs test will be used to compare expression levels in paired pre- and post-MK-2206 tissue.
- PI3K/AKT expression [ Time Frame: Up to 4 weeks ] [ Designated as safety issue: No ]The Spearman rank correlation coefficient will be used to analyze any relationship between the expression levels of different biomarkers. The Wilcoxon signed-rank (matched-pairs) test will be used to compare expression levels between matched pre-and post-treatment samples. All p-values will be two-sided with statistical significance evaluated at the 0.05 alpha level. Ninety-five percent confidence intervals will be calculated to assess the precision of the obtained estimates. All analyses will be performed in SAS version 9.2 and STATA version 9.0.
- KI-67 expression [ Time Frame: Up to 4 weeks ] [ Designated as safety issue: No ]The Spearman rank correlation coefficient will be used to analyze any relationship between the expression levels of different biomarkers. The Wilcoxon signed-rank (matched-pairs) test will be used to compare expression levels between matched pre-and post-treatment samples. All p-values will be two-sided with statistical significance evaluated at the 0.05 alpha level. Ninety-five percent confidence intervals will be calculated to assess the precision of the obtained estimates. All analyses will be performed in SAS version 9.2 and STATA version 9.0.
- Toxicity assessed using NCI CTCAE version 4.0 [ Time Frame: Up to 4 weeks ] [ Designated as safety issue: Yes ]
- Biologic response to treatment [ Time Frame: Up to 4 weeks ] [ Designated as safety issue: No ]
| Estimated Enrollment: | 30 |
| Study Start Date: | April 2011 |
| Estimated Primary Completion Date: | April 2014 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
|
Experimental: Arm I
Patients receive Akt inhibitor MK2206 orally on days -9 and -2, and undergo segmental resection or total mastectomy on day 0.
|
Drug: Akt inhibitor MK2206
Other Name: MK2206
Procedure: therapeutic conventional surgery
Genetic: microarray analysis
Other Name: gene expression profiling
Genetic: mutation analysis
Genetic: western blotting
Other Names:
Other: immunohistochemistry staining method
Other Name: immunohistochemistry
Other: diagnostic laboratory biomarker analysis
Other: pharmacological study
Other Name: pharmacological studies
Procedure: neoadjuvant therapy
|
Detailed Description:
PRIMARY OBJECTIVES:
I. Assess for a decrease in phospho-Akt (Ser^473) levels in tissue after a pre-surgical trial of weekly Akt inhibitor MK2206 (MK2206) (2 doses) in patients with operable invasive breast cancer.
SECONDARY OBJECTIVES:
I. Evaluate the effects of MK2206 on the immunohistochemical expression of other PI3K/AKT pathway biomarkers on pre-and post-MK2206 tumor tissue, such as phospho-S6 kinase.
II. Assess modulation of PI3K/AKT signaling following MK2206 use with reverse-phase protein microarray analysis.
III. Explore whether PIK3CA mutations demonstrate different modulation of PI3K/Akt-pathway signaling as compared to tumors with loss of PTEN.
IV. Explore whether MK2206 alters PI3K/Akt pathway signaling differently in hormone receptor-positive/HER2-negative tumors, as compared to triple-negative or HER2-positive breast cancers.
V. Evaluate whether tumor proliferation, as measured by Ki-67 staining of breast tumor cells, is reduced in patients taking MK2206 pre-surgically and correlate Ki-67 modulation with changes in PI3K/AKT signaling.
VI. Determine safety and tolerability of MK2206 in patients with early-stage breast cancer.
VII. Collect fasting blood for evaluation of predictive markers of drug effect, such as markers in the insulin growth-factor receptor pathway (i.e., fasting insulin, c-peptide, IGF-1, and IGFBP-1 and 3), as well as modulation of phospho-markers in peripheral blood mononuclear cells.
OUTLINE: This is a multicenter study.
Patients receive Akt inhibitor MK2206 orally on days -9 and -2, and undergo segmental resection or total mastectomy on day 0.
Blood is collected at baseline and before surgery for fasting insulin, c-peptide, IGF-1, IGFBP-1 and 3, pharmacokinetics, and the pharmacodynamic effects of MK2206 on peripheral blood mononuclear cells by western blotting and reverse-phase protein microarray (RPPA). Tumor tissue samples are also collected at baseline and during surgery for PI3K/AKT pathway and Ki-67 modulation by IHC and RPPA analysis.
After completion of therapy, patients are followed up for 4 weeks.
Eligibility| Ages Eligible for Study: | 18 Years and older |
| Genders Eligible for Study: | Female |
| Accepts Healthy Volunteers: | No |
Inclusion Criteria:
- Patients must have histologically confirmed operable, invasive adenocarcinoma of the breast and haveundergone core-needle biopsy with an anticipated surgical resection for residual diseaseafter enrollment
- Clinical stage IB-IIIC invasive breast (invasive tumor must be ≥ T1c by radiograph or palpation)
Patients must have available tissue from core biopsies for biomarker assessment
- It is recommended that at least 4 cores be performed with 12-gauge (or smaller gauge) needles, including cores underneath ultrasound-guidance
- Patients planning to undergo surgical treatment with either segmental resection or total mastectomy required
- Patients may have a history of contralateral breast cancer, provided there is no evidenceof recurrence of the initial primary breast cancer
- Patients must agree to biomarker assessment of pre-treatment diagnostic corebiopsy tissue and the surgical resection tissue (i.e., excision or mastectomy) and also agree to pre- and post-treatment fasting blood biomarker collection
- Patients may not have any known evidence of distant metastatic disease (i.e., lung, liver,bone, or brain metastases) or locally recurrent breast cancer
- No inflammatory breast cancer
- Estrogen receptor, progesterone receptor, and HER2 positive or negative
- ECOG performance status (PS) 0-1 (Karnofsky PS 80-100%)
- Menopausal status not specified
- WBC ≥ 3,000/μL
- Platelet count ≥ 100,000/μL
- Hemoglobin ≥ 9 g/dL
- Creatinine ≤ 1.5 times upper limit of normal (ULN)
- PT, PTT ≤ 1.2 times ULN
- Total bilirubin ≤ 1.5 times ULN
- ALT and AST < 2.5 times ULN
- Negative pregnancy test
- Women of childbearing potential must use two forms of contraception (hormonal, barrier method of birth control, or abstinence) prior to study entry and for the duration of study participation
- Not pregnant or nursing
- Patient must be able to swallow oral tablets
- No history of allergic reactions attributed to compounds of similarchemical or biologic composition to Akt inhibitor MK2206 used in the study
- No known diabetes that ispoorly controlled (HBA1C ≥ 8%)
- No baseline QTc > 470 msec
- No baseline bundle branch block
- No uncontrolled intercurrent illness including, but not limited to, ongoing or active infection,symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
- No concurrent combination antiretroviral therapy for HIV-positive patients
- More than 6 months since prior chemotherapy or radiotherapy
- Concurrent metformin allowed provided patient has been taking it for > 3 months
- No prior neoadjuvant therapy
- No other concurrent investigational agents, including other inhibitors of PI3K, Akt, or mTOR
Contacts and Locations| United States, New York | |
| Montefiore Medical Center | Recruiting |
| Bronx, New York, United States, 10467-2490 | |
| Contact: Joseph A. Sparano 718-904-2555 jsparano@montefiore.org | |
| Principal Investigator: Kevin M. Kalinsky | |
| Principal Investigator: | Kevin Kalinsky | Albert Einstein College of Medicine of Yeshiva University |
More Information
No publications provided
| Responsible Party: | National Cancer Institute (NCI) |
| ClinicalTrials.gov Identifier: | NCT01319539 History of Changes |
| Other Study ID Numbers: | NCI-2011-02513, AECM-AAAF3912, N01CM62204, CDR0000696821 |
| Study First Received: | March 18, 2011 |
| Last Updated: | December 4, 2012 |
| Health Authority: | United States: Food and Drug Administration |
Additional relevant MeSH terms:
|
Breast Neoplasms Neoplasms by Site Neoplasms Breast Diseases Skin Diseases |
ClinicalTrials.gov processed this record on May 22, 2013