Akt Inhibitor MK-2206 and Anastrozole With or Without Goserelin Acetate in Treating Patients With Stage II-III Breast Cancer

This study is currently recruiting participants. (see Contacts and Locations)
Verified August 2014 by National Cancer Institute (NCI)
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT01776008
First received: January 23, 2013
Last updated: September 16, 2014
Last verified: August 2014
  Purpose

This phase II trial studies how well Akt inhibitor MK-2206 (MK-2206) and anastrozole with or without goserelin acetate works in treating patients with stage II-III breast cancer. MK-2206 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Estrogen can cause the growth of breast cancer cells. Hormone therapy using anastrozole and goserelin acetate may fight breast cancer by blocking the use of estrogen by the tumor cells. Giving MK-2206, anastrozole, and goserelin acetate together may kill more tumor cells.


Condition Intervention Phase
Estrogen Receptor-positive Breast Cancer
HER2-negative Breast Cancer
Recurrent Breast Cancer
Stage IIA Breast Cancer
Stage IIB Breast Cancer
Stage IIIA Breast Cancer
Stage IIIB Breast Cancer
Stage IIIC Breast Cancer
Drug: Akt inhibitor MK2206
Drug: anastrozole
Drug: goserelin acetate
Procedure: neoadjuvant therapy
Procedure: therapeutic conventional surgery
Other: laboratory biomarker analysis
Other: pharmacological study
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase II Trial of Neoadjuvant MK-2206 in Combination With Either Anastrozole if Postmenopausal or Anastrozole and Goserelin if Premenopausal in Women With Clinical Stage 2 or 3 PIK3CA Mutant Estrogen Receptor Positive and HER2 Negative Invasive Breast Cancer

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Pathological complete response based on tumor Ki-67 value [ Time Frame: Up to day 17 of course 1 ] [ Designated as safety issue: No ]
    A ninety percent confidence interval for the true pathologic complete response rate will be calculated using the Duffy-Santer approach.


Secondary Outcome Measures:
  • Clinical response rate, estimated by the number of patients whose disease meets the WHO criteria of complete or partial response divided by the total number of eligible patients [ Time Frame: Up to 3 weeks following the last dose of Akt inhibitor MK-2206 ] [ Designated as safety issue: No ]
    A ninety percent confidence interval for the true clinical response rate will be calculated using the Duffy-Santer approach.

  • Radiological response rate, estimated by the number of patients whose disease meets with WHO criteria for complete or partial response divided by the total number of eligible patients [ Time Frame: Up to 3 weeks following the last dose of Akt inhibitor MK-2206 ] [ Designated as safety issue: No ]
    A ninety percent confidence interval for the true radiographic response rate will be calculated using the Duffy-Santer approach.

  • Incidence of adverse events, based on the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 [ Time Frame: Up to 60 days after completion of study treatment ] [ Designated as safety issue: Yes ]
    The maximum grade for each type of adverse event will be recorded for each patient, and frequency tables will be reviewed to determine patterns. Additionally, the relationship of the adverse event(s) to the study treatment will be taken into consideration.


Other Outcome Measures:
  • Serum estradiol levels [ Time Frame: At baseline, following 4 weeks of anastrozole alone, day 1 of course 3, and at pre-surgery ] [ Designated as safety issue: No ]
  • Percent change in the apoptotic index [ Time Frame: From 2 weeks of combination therapy with Akt inhibitor MK2206 and anastrozole (day 17 of course 1) to after 4 weeks of treatment with anastrozole alone ] [ Designated as safety issue: No ]
  • Change in Ki67 levels [ Time Frame: From 2 weeks of combination therapy with Akt inhibitor MK2206 and anastrozole (day 17 of course 1) to after 4 weeks of treatment with anastrozole alone ] [ Designated as safety issue: No ]
  • Proportion of patients whose Ki67 values is at most 10% [ Time Frame: From 2 weeks of combination therapy with Akt inhibitor MK2206 and anastrozole (day 17 of course 1) to after 4 weeks of treatment with anastrozole alone ] [ Designated as safety issue: No ]
    A 95% binomial confidence intervals will be constructed for the true proportion of patients whose pre Akt inhibitor MK2206 ki67 value is at most 10% as well as for the true proportion of patients with a C1D17 Ki67 value that is at most 10% among those patients whose pre Akt inhibitor MK2206 Ki67 was more than 10%.

  • The pharmacodynamic effect of Akt inhibitor MK2206 in combination with anastrozole on the PI3K pathway activities, assessed by phosphoroproteomics and immunohistochemistry analysis on serial tumor biopsies [ Time Frame: Up to 3 weeks following the last dose of Akt inhibitor MK-2206 ] [ Designated as safety issue: No ]

Estimated Enrollment: 87
Study Start Date: January 2013
Estimated Primary Completion Date: March 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (MK2206, anastrozole, goserelin acetate)
Patients receive Akt inhibitor MK-2206 PO on days 2, 9, 16, and 23; anastrozole PO daily on days 1-28; and goserelin acetate SC on day 1 (premenopausal patients only). Treatment repeats every 28 days for 4 courses in the absence of disease progression or unacceptable toxicity.
Drug: Akt inhibitor MK2206
Given PO
Other Name: MK2206
Drug: anastrozole
Given PO
Other Names:
  • ANAS
  • Arimidex
  • ICI-D1033
Drug: goserelin acetate
Given SC
Other Names:
  • ICI-118630
  • ZDX
  • Zoladex
Procedure: neoadjuvant therapy
Given before standard-care surgery
Procedure: therapeutic conventional surgery
Undergo standard-care surgery
Other: laboratory biomarker analysis
Correlative studies
Other: pharmacological study
Correlative studies
Other Name: pharmacological studies

  Show Detailed Description

  Eligibility

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

Inclusion Criteria:

  • Clinical T2-T4c, any N, M0 invasive ER+ (Allred score of 6-8) and HER2 negative (0 or 1+ by immunohistochemistry [IHC] or fluorescence in situ hybridization [FISH] negative for amplification) breast cancer, by American Joint Committee on Cancer (AJCC) 7th edition clinical staging, with the goal being surgery to completely excise the tumor in the breast and the lymph node;

    • Note: if the patient has invasive or ductal carcinoma in situ (DCIS) in the contralateral breast the patient is not eligible for this study
  • >= 1 measurable lesion that is palpable, its size can be measured by bi-dimensional tape, ruler or caliper technique, and the minimum size of the largest tumor diameter is greater than 2.0 cm by imaging or physical examination
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2
  • Life expectancy > 4 months
  • Leukocytes >= 3,000/mcL
  • Absolute neutrophil count >= 1,500/mcL
  • Platelets >= 100,000/mcL
  • Total bilirubin =< upper limit of normal (ULN)
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional ULN
  • Creatinine =< ULN OR creatinine clearance >= 60 mL/min/1.73 m^2 for patients with creatinine above institutional normal
  • Patient with diabetes mellitus: fasting glucose =< 120 mg/dL and hemoglobin A1c (HbA1c) =< 8%
  • Negative serum pregnancy test =< 7 days prior to pre-registration for women of childbearing potential
  • Ability to understand and the willingness to sign a written informed consent document
  • Patient is postmenopausal or premenopausal

    • NOTE: postmenopausal women, verified by

      • Bilateral surgical oophorectomy, or
      • No spontaneous menses >= 1 year or
      • No menses for < 1 year with follicle stimulating hormone (FSH) and estradiol levels in postmenopausal range, according to institutional standards or
    • Premenopausal women, verified by:

      • Regular menses or
      • FSH and estradiol levels in premenopausal range, according to institutional standards
  • Willingness to provide biologic samples for PIK3CA sequencing and correlative studies
  • Positive for PIK3CA mutation based on central laboratory testing
  • In premenopausal women, serum estradiol level in postmenopausal range =< 7 days prior to registration

Exclusion Criteria:

  • Any of the following for treatment of this cancer including:

    • Surgery
    • Radiation therapy
    • Chemotherapy
    • Biotherapy
    • Hormonal therapy
    • Investigational agent prior to study entry
  • Receiving any other investigational agents
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to MK-2206 or other agents used in this study
  • Prior axillary lymph node sampling (sentinel lymph node biopsy or axillary lymph node dissection); NOTE: fine needle aspiration (FNA) of axillary lymph node is acceptable
  • Invasive cancer or DCIS in the contralateral breast
  • Receiving any medications or substances that are strong inhibitors or inducers of cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP450 3A4);

    • NOTE: oxidative metabolism of MK-2206 in human liver microsomes is catalyzed primarily by CYP3A4, although direct glucuronidation also occurs; at least 7 days washout period is required in patients who were previously taking strong inhibitors or inducers of CYP.450 3A4; patients who are currently taking moderate inhibitors or inducers of CYP450 3A4 are encouraged to switch to other medications that do not interact with CYP450 3A4
  • Corrected QT interval (QTc) prolongation (defined as a QTc interval > 480 msec) or other significant electrocardiogram (ECG) abnormalities
  • Receiving any medications or substances with risk of torsades de pointes; Note: medications or substances on the list "Drugs with Risk of Torsades de Pointes" are prohibited; medications or substances on the list "Drugs with Possible or Conditional Risk of Torsades de Pointes" may be used while on study with extreme caution and careful monitoring
  • Uncontrolled intercurrent illness including, but not limited to:

    • Ongoing or active infection
    • Symptomatic congestive heart failure
    • Unstable angina pectoris
    • Uncontrolled symptomatic cardiac arrhythmia
    • Psychiatric illness/social situations that would limit compliance with study requirements
  • Any of the following:

    • Pregnant women
    • Nursing women
    • Women of childbearing potential who are unwilling to employ adequate contraception
    • NOTE: breastfeeding should be discontinued if the mother is treated with MK-2206; women of childbearing potential must use two forms of contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation
  • Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy; NOTE: HIV-positive patients on combination antiretroviral therapy are ineligible; in addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy
  • Evidence of inflammatory cancer (clinical presentation of skin erythema involving more than one third of the breast or pathological evidence of dermal lymphatic involvement)
  • Patients with known metastatic disease are excluded
  • Current use of therapeutic anticoagulation therapy
  • Previous excisional biopsy of the breast cancer
  • Any condition (e.g., gastrointestinal tract disease resulting in an inability to take oral medication or a requirement for intravenous [IV] alimentation, prior surgical procedures affecting absorption) that impairs patients ability to swallow MK-2206 tablets
  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: NCT01776008

Locations
United States, Arizona
Mayo Clinic in Arizona Recruiting
Scottsdale, Arizona, United States, 85259
Contact: Donald W. Northfelt    480-301-8296    Northfelt.Donald@mayo.edu   
Principal Investigator: Donald W. Northfelt         
United States, Illinois
University of Chicago Recruiting
Chicago, Illinois, United States, 60637
Contact: Gini F. Fleming    773-702-6712    gfleming@medicine.bsd.uchicago.edu   
Principal Investigator: Gini F. Fleming         
United States, Iowa
University of Iowa Hospitals and Clinics Recruiting
Iowa City, Iowa, United States, 52242
Contact: Mark W. Karwal    319-353-7900    mark-karwal@uiowa.edu   
Principal Investigator: Mark W. Karwal         
United States, Maryland
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital Recruiting
Baltimore, Maryland, United States, 21231
Contact: Vered Stearns    443-287-6489    vstearn1@jhmi.edu   
Principal Investigator: Vered Stearns         
United States, Minnesota
Mayo Clinic Recruiting
Rochester, Minnesota, United States, 55905
Contact: Matthew P. Goetz    507-284-2511    goetz.matthew@mayo.edu   
Principal Investigator: Matthew P. Goetz         
Metro-Minnesota CCOP Recruiting
Saint Louis Park, Minnesota, United States, 55416
Contact: Bronaugh P. Murphy    952-993-1517    bronaugh.murphy@usoncology.com   
Principal Investigator: Bronaugh P. Murphy         
United States, Missouri
Washington University School of Medicine Recruiting
Saint Louis, Missouri, United States, 63110
Contact: Cynthia X. Ma    314-362-9383    cma@dom.wustl.edu   
Principal Investigator: Cynthia X. Ma         
United States, Wisconsin
University of Wisconsin Hospital and Clinics Recruiting
Madison, Wisconsin, United States, 53792
Contact: Mark E. Burkard    608-262-2803    mburkard@wisc.edu   
Principal Investigator: Mark E. Burkard         
Sponsors and Collaborators
Investigators
Principal Investigator: Cynthia Ma Mayo Phase 2 Consortium
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT01776008     History of Changes
Other Study ID Numbers: NCI-2013-00080, NCI-2013-00080, MC1139, 9170, N01CM00071, P30CA015083, N01CM00099
Study First Received: January 23, 2013
Last Updated: September 16, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Goserelin
Anastrozole
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Aromatase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on September 22, 2014