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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


Phase 2
18 Years
N/A
Open (Enrolling)
Female
Estrogen Receptor-positive Breast Cancer, HER2-negative Breast Cancer, Recurrent Breast Cancer, Stage II Breast Cancer, Stage IIIA Breast Cancer, Stage IIIB Breast Cancer, Stage IIIC Breast Cancer

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Trial Information

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


PRIMARY OBJECTIVES:

I. To determine the pathologic complete response (pCR) rate of neoadjuvant MK-2206 (Akt
inhibitor MK-2206) in combination with anastrozole (goserelin [goserelin acetate] is added
if premenopausal) in women with clinical stage II or III
phosphatidlinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) mutated
estrogen receptor (ER)+/human epidermal growth factor receptor 2 (HER2)- breast cancer.

SECONDARY OBJECTIVES:

I. To determine the safety profile of neoadjuvant MK-2206 in combination with anastrozole
(goserelin is added if premenopausal) in women with clinical stage II or III PIK3CA mutated
ER+/HER2- breast cancer.

II. To estimate the rate of clinical response and radiologic response using the World Health
Organization (WHO) criteria.

TERTIARY OBJECTIVES:

I. For pre and post-menopausal women separately, to examine serum estradiol levels prior to
pre-registration, prior to registration, after 2 cycles of anastrozole plus MK-2206 (cycle 3
day 1) and pre surgery.

II. To examine the percent change in the apoptotic index after 2 weeks of combination
therapy with MK-2206 and anastrozole (cycle 1 day 17) relative to apoptotic index after 4
weeks of treatment with anastrozole alone (pre MK-2206).

III. To examine the change in Ki67 levels after 2 weeks of combination therapy with MK-2206
and anastrozole (cycle 1 day 17) relative to that after 4 weeks of treatment with
anastrozole alone (pre MK-2206).

IV. To estimate the proportion of patients whose Ki67 values is at most 10% after 2 weeks of
combination therapy with MK-2206 and anastrozole (cycle 1 day 17) among those whose Ki67 was
more than 10% or more after 4 weeks of treatment with anastrozole alone (pre MK-2206).

V. To examine the pharmacodynamic effect of MK-2206 in combination with anastrozole (or
anastrozole in combination with goserelin) on PI3K pathway signaling using serially
collected tumor specimens.

VI. To explore molecular mechanisms which could affect tumor response to combination MK-2206
and anastrozole (or anastrozole in combination with goserelin) in PIK3CA mutant ER+ breast
cancer.

VII. To examine the PIK3CA mutation status in circulating plasma DNA prior to and following
therapy on serially collected peripheral blood (pre anastrozole, pre MK-2206, cycle 1 day
17, and at the time of surgery) and to correlate with tumor tissue PIK3CA status.

VIII. To examine PIK3CA mutation status of the residual cancer collected at the time of
surgery post 4 cycles of neoadjuvant MK-2206 and anastrozole.

OUTLINE:

Patients receive Akt inhibitor MK-2206 orally (PO) on days 2, 9, 16, and 23; anastrozole PO
daily on days 1-28; and goserelin acetate subcutaneously (SC) on day 1 (premenopausal
patients only). Treatment repeats every 28 days for 4 courses in the absence of disease
progression or unacceptable toxicity.

Standard of care surgery (breast and axillary lymph node surgery) is performed 1-3 weeks
following the last dose of Akt inhibitor MK-2206.

After completion of study treatment, patients are followed up for 30-60 days.


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 3A4 (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 CYP450 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

Type of Study:

Interventional

Study Design:

Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Pathological complete response (pCR) based on tumor Ki-67 value

Outcome Description:

A ninety percent confidence interval for the true pathologic complete response rate will be calculated using the Duffy-Santer approach.

Outcome Time Frame:

Up to day 17 of course 1

Safety Issue:

No

Principal Investigator

Cynthia Ma

Investigator Role:

Principal Investigator

Investigator Affiliation:

Mayo Clinic

Authority:

United States: Food and Drug Administration

Study ID:

NCI-2013-00080

NCT ID:

NCT01776008

Start Date:

January 2013

Completion Date:

Related Keywords:

  • Estrogen Receptor-positive Breast Cancer
  • HER2-negative Breast Cancer
  • Recurrent Breast Cancer
  • Stage II Breast Cancer
  • Stage IIIA Breast Cancer
  • Stage IIIB Breast Cancer
  • Stage IIIC Breast Cancer
  • Breast Neoplasms

Name

Location

Washington University School of MedicineSaint Louis, Missouri  63110
University of Chicago Comprehensive Cancer CenterChicago, Illinois  60637-1470