Clinical Trials /

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

NCT01776008

Description:

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.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Terminated

Phase:

Phase 2

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: NCI-2013-00080
  • SECONDARY ID: NCI-2013-00080
  • SECONDARY ID: MC1139
  • SECONDARY ID: MC1139
  • SECONDARY ID: 9170
  • SECONDARY ID: N01CM00071
  • SECONDARY ID: N01CM00099
  • SECONDARY ID: P30CA015083
  • NCT ID: NCT01776008

Conditions

  • Estrogen Receptor Positive
  • HER2/Neu Negative
  • Recurrent Breast Carcinoma
  • Stage IIA Breast Cancer
  • Stage IIB Breast Cancer
  • Stage IIIA Breast Cancer
  • Stage IIIB Breast Cancer
  • Stage IIIC Breast Cancer

Interventions

DrugSynonymsArms
Akt Inhibitor MK2206MK2206Treatment (MK2206, anastrozole, goserelin acetate)
AnastrozoleAnastrazole, Arimidex, ICI D1033, ICI-D1033, ZD-1033Treatment (MK2206, anastrozole, goserelin acetate)
Goserelin AcetateZDX, ZoladexTreatment (MK2206, anastrozole, goserelin acetate)

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.

Detailed Description

      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 deoxyribonucleic acid (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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (MK2206, anastrozole, goserelin acetate)ExperimentalPatients 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.
  • Akt Inhibitor MK2206
  • Anastrozole
  • Goserelin Acetate

Eligibility 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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Pathological complete response based on tumor Ki-67 value
Time Frame:Up to day 17 of course 1
Safety Issue:
Description:A ninety percent confidence interval for the true pathologic complete response rate will be calculated using the Duffy-Santer approach.

Secondary Outcome Measures

Measure: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
Safety Issue:
Description:A ninety percent confidence interval for the true clinical response rate will be calculated using the Duffy-Santer approach.
Measure: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
Safety Issue:
Description: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.
Measure: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
Safety Issue:
Description:A ninety percent confidence interval for the true radiographic response rate will be calculated using the Duffy-Santer approach.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:National Cancer Institute (NCI)

Last Updated

April 24, 2017