MK2206 and Anastrozole, Letrozole, Exemestane, or Fulvestrant in Treating Postmenopausal Women With Metastatic Breast Cancer

• Maximum tolerated dose (MTD) of MK-2206 in combination with anastrozole determined according to dose-limiting toxicities (DLTs) graded using Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0) (Phase IA) [ Time Frame: 4 weeks ] [ Designated as safety issue: Yes ]
• Recommended phase II treatment dose (RPTD) of MK-2206 in combination with anastrozole evaluated by the tolerability of prolonged administration at the MTD assessed by CTCAE v4.0 (Phase IB) [ Time Frame: 3 months ] [ Designated as safety issue: Yes ]
• RPTD of fulvestrant in combination with MK-2206 assessed by CTCAE v4.0 (Phase IC) [ Time Frame: 3 months ] [ Designated as safety issue: Yes ]
• RPTD of anastrozole plus fulvestrant in combination with MK-2206 assessed by CTCAE v4.0 (Phase ID) [ Time Frame: 3 months ] [ Designated as safety issue: Yes ]

• Adverse events of prolonged administration (4 months) of MK-2206 in combination with anastrozole at the MTD (Phase IB) [ Designated as safety issue: Yes ]
• MTD of MK-2206 and anastrozole (Phase IA) [ Designated as safety issue: No ]
• Toxicity profile of MK-2206 in combination with letrozole (Arm C) [ Designated as safety issue: Yes ]

• Frequency and severity of toxicity incidents assessed by CTCAE v4.0 [ Time Frame: Up to 2 years ] [ Designated as safety issue: Yes ]
• Clinical benefit rate (CR+PR+SD for more than 6 months) [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]
• Serum levels of estradiol prior to and following 1 course of MK2206 therapy [ Time Frame: Baseline and day 28 ] [ Designated as safety issue: No ]

• Toxicity profile of MK2206 in combination with anastrozole or letrozole [ Designated as safety issue: Yes ]
• Clinical benefit rate (CR+PR+SD) for more than 6 months [ Designated as safety issue: No ]
• Response rate (CR + PR), and percentage of progression-free survival at 6 months [ Designated as safety issue: No ]
• Serum levels of estradiol prior to and following 1 course of MK2206 therapy [ Designated as safety issue: No ]

This phase I trial is studying the side effects and the best dose of MK2206 when given with anastrozole, letrozole, exemestane, or fulvestrant in treating postmenopausal women with metastatic breast cancer. Estrogen can cause the growth of breast cancer cells. Hormone therapy using anastrozole, letrozole, exemestane, or fulvestrant may fight breast cancer by lowering the amount of estrogen the body makes. MK2206 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving MK2206 together with anastrozole, letrozole, exemestane, or fulvestrant may kill more tumor cells.

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) of MK-2206 in combination with anastrozole based on toxicities observed during cycle 1 therapy. (Phase IA) II. To evaluate the tolerability of prolonged administration (3 months) of MK-2206 in combination with anastrozole at the MTD defined in Phase IA. (Phase IB) III. To determine the recommended phase II treatment dosing (RPTD) of MK-2206 in combination with anastrozole based on toxicities observed with prolonged drug administration. (Phase IB) IV. To determine the tolerability of fulvestrant (Arm C), or fulvestrant plus anastrozole (Arm D), respectively, in combination with MK-2206 (at the RPTD defined in Phase 1B). (Arms C and D) V. To determine the recommended phase II treatment dose (RPTD) of fulvestrant (Arm C) or fulvestrant plus anastrozole (Arm D), respectively, in combination with MK-2206 based on toxicities observed with prolonged drug administration (3 months). (Arms C and D) VI. To evaluate the toxicity profile of MK-2206 in combination with fulvestrant (Arm C) or fulvestrant plus anastrozole (Arm D), respectively, with prolonged drug administration. (Arms C and D)

SECONDARY OBJECTIVES:

I. To evaluate the toxicity profile of MK-2206 in combination with anastrozole, or fulvestrant, or anastrozole plus fulvestrant.

II. To evaluate the Clinical Benefit Rate (CBR: complete response [CR]+partial response [PR]+stable disease [SD] > 6 months), Response Rate (CR+PR), and Percent of Patients Progression Free at 6 months with the treatment of MK-2206 in combination with anastrozole, or fulvestrant or anastrozole plus fulvestrant in patients with estrogen receptor positive (ER+) metastatic breast cancer.

III. To examine serum levels of estradiol prior to and following 1 cycle of MK-2206 therapy.

TERTIARY OBJECTIVES:

I. To examine baseline tumor specimens for PI3K pathway abnormalities and to explore its relationship with treatment response.

II. To evaluate the effect of MK-2206 on tumor cell AKT signaling, proliferation, and apoptosis using serially collected tumor samples in available cases.

III. To examine changes in tumor cell glucose uptake by positron emission tomography (PET) with 2-[18F]fluoro-2-deoxy-D-glucose (FDG) at baseline and 24 h post day 1 MK-2206. (Phase IA) IV. To examine the PIK3CA mutation status in circulating deoxribonucleic acid (DNA) at baseline and following study therapy and to correlate with tumor tissue PIK3CA status and treatment response.

OUTLINE: This is a phase I, dose-escalation study of Akt inhibitor MK2206 (MK-2206) followed by a recommended phase II dose (RPTD) study. Patients are assigned to the treatment arm that is currently open.

ARM A: Patients receive anastrozole orally (PO) on days 1-28. Beginning in course 2, patients receive MK-2206 PO on days 1, 8, 15, and 22. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

ARM B: The RPTD of MK-2206 with anastrozole is determined after 4 courses, administered as in arm A.

ARM C: Patients receive letrozole PO on days 1-28. Beginning in course 2, patients receive MK-2206 PO on days 1, 8, 15, and 22. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

ARM D: Patients receive exemestane PO on days 1-28. Beginning in course 2, patients receive MK-2206 PO on days 1, 8, 15, and 22. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

ARM E: For patients who have not been started on fulvestrant, fulvestrant will be administered intramuscularly (IM) on day 1 and day 15 on course 1 and then on day 1 of course 2 and each subsequent course of the study. MK2206 is added on day 1 of course 2 of the study. For patients who have completed at least 2 doses of fulvestrant, MK2206 will start on day 1 of the scheduled monthly fulvestrant injection at course 1 of the study. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study therapy, patients are followed up for 30 days.

• Estrogen Receptor-positive Breast Cancer
• Recurrent Breast Cancer
• Stage IV Breast Cancer

• Drug: Akt inhibitor MK2206
  Given orally
  Other Name: MK2206
• Drug: anastrozole
  Given orally
  Other Names:

  • ANAS
  • Arimidex
  • ICI-D1033
• Drug: exemestane
  Given orally
  Other Names:

  • Aromasin
  • FCE-24304
  • PNU 155971
• Drug: fulvestrant
  Given intramuscularly
  Other Names:

  • Faslodex
  • ICI 182,780
• Drug: letrozole
  Given orally
  Other Names:

  • CGS 20267
  • Femara
  • LTZ
• Other: laboratory biomarker analysis
  Correlative studies

• Experimental: Arm A (anastrozole)
  Patients receive anastrozole PO on days 1-28. Beginning in course 2, patients receive MK-2206 PO on days 1, 8, 15, and 22. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  Interventions:

  • Drug: Akt inhibitor MK2206
  • Drug: anastrozole
  • Other: laboratory biomarker analysis
• Experimental: Arm B (MK-2206 and anastrozole)
  The RPTD of MK-2206 with anastrozole is determined after 4 courses, administered as in arm A.
  Interventions:

  • Drug: Akt inhibitor MK2206
  • Drug: anastrozole
  • Other: laboratory biomarker analysis
• Experimental: Arm C (letrozole and MK-2206)
  Patients receive letrozole PO on days 1-28. Beginning in course 2, patients receive MK-2206 PO on days 1, 8, 15, and 22. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  Interventions:

  • Drug: Akt inhibitor MK2206
  • Drug: letrozole
  • Other: laboratory biomarker analysis
• Experimental: Arm D (exemestane and MK-2206)
  Patients receive exemestane PO on days 1-28. Beginning in course 2, patients receive MK-2206 PO on days 1, 8, 15, and 22. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  Interventions:

  • Drug: Akt inhibitor MK2206
  • Drug: exemestane
  • Other: laboratory biomarker analysis
• Experimental: Arm E (fulvestrant and MK-2206)
  For patients who have not been started on fulvestrant, fulvestrant will be administered IM on day 1 and day 15 of course 1 and then on day 1 of course 2 and each subsequent course of the study. MK2206 is added on day 1 of course 2 of the study. For patients who have completed at least 2 doses of fulvestrant, MK2206 will start on day 1 of the scheduled monthly fulvestrant injection at course 1 of the study. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  Interventions:

  • Drug: Akt inhibitor MK2206
  • Drug: fulvestrant
  • Other: laboratory biomarker analysis

Inclusion Criteria:

• Patients must have histologically or cytologically confirmed invasive breast cancer that is metastatic stage IV or recurrent metastatic (histologic/cytologic confirmation of recurrence preferred, but not required)
• Either the primary or the metastatic tumor must be positive for estrogen-receptor (> 1% tumor cell staining by immunohistochemistry or an Allred Score of >= 3 by immunohistochemistry)

• Patient must have measurable or non-measurable lesions (defined by Response Evaluation Criteria In Solid Tumors [RECIST] 1.1 criteria)

  • To be eligible for the positron emission tomography 2-[18F]fluoro-2-deoxy-D-glucose (FDG PET) imaging studies in Phase IA, the presence of measurable lesions of at least 1.5 cm or the presence of bone lesions is required
• Patients may not have had disease progression on anastrozole (Arm A and Arm B), letrozole (Arm C), exemestane (Arm D), or fulvestrant (Arm E) in either the neoadjuvant, adjuvant (defined as disease recurrence identified within 6 months of adjuvant discontinuation), or metastatic setting
• Patients with known brain metastases are eligible if stable (no evidence of local progression) > 3 months after local therapy and are off steroids
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1 (Karnofsky PS 70-100%)

• Patients must be postmenopausal as defined by one of the following:

  • Women > 60 years
  • Women =< 60 years with spontaneous cessation of menses > 12 months prior to registration
  • Women =< 60 years with cessation of menses of duration < 12 months or secondary to hysterectomy AND an FSH (follicle-stimulating hormone) level in the postmenopausal range according to institutional standards (or > 34.4 IU/L if institutional range is not available) prior to registration
  • Women =< 60 years on hormonal replacement therapy who have discontinued hormonal therapy AND an FSH level in the postmenopausal range according to institutional standards (or > 34.4 IU/L if institutional range is not available) prior to registration
  • Status post bilateral surgical oophorectomy
  • Premenopausal women on a gonadotropin-releasing hormone (GnRH) analog
• Patients must have a life expectancy greater than 4 months
• Leukocytes >= 3,000/mm^3
• Absolute neutrophil count (ANC) >= 1,5000/mm^3
• Platelet count >= 100,000/mm^3
• Total bilirubin normal
• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 times upper limit of normal
• Creatinine normal OR creatinine clearance >= 60 mL/min
• If patients have diabetes mellitus, fasting glucose must be =< 120 mg/dL and hemoglobin (Hb)A1c =< 8%
• Patients may not have a history of allergic reactions attributed to compounds of similar chemical or biologic composition to Akt inhibitor MK2206 (MK-2206) or other agents used in the study
• Baseline QTcF > 450 msec (male) or QTcF > 470 msec (female) will exclude patients from entry on study
• Patients may not have 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
• Patients with known human immunodeficiency virus (HIV)-positive status are excluded from this study
• Patients may not have had grade 3 or intolerable grade 2 adverse events during run-in AI or fulvestrant therapy prior to starting MK-2206
• See Disease Characteristics

• Patients may have undergone any number of prior lines of chemotherapy or endocrine regimens but must not have a history of disease progression on anastrozole (Arm A and Arm B), letrozole (Arm C), exemestane (Arm D), or fulvestrant (Arm E)

  • Patients on Arm A and Arm B must meet one of the following criteria:

    • Currently being treated with anastrozole with no evidence of disease progression
    • Currently being treated with letrozole or exemestane with no evidence of disease progression and willing to switch to anastrozole for study
    • Considering switching to anastrozole due to disease progression from the most recent anti-cancer therapy

  • Patients on Arm C must meet one of the following criteria:

    • Currently being treated with letrozole with no evidence of disease progression
    • Currently being treated with anastrozole or exemestane with no evidence of disease progression and willing to switch to letrozole for study
    • Considering switching to letrozole due to disease progression from the most recent anti-cancer therapy

  • Patients on Arm D must meet one of the following criteria:

    • Currently being treated with exemestane with no evidence of disease progression
    • Currently being treated with anastrozole or letrozole with no evidence of disease progression and willing to switch to exemestane for study enrollment
    • Considering switching to exemestane due to disease progression from the most recent anti-cancer therapy

  • Patients on Arm E must meet one of the following criteria:

    • Currently being treated with fulvestrant with no evidence of disease progression
    • Considering switching to fulvestrant due to disease progression from the most recent anti-cancer therapy

• Patients may not have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study

  • Patient must have recovered from adverse events due to agents administered more than 4 weeks earlier
• Patients may not have had prior therapy with a PI3K/Akt/mTOR inhibitor
• Patients may not be receiving any other investigational agent

• Patients receiving any medications or substances that are strong inhibitors or inducers of CYP 450 3A4 are ineligible

  • One-week washout period is required for 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