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A Phase 1 Trial of MK-2206 in Combination With Anastrozole, Fulvestrant, or Anastrozole Plus Fulvestrant in Postmenopausal Women With Estrogen Receptor Positive Metastatic Breast Cancer


Phase 1
18 Years
N/A
Open (Enrolling)
Female
Estrogen Receptor-positive Breast Cancer, Recurrent Breast Cancer, Stage IV Breast Cancer

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Trial Information

A Phase 1 Trial of MK-2206 in Combination With Anastrozole, Fulvestrant, or Anastrozole Plus Fulvestrant in Postmenopausal Women With Estrogen Receptor Positive Metastatic Breast Cancer


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.


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

Type of Study:

Interventional

Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

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)

Outcome Time Frame:

4 weeks

Safety Issue:

Yes

Principal Investigator

Cynthia Ma

Investigator Role:

Principal Investigator

Investigator Affiliation:

Washington University School of Medicine

Authority:

United States: Food and Drug Administration

Study ID:

NCI-2011-02586

NCT ID:

NCT01344031

Start Date:

April 2011

Completion Date:

Related Keywords:

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

Name

Location

Washington University School of MedicineSaint Louis, Missouri  63110