Recurrent Breast Carcinoma Clinical Trial
Official title:
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
This phase I trial studies the side effects and the best dose of MK 2206 (Akt inhibitor MK2206) when given with anastrozole, fulvestrant, or anastrozole and fulvestrant in treating postmenopausal women with breast cancer that has spread to other parts of the body. Estrogen can cause the growth of breast cancer cells. Hormone therapy using anastrozole or fulvestrant may fight breast cancer by lowering the amount of estrogen the body makes. Akt inhibitor MK2206 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving Akt inhibitor MK2206 together with anastrozole, fulvestrant, or anastrozole and 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 alterations in phosphatidylinositol 3 kinase
(PI3K) and other pathway genes and to explore their relationship with treatment response.
II. To evaluate the effect of MK-2206 on tumor cell v-akt murine thymoma viral oncogene
homolog 1 (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 phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit
alpha (PIK3CA) mutation status in circulating deoxyribonucleic 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 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 Akt inhibitor 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 Akt inhibitor MK2206 with anastrozole is determined after 3 courses,
administered as in Arm A.
ARM C: Patients receive Akt inhibitor MK2206 PO on days 1, 8, 15, and 22, fulvestrant
intramuscularly (IM) on day 1 and day 15 of course 1 and then on day 1 of each course in each
subsequent courses. Courses repeat every 28 days in the absence of disease progression or
unacceptable toxicity.
ARM D: Patients receive Akt inhibitor MK2206 PO as in Arm A, anastrozole PO on days 1-28 and
fulvestrant IM on day 1. Courses repeat every 28 days in the absence of disease progression
or unacceptable toxicity.
NOTE: As of 8/19/2015, in all Arms, patients no longer receive Akt inhibitor MK2206.
After completion of study therapy, patients are followed up for 30 days.
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