Triciribine Phosphate, Paclitaxel, Doxorubicin Hydrochloride, and Cyclophosphamide in Treating Patients With Stage IIB-IV Breast Cancer

PRIMARY OBJECTIVES:

I. To determine the recommended phase II dose of PTX-200 (triciribine phosphate) given on
days 1, 8, and 15 every 28 days (maximum of 9 doses) when combined with weekly paclitaxel (80
mg/m^2) for 12 weeks in patients with metastatic breast cancer. (Phase I and Expansion
Cohort) II. To determine the pathologic response rate (Residual Cancer Burden [RCB] score
0-1) after sequential weekly paclitaxel plus PTX 200 weekly, 3 weeks out of 4, followed by
doxorubicin (doxorubicin hydrochloride) (60 mg/m^2) and cyclophosphamide (600 mg/m^2) every 2
weeks x 4 cycles in patients with clinical stage IIB-IIIC breast cancer. (Phase II).

III. To determine the feasibility and safety of the combination of sequential weekly
paclitaxel plus PTX-200 (days 1, 8, and 15) followed by doxorubicin/cyclophosphamide. (Phase
II)

SECONDARY OBJECTIVES:

I. To correlate pre-treatment levels of erb-b2 receptor tyrosine kinase (ErbB)1, 2, 3, 4 and
zinc finger protein 217 (ZNF217), and phosphorylated levels of v-akt murine thymoma viral
oncogene homolog 1 (Akt), signal transducer and activator of transcription 3 (acute-phase
response factor) (STAT3), extracellular signal-regulated protein kinases 1 and 2 (Erk1/2) to
pathologic (RCB score 0-1) response (Sebti laboratory [lab]). (Phase I or II) II. To
correlate the percent decrease in the levels of phosphorylated (phospho-)Akt (S473),
phospho-S6 (S235-236), phospho-proline-rich Akt substrate, 40 kDa (PRAS40) (threonine
[Thr]246), phosphatase and tensin homolog (PTEN), Stathmin, pyruvate dehydrogenase kinase,
isozyme 1 (PDK1), cyclin D1, phospho-STAT3, ras homolog gene family, member C (Rho C), and
phospho-Erk 1-2 with pathologic response rate (RCB score 0-1), percent inhibition of
proliferation (Ki-67) and percent induction of apoptosis (terminal deoxynucleotidyl
transferase dUTP nick end labeling [Tunel]) (Sebti lab). (Phase I or II)

OUTLINE: This is a phase I, dose-escalation study of triciribine phosphate followed by an
expansion cohort and a phase II study.

COURSES A 1-12 (PHASE I & II): Patients receive triciribine phosphate intravenously (IV) over
60 minutes on days 1, 8, and 15, 29, 36, 43, 57, 64, and 71 and paclitaxel IV over 1 hour on
days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 79. Treatment repeats every week for 12
courses in the absence of disease progression or unacceptable toxicity.

COURSES B 1-4 (PHASE II): Patients receive doxorubicin hydrochloride IV over 5-10 minutes and
cyclophosphamide IV over 30-60 minutes on day 1. Treatment repeats every 14 days for 4
courses in the absence of disease progression or unacceptable toxicity.

SURGERY (PHASE II): Eligible patients undergo modified radical mastectomy, radical
mastectomy, segmental mastectomy or lumpectomy with an axillary lymph node dissection or
biopsy.

After completion of study treatment, patients with metastatic disease are followed up every 3
months for 1 year and patients with locally advanced disease are followed up every 6 months
for 2 years and then yearly for 3 years.

Inclusion Criteria:

- Phase I and expansion cohort: Patients must have histologically or cytologically
confirmed adenocarcinoma of the breast associated with clinical stage: IV (see
American Joint Committee on Cancer [AJCC] staging criteria, 7th edition) or stage
IIB-IIIC (expansion cohort only)

- Phase II: Patients must have histologically or cytologically confirmed adenocarcinoma
of the breast associated with the following clinical stage: IIB, IIIA, IIIB, or IIIC
(see AJCC staging criteria, 7th edition); the tumor must be human epidermal growth
factor receptor 2 (Her2)/neu negative (by DAKO HercepTest, fluorescence based in situ
hybridization [FISH], or other approved assay)

- Phase I and expansion cohort: Up to two prior non-taxane chemotherapy regimens for
metastatic disease are permitted for patients enrolled on the phase I portion of the
trial; patients with HER2/neu positive breast cancer are not eligible; patients
treated with prior anthracycline therapy as neoadjuvant, adjuvant, or metastatic
therapy are not eligible unless the following conditions are met: (a) prior cumulative
doxorubicin dose is =< 240 mg/m^2 (or epirubicin dose is =< 400 mg/m^2), and (b) left
ventricular ejection fraction (LVEF) obtained at baseline is at least 50% (or >= 5%
above lower institutional limits of normal whichever is higher); patients with
estrogen receptor (ER)-positive disease are required to have relapse or progression on
at least one line of endocrine therapy

- Phase II: No prior chemotherapy, irradiation, or definitive therapeutic surgery (e.g.,
mastectomy or lumpectomy or axillary dissection) for this malignancy; patients who
have had a prior sentinel lymph node biopsy for this malignancy are eligible

- Patients who received tamoxifen or another selective estrogen receptor modulator
(SERM) for prevention or treatment of breast cancer or for other indications (e.g.,
osteoporosis, prior ductal carcinoma in situ [DCIS]), or who receive aromatase
inhibitors for prevention or treatment of breast cancer, are eligible; patients who
are hormone-receptor positive and who have received other hormonal agents for the
treatment of breast cancer (e.g., Fulvestrant) are also eligible; tamoxifen therapy or
other hormonal agents should be discontinued at least 1 week before the patient is
enrolled on this study

- Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1

- Leukocytes >= 3,000/uL

- Absolute neutrophil count =< 1,500/uL

- Platelets >= 100,000/uL

- Total bilirubin within normal institutional limits

- Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x institutional
upper limit of normal

- Left ventricular ejection fraction (LVEF) within normal institutional limits

- Creatinine within normal institutional limits

- LVEF at or above institutional lower limits of normal (>= 50%), or at least 5% above
lower limits of normal if prior anthracycline exposure (by echocardiogram or nuclear
scan within 12 weeks of registration)

- Electrocardiogram (ECG) corrected QT (QTC) < 450 msec

- Serum calcium within normal institutional limits

- Serum phosphorus within normal institutional limits

- Fasting glucose within normal limits

- Patients must be disease-free of prior invasive malignancies for >= 2 years with the
exception of curatively-treated basal cell or squamous cell carcinoma of the skin,
carcinoma in situ of the cervix (for phase II only); patients with the following prior
or concurrent diagnoses are eligible: lobular carcinoma in situ, contralateral ductal
carcinoma in situ, or contralateral invasive ductal and/or lobular cancer (and no
prior adjuvant chemotherapy for previous breast malignancy)

- Women of childbearing potential must agree to use adequate contraception (hormonal or
barrier method of birth control) prior to study entry and for the duration of study
participation; should a woman become pregnant or suspect she is pregnant while
participating in this study, she should inform her treating physician immediately

- Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

- Patients may not be receiving any other investigational agents during protocol
therapy, or up to 30 days prior to beginning protocol therapy; there should be a least
a 1-week interval between last dose of endocrine therapy and protocol therapy, and at
least 3 weeks for the last dose of biologic therapy (eg, bevacizumab) or cytotoxic
therapy (or 2 weeks for capecitabine or weekly paclitaxel, 6 weeks for mitomycin-C and
nitrosoureas), and adequately recovered from adverse effects from prior therapy to
meet all other eligibility criteria

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to PTX-200 or other agents used in the study (e.g., imidazoles,
quinolones)

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, diabetes mellitus requiring therapy (insulin or oral hypoglycemic agents),
congenital prolonged QT syndrome, requirement for a drug known to prolong the QT
interval, a history of QT prolongation, a screening QTc >= 450 msec,
hypertriglyceridemia requiring therapy, symptomatic congestive heart failure, unstable
angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that
would limit compliance with study requirements

- Pregnant women are excluded from this study; breastfeeding should be discontinued if
the mother is treated with PTX-200; these potential risks may also apply to other
agents used in this study

- Human immunodeficiency virus (HIV)-positive patients receiving combination
antiretroviral therapy are excluded from the study