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

Information source: Albert Einstein College of Medicine of Yeshiva University
ClinicalTrials.gov processed this data on August 20, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Breast Adenocarcinoma; Estrogen Receptor Positive; HER2/Neu Negative; Recurrent Breast Carcinoma; Stage IIB Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Stage IV Breast Cancer

Intervention: Cyclophosphamide (Drug); Doxorubicin Hydrochloride (Drug); Laboratory Biomarker Analysis (Other); Paclitaxel (Drug); Therapeutic Conventional Surgery (Procedure); Triciribine Phosphate (Drug)

Phase: Phase 1/Phase 2

Status: Recruiting

Sponsored by: Albert Einstein College of Medicine of Yeshiva University

Official(s) and/or principal investigator(s):
Joseph Sparano, Principal Investigator, Affiliation: Albert Einstein College of Medicine of Yeshiva University

Summary

This phase I/II trial studies the side effects and the best dose of triciribine phosphate when given together with paclitaxel, doxorubicin hydrochloride, and cyclophosphamide and to see how well they work in treating patients with stage IIB-IV breast cancer. Triciribine phosphate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as paclitaxel, doxorubicin hydrochloride, and cyclophosphamide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving triciribine phosphate with paclitaxel, doxorubicin hydrochloride, and cyclophosphamide may be a better treatment for breast cancer.

Clinical Details

Official title: A Phase I-II Study of Triciribine Phosphate Monohydrate (TCN-PM) Plus Sequential Weekly Paclitaxel Followed by Dose-Dense Doxorubicin and Cyclophosphamide in Patients With Metastatic and Locally Advanced Breast Cancer

Study design: Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome:

Pathologic complete response (pCR), assessed using the criteria of Chevallier (Phase II)

Recommended phase II dose of triciribine phosphate, based on the incidence of dose-limiting toxicity graded using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 (Phase I)

Secondary outcome: Clinical complete response and partial response, based on tumor measurements obtained by physical exam

Detailed description: PRIMARY OBJECTIVES: I. To determine the recommended phase II dose of triciribine (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. II. To determine the pathologic complete response rate (including breast and breast plus axillary nodes) after sequential weekly paclitaxel triciribine 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 triciribine, followed by doxorubicin/cyclophosphamide. (Phase II) SECONDARY OBJECTIVES: I. To correlate pre-treatment levels of epidermal growth factor receptor, avian erythroblastic leukemia viral (v-erb-b) oncogene homolog1, 2, 3, 4 (ErbB1,2,3,4), and phosphorylated levels of protein kinase B (Akt), signal transducer and activator of transcription 3 (STAT3), extracellular signal-regulated kinase (Erk)1/2 to clinical response (Sebti 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 clinical response rates, 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 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.

Eligibility

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

Inclusion Criteria:

- Phase I: Patients must have histologically or cytologically confirmed adenocarcinoma

of the breast associated with the following clinical stage: clinical IV (see American Joint Committee on Cancer [AJCC] staging criteria, 7th Edition)

- 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, fluorescent in situ hybridization [FISH], or other approved assay)

- Phase I: Up to two prior non-taxane chemotherapy regimens for metastatic disease is

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; 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) (serum glutamic oxaloacetic transaminase

[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2. 5 x institutional upper limit of normal

- Left ventricular ejection fraction within normal institutional limits

- Creatinine within normal institutional limits

- Left ventricular ejection fraction at or above institutional lower limits of normal

(by echocardiogram or nuclear scan within 12 weeks of registration)

- Electrocardiogram (EKG) 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); patient 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 (an no prior adjuvant chemotherapy for previous breast malignancy)

- Women of child-bearing 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

- History of allergic reactions attributed to compounds of similar chemical or biologic

composition to triciribine 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 triciribine; these potential risks may also apply to other agents used in this study

- Human immunodeficiency virus (HIV)-positive patients receiving combination

anti-retroviral therapy are excluded from the study

Locations and Contacts

Moffitt Cancer Center, Tampa, Florida 33612, United States; Recruiting
Hyo S. Han, Phone: 813-745-8480, Email: hyo.han@moffitt.org
Hyo S. Han, Principal Investigator

Albert Einstein College of Medicine, Bronx, New York 10461, United States; Recruiting
Joseph A. Sparano, Phone: 718-405-8404, Email: jsparano@montefiore.org
Joseph A. Sparano, Principal Investigator

Additional Information

Starting date: January 2012
Last updated: June 25, 2015

Page last updated: August 20, 2015

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