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

This study has suspended participant recruitment.
(FDA hold pending response)
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Joseph Sparano, Albert Einstein College of Medicine of Yeshiva University
ClinicalTrials.gov Identifier:
NCT01697293
First received: September 13, 2012
Last updated: July 1, 2014
Last verified: July 2014
  Purpose

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 or other cancers. 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 or by stopping them from dividing. Giving triciribine phosphate with paclitaxel, doxorubicin hydrochloride, and cyclophosphamide may be an effective treatment for breast cancer.


Condition Intervention Phase
HER2-negative Breast Cancer
HER2-positive Breast Cancer
Male Breast Cancer
Malignant Neoplasm
Recurrent Breast Cancer
Stage II Breast Cancer
Stage IIIA Breast Cancer
Stage IIIB Breast Cancer
Stage IIIC Breast Cancer
Stage IV Breast Cancer
Drug: triciribine phosphate
Drug: paclitaxel
Drug: doxorubicin hydrochloride
Drug: cyclophosphamide
Procedure: therapeutic conventional surgery
Other: laboratory biomarker analysis
Phase 1
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by Albert Einstein College of Medicine of Yeshiva University:

Primary Outcome Measures:
  • Recommended phase II dose of triciribine phosphate, based on the incidence of dose-limiting toxicity (DLT) graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 (Phase I) [ Time Frame: 28 days ] [ Designated as safety issue: Yes ]
    Adverse effects will be summarized using frequency tables. The proportion of patients who completed all 12 courses of paclitaxel (at full dose or with dose modification) will be tabulated.

  • Pathologic complete response (pCR), assessed using the criteria of Chevallier (Phase II) [ Time Frame: At time of surgery ] [ Designated as safety issue: No ]
    The estimated pCR along with exact confidence interval will be presented.


Secondary Outcome Measures:
  • Clinical complete response and partial response, based on tumor measurements obtained by physical exam [ Time Frame: Up to 20 weeks (completion of courses B 1-4) ] [ Designated as safety issue: No ]

Estimated Enrollment: 56
Study Start Date: January 2012
Estimated Primary Completion Date: January 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (chemotherapy, surgery)

COURSES A 1-12 (PHASE I & II): Patients receive triciribine phosphate 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 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 2 weeks 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.

Drug: triciribine phosphate
Given IV
Other Names:
  • TCN-P
  • tricyclic nucleoside 5'-phosphate
  • tricycloside phosphate
Drug: paclitaxel
Given IV
Other Names:
  • Anzatax
  • Asotax
  • TAX
  • Taxol
Drug: doxorubicin hydrochloride
Given IV
Other Names:
  • ADM
  • ADR
  • Adria
  • Adriamycin PFS
  • Adriamycin RDF
Drug: cyclophosphamide
Given IV
Other Names:
  • CPM
  • CTX
  • Cytoxan
  • Endoxan
  • Endoxana
Procedure: therapeutic conventional surgery
Undergo modified radical mastectomy, radical mastectomy, segmental mastectomy or lumpectomy with an axillary lymph node dissection or biopsy
Other: laboratory biomarker analysis
Correlative studies

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 or other cancers. (Phase I) 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 (ErbB1), avian erythroblastic leukemia viral (v-erb-b) oncogene homolog 2, 3, 4 (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).

II. To correlate the percent decrease in the levels of phospho-Akt (S473), phospho-S6 (S235-236), phospho-proline-rich Akt substrate, 40 kDa (PRAS40) (Thr246), 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 terminal deoxynucleotidyl transferase dUTP nick end labeling (Tunel) (Sebti lab).

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 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 2 weeks 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

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Phase I: Patients must have histologically or cytologically confirmed adenocarcinoma of the breast associated with the following clinical stage: clinical IIIC or IV (see American Joint Committee on Cancer [AJCC] staging criteria, 7th Edition); patients with other cancers for whom no curative therapy exists are also eligible
  • 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 must have had progressive disease after at least prior anti-HER2 directed therapy for metastatic disease containing trastuzumab
  • Phase II: No prior chemotherapy, irradiation, or definitive therapeutic surgery (eg, 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 (eg, 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 for patients treated in the phase II portion of the trial who will receive doxorubicin hydrochloride and cyclophosphamide [AC] chemotherapy)
  • 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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01697293

Locations
United States, Florida
H. Lee Moffitt Cancer Center and Research Institute
Tampa, Florida, United States, 33612
United States, New York
Albert Einstein College of Medicine
Bronx, New York, United States, 10461
Sponsors and Collaborators
Albert Einstein College of Medicine of Yeshiva University
Investigators
Principal Investigator: Joseph Sparano Albert Einstein College of Medicine of Yeshiva University
  More Information

No publications provided

Responsible Party: Joseph Sparano, Principal Investigator, Albert Einstein College of Medicine of Yeshiva University
ClinicalTrials.gov Identifier: NCT01697293     History of Changes
Other Study ID Numbers: 2011-269, NCI-2013-01311, 11-051, TCN-PM, 2011-269, P30CA013330, R01CA098473
Study First Received: September 13, 2012
Last Updated: July 1, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Breast Neoplasms, Male
Breast Neoplasms
Neoplasms
Neoplasms by Site
Breast Diseases
Skin Diseases
Paclitaxel
Liposomal doxorubicin
Cyclophosphamide
Doxorubicin
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Myeloablative Agonists
Antibiotics, Antineoplastic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors

ClinicalTrials.gov processed this record on October 19, 2014