Clinical trial NCT00789581: A Randomized Trial of Ixempra Versus Taxol in Adjuvant Therapy of Triple Negative Breast Cancer
Official title: Phase III Study of Doxorubicin/Cyclophosphamide (AC) Followed by Ixabepilone vs. AC Followed by Paclitaxel in Patients With Triple-Negative Early-Stage Breast Cancer
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Breast Cancer
Keywords: Breast Cancer
Adjuvant
Doxorubicin
Cyclophosphamide
Paclitaxel
Ixabepilone
TITAN
Lead sponsor: SCRI Development Innovations, LLC
Sponsor class: OTHER
Collaborators: name: Bristol-Myers Squibb
First posted: 2008-11-13
Enrollment: 614
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a randomized, Phase III, open-label, multicenter study.

Detailed description: Patients will be randomized in a 1:1 ratio to receive one of two different treatment arms. Patients in treatment arm 1 will receive AC followed by ixabepilone. Patients in treatment arm 2 will receive AC followed by weekly paclitaxel.

Eligibility criteria: Inclusion Criteria:

1. Female patients greater than or equal to18 years of age.
2. Histologically confirmed invasive unilateral breast cancer (regardless of

   histology).
3. Early-stage breast cancer, defined as:

   * Node-positive disease: \>0.2-mm metastasis in at least one lymph node (pN1mipN2b)OR
   * Node-negative, with primary tumor \>1.0 cm (T1c-T3).
4. Definitive loco-regional surgery must have been completed as specified

   below:
   * Patients must have undergone either breast conservation surgery

     (i.e., lumpectomy) or total mastectomy.
   * Surgical margins of the resected section must be histologically free of

   invasive adenocarcinoma and ductal carcinoma in situ.
   * Surgical margins involved with lobular carcinoma in situ (LCIS) will not

   be considered as a positive margin; therefore, such patients will be eligible for this study without additional resection.
   * Patients must have completed axillary lymph node sampling for the pathologic evaluation of axillary lymph nodes as specified below:

   Sentinel node biopsy and/or either lymph node sampling procedure or axillary dissection.
5. Multicentric and multifocal invasive breast cancer is eligible if loco-regional surgery has been completed as described above.
6. Patients with synchronous bilateral cancers are eligible only if:

   * All cancers are of triple-negative phenotype, defined as ER-, PR-, HER2-.
   * Eligibility based on the highest stage grouping.
7. HER2 negative tumors. HER2 negativity must be confirmed by one of the

   following:
   * FISH-negative (FISH ratio \<2.2), or
   * IHC 0-1+, or
   * IHC 2-3+ AND FISH-negative (FISH ratio \<2.2).
8. Estrogen receptor negative (\<10% staining by IHC for estrogen receptor).
9. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.
10. Patient must be \<= 84 days from having completed definitive primary breast surgery (either lumpectomy or mastectomy).
11. MammoSite brachytherapy radiation is acceptable if it is performed

    immediately following surgery and prior to chemotherapy. It is recommended that chemotherapy be started no earlier than 2 weeks following the removal of the MammoSite balloon catheter.
12. Adequate hematologic function, defined by:

    * Absolute neutrophil count (ANC) \>1500/mm3
    * Platelet count \>=100,000/mm3
    * Hemoglobin \>9 g/dL
13. Adequate liver function, defined by:

    * AST and ALT \<=2.5 x the upper limit of normal (ULN)
    * Total bilirubin \<=1.5 x ULN (unless the patient has grade 1 bilirubin

    elevation due to Gilbert's disease or a similar syndrome involving slow

    conjugation of bilirubin).
14. Adequate renal function, defined by:

    * Serum creatinine \<=1.5 x ULN
15. Complete staging work-up \<=12 weeks prior to initiation of study treatment

    with computed tomography (CT) scans of the chest and abdomen/pelvis (abdomen/pelvis preferred; abdomen accepted), and either a positron emission tomography (PET) scan or a bone scan.
16. Adequate cardiac function, defined by a left ventricular ejection fraction

    (LVEF) value of \>50% (or normal per institutional guidelines) by MUGA scan or echocardiogram (ECHO).
17. Adequate recovery from recent surgery. At least 1 week must have elapsed from the time of a minor surgery (i.e., sentinel node biopsy, port-acath (placement); at least 3 weeks must have elapsed from the time of a major surgery (i.e., lumpectomy, partial or total mastectomy, axillary lymph node dissection, breast reconstruction procedure).
18. Patients with previous history of invasive cancers (including breast cancer)

    are eligible if definitive treatment was completed more than 5 years prior to

    initiating current study treatment, and there is no evidence of recurrent disease.
19. Women of childbearing potential must have a negative serum or urine pregnancy test performed within 7 days prior to start of treatment. If a woman becomes pregnant or suspects she is pregnant while participating in this study, she must agree to inform her treating physician immediately.
20. Patient must be accessible for treatment and follow-up.
21. Women of childbearing potential must agree to use an acceptable method of birth control to avoid pregnancy for the duration of study treatment, and for 3 months thereafter.
22. All patients must be able to understand the investigational nature of the

study and give written informed consent prior to study entry.

Exclusion Criteria:

1. Women who are pregnant or breastfeeding.
2. History of previous diagnosis of invasive breast cancer (unless treated \>5 years previously with no recurrence). History of previously treated ductal carcinoma in situ (DCIS) is acceptable.
3. Any evidence or suspicion of metastatic disease other than ipsilateral

   axillary lymph nodes.
4. Any tumor \>=T4 (cutaneous invasion, deep adherence, inflammatory breast cancer).
5. Previous anthracycline chemotherapy.
6. Concurrent use of CYP3A4 inhibitors from 72 hours prior to initiation of

   study treatment until the end of treatment with ixabepilone.
7. Previous treatment for this breast cancer (including neoadjuvant

   chemotherapy).
8. Previous cancer (with the exception of non-melanoma skin cancer or cervical carcinoma in situ) in the past 5 years (including invasive contralateral breast cancer).
9. Peripheral neuropathy of \> grade 1 per NCI CTCAE v3.0.
10. Cardiac disease, including: congestive heart failure (CHF) \> Class II per

    New York Heart Association (NYHA) classification; unstable angina (anginal symptoms at rest) or new-onset angina (i.e., began within the last 3 months), or myocardial infarction within the past 6 months; symptomatic CHF, unstable angina pectoris, cardiac arrhythmia, or cardiac ventricular arrhythmias requiring anti-arrhythmic therapy.
11. History of hypersensitivity to CremophorEL (polyoxyethylated castor oil) or

    a drug formulated in CremophorEL such as paclitaxel.
12. Use of any investigational agent within 30 days of administration of the first dose of study drug.
13. Patients may not receive any other investigational or anti-cancer treatments while participating in this study.
14. Concurrent severe, uncontrolled infection or intercurrent illness including,

    but not limited to, ongoing or active infection, or psychiatric illness/social

    situations that would limit compliance with study requirements.
15. Mental condition that would prevent patient comprehension of the nature of, and risk associated with, the study.
16. Inability to comply with study and/or follow-up procedures.

Primary outcomes:
measure: Disease-free Survival
timeFrame: up to 5.25 years (63 months)
Secondary outcomes:
measure: Overall Survival
timeFrame: up to 5.25 years (63 months)
Other outcomes:
Locations:
city: Anniston
country: United States
facility: Northeast Alabama Regional Medical Center
state: Alabama
city: Huntsville
country: United States
facility: Cancer Center of Huntsville
state: Alabama
city: Huntsville
country: United States
facility: Clearview Cancer Institute
state: Alabama
city: Mobile
country: United States
facility: University of Southern Alabama
state: Alabama
city: Jonesboro
country: United States
facility: Northeast Arkansas Clinic
state: Arkansas
city: La Verne
country: United States
facility: Wilshire Oncology Medical Group
state: California
city: Pomona
country: United States
facility: New Hope Cancer and Research Institute
state: California
city: Norwich
country: United States
facility: Eastern Connecticut Hematology Oncology
state: Connecticut
city: Aventura
country: United States
facility: Aventura Medical Center
state: Florida
city: Boca Raton
country: United States
facility: Lynn Cancer Institute
state: Florida
city: Davie
country: United States
facility: Florida Cancer Care
state: Florida
city: Fort Lauderdale
country: United States
facility: Holy Cross Hospital
state: Florida
city: Fort Myers
country: United States
facility: Florida Cancer Specialists
state: Florida
city: Hollywood
country: United States
facility: Memorial Regional Cancer Center
state: Florida
city: Jacksonville
country: United States
facility: Integrated Community Oncology Network
state: Florida
city: Lakeland
country: United States
facility: Watson Clinic Center for Cancer Care and Research
state: Florida
city: Titusville
country: United States
facility: Space Coast Medical Associates
state: Florida
city: Atlanta
country: United States
facility: Piedmont Healthcare
state: Georgia
city: Atlanta
country: United States
facility: Emory/Winship Cancer Institute
state: Georgia
city: Augusta
country: United States
facility: Augusta Oncology Associates
state: Georgia
city: Augusta
country: United States
facility: Medical Oncology Associates of Augusta
state: Georgia
city: Augusta
country: United States
facility: Medical College of Georgia Cancer Specialists
state: Georgia
city: Gainesville
country: United States
facility: Northeast Georgia Medical Center
state: Georgia
city: Lawrenceville
country: United States
facility: Suburban Hem Onc
state: Georgia
city: Normal
country: United States
facility: Mid-Illinois Hematology & Oncology
state: Illinois
city: Skokie
country: United States
facility: Hematology Oncology of the North Shore
state: Illinois
city: Evansville
country: United States
facility: Oncology Hematology Associates of SW Indiana
state: Indiana
city: Indianapolis
country: United States
facility: Hematology Oncology of Indiana
state: Indiana
city: Terre Haute
country: United States
facility: Providence Medical Group
state: Indiana
city: Overland Park
country: United States
facility: Kansas City Cancer Centers
state: Kansas
city: Topeka
country: United States
facility: Cotton O'Neil Cancer Center
state: Kansas
city: Louisville
country: United States
facility: Consultants in Blood Disorders and Cancer
state: Kentucky
city: Baton Rouge
country: United States
facility: Baton Rouge General Medical Center
state: Louisiana
city: Portland
country: United States
facility: Mercy Hospital
state: Maine
city: Baltimore
country: United States
facility: Weinberg Cancer Institute at Franklin Square
state: Maryland
city: Bethesda
country: United States
facility: Center for Cancer and Blood Disorders
state: Maryland
city: Worcester
country: United States
facility: Fallon Clinic
state: Massachusetts
city: Grand Rapids
country: United States
facility: Grand Rapids Clinical Oncology Program
state: Michigan
city: Edina
country: United States
facility: Fairview Medical Oncology Clinic
state: Minnesota
city: Chesterfield
country: United States
facility: St. Louis Cancer Care
state: Missouri
city: Kansas City
country: United States
facility: Research Medical Center
state: Missouri
city: Springfield
country: United States
facility: St. John's Clinic
state: Missouri
city: Omaha
country: United States
facility: Methodist Cancer Center
state: Nebraska
city: Denville
country: United States
facility: St. Clare's Hospital Oncology and Hematology
state: New Jersey
city: Morristown
country: United States
facility: Hematology Oncology Associates of Northern NJ
state: New Jersey
city: Vineland
country: United States
facility: Southern Oncology and Hematology
state: New Jersey
city: Albuquerque
country: United States
facility: New Mexico Oncology Hematology Consultants
state: New Mexico
city: Burlington
country: United States
facility: Alamance Regional Medical Center
state: North Carolina
city: Cincinnati
country: United States
facility: Oncology Hematology Care
state: Ohio
city: Columbus
country: United States
facility: Mid Ohio Oncology/Hematology, Inc./ The Mark H. Zangmeister Center
state: Ohio
city: Elyria
country: United States
facility: Hematology/Oncology Inc
state: Ohio
city: Sylvania
country: United States
facility: Hickman Cancer Center (Flower Hospital)
state: Ohio
city: Pittsburgh
country: United States
facility: University of Pittsburgh Medical Center
state: Pennsylvania
city: Rockledge
country: United States
facility: Bux-Mont Oncology, Fox Chase Cancer Center
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Columbia
country: United States
facility: South Carolina Oncology Associates, PA
state: South Carolina
city: Mount Pleasant
country: United States
facility: Lowcountry Hematology Oncology
state: South Carolina
city: Myrtle Beach
country: United States
facility: Coastal Cancer Center
state: South Carolina
city: Spartanburg
country: United States
facility: Spartanburg Regional Medical Center
state: South Carolina
city: Chattanooga
country: United States
facility: Associates in Hematology Oncology
state: Tennessee
city: Chattanooga
country: United States
facility: Chattanooga Oncology Hematology Associates
state: Tennessee
city: Collierville
country: United States
facility: Family Cancer Center
state: Tennessee
city: Nashville
country: United States
facility: Tennessee Oncology, PLLC
state: Tennessee
city: Corpus Christi
country: United States
facility: Coastal Bend Cancer Center
state: Texas
city: Fort Worth
country: United States
facility: Center for Cancer and Blood Disorders
state: Texas
city: Houston
country: United States
facility: Medical Oncology Methodist Hospital
state: Texas
city: San Antonio
country: United States
facility: South Texas Oncology and Hematology
state: Texas
city: Newport News
country: United States
facility: Peninsula Cancer Institute
state: Virginia
city: Richmond
country: United States
facility: Virginia Cancer Institute
state: Virginia
city: San Juan
country: Puerto Rico
facility: San Juan Hospital
Study officials:
affiliation: SCRI Development Innovations, LLC
name: Denise A Yardley, M.D.
role: STUDY_CHAIR
References:
citation: Yardley DA, Arrowsmith ER, Daniel BR, Eakle J, Brufsky A, Drosick DR, Kudrik F, Bosserman LD, Keaton MR, Goble SA, Bubis JA, Priego VM, Pendergrass K, Manalo Y, Bury M, Gravenor DS, Rodriguez GI, Inhorn RC, Young RR, Harwin WN, Silver C, Hainsworth JD, Burris HA 3rd. TITAN: phase III study of doxorubicin/cyclophosphamide followed by ixabepilone or paclitaxel in early-stage triple-negative breast cancer. Breast Cancer Res Treat. 2017 Aug;164(3):649-658. doi: 10.1007/s10549-017-4285-6. Epub 2017 May 15.