A Phase III Open Label, Randomized, 2 Arm Study of Ixabepilone Administered Every 21 Days Versus Paclitaxel Or Doxorubicin Administered Every 21 Days in Women with Advanced Endometrial Cancer Who Have Previously Been Treated with Chemotherapy

• Register: REBEC
• Last refreshed on: 29 April 2013
• Main ID: RBR-7spw98
• Date of registration: 21/06/2011
• Primary sponsor: Bristol-Myers Squibb - Brazil
• Public title: A Phase III Open Label, Randomized, 2 Arm Study of Ixabepilone Administered Every 21 Days Versus Paclitaxel Or Doxorubicin Administered Every 21 Days in Women with Advanced Endometrial Cancer Who Have Previously Been Treated with Chemotherapy
• Scientific title: A Phase III Open Label, Randomized, 2 Arm Study of Ixabepilone Administered Every 21 Days Versus Paclitaxel Or Doxorubicin Administered Every 21 Days in Women with Advanced Endometrial Cancer Who Have Previously Been Treated with Chemotherapy - IXAMPLE2
• Date of first enrolment: 01/03/2010
• Target sample size: 500
• Recruitment status: recruiting
• URL: http://www.ensaiosclinicos.gov.br/rg/RBR-7spw98/
• Study design: Therapeutic, multicenter, open, randomized, parallel with 2 arms and phase 3.

Countries of recruitment

Australia, Austria, Belgium, Brazil, Canada, Czech Republic, Denmark, Finland, France, Germany, Greece, Hungary, Italy, Norway, Poland, Russian Federation, Sweden, United Kingdom, United States

Contacts

• Name: Juliana Castro
• Affiliation: Bristol-Myers Squibb

• Name: Juliana Castro
• Affiliation: Bristol-Myers Squibb

Key inclusion & exclusion criteria

Inclusion criteria: All subjects must be informed of the investigational nature of this study and must
sign and give written informed consent in accordance with institutional and
federal guidelines.
Histologic or cytologic diagnosis of endometrial carcinoma.
Evidence that the cancer is locally advanced, recurrent or metastatic and not
curable by local measures (ie, surgery, radiation).
Karnofsky performance status (KPS) 70, 80, 90, or 100 (see Appendix 2).
Subjects must have measurable or non-measurable disease (see Section 6.4.3) that
has progressed since last treatment. A maximum of 140 subjects with
non-measurable disease will be randomized.
Notes:
If the subject’s only disease is confined to a solitary lesion, its neoplastic
nature must be confirmed by histology or cytology.
Disease in a previously irradiated field is acceptable as the only site of
measurable disease only if there has been clear progression since completion
of radiotherapy.
All therapy directed at endometrial cancer must be discontinued 21 days prior to start of treatment, except for hormonal therapy which must be discontinued at
least 1 week prior to start of study treatment. Note: concurrent administration of hormone replacement therapy is allowed.
Subjects must have received one and only one prior chemotherapy (ie, cytotoxic)
regimen for locally advanced, recurrent or metastatic endometrial cancer. Subjects
with 1 additional prior chemotherapy regimen in the neoadjuvant or adjuvant
setting are allowed. Adjuvant/neoadjuvant therapy is defined as post or
preoperative therapy for Stage 1, 2, or 3 disease.
Subjects may have received any number of prior non-cytotoxic regimens such as
monoclonal antibodies, cytokines, signal transduction inhibitors, or hormonal
therapy.
Previous radiation therapy is allowed.
Women, ages 18 to older.
Women of childbearing potential (WOCBP) must be using an adequate method of
contraception to avoid pregnancy throughout the study and for up to 4 weeks after the last dose of investigational product in such a manner that the risk of pregnancy is minimized.
WOCBP include any female who has experienced menarche and who has not
undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or is not postmenopausal. Post menopause is defined as:
Amenorrhea ? 12 consecutive months without another cause or
For women with irregular menstrual periods and on hormone replacement
therapy (HRT), a documented serum follicle stimulating hormone (FSH) level > 35 mIU/mL
Women who are using oral contraceptives, other hormonal contraceptives
(vaginal products, skin patches, or implanted or injectable products), or
mechanical products such as an intrauterine device or barrier methods
(diaphragm, condoms, spermicides) to prevent pregnancy, or are practicing
abstinence or where their partner is sterile (eg, vasectomy) should be considered to be of childbearing potential.
WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 72 hours prior to the start of investigational product.
Exclusion criteria: WOCBP who are unwilling or unable to use an acceptable method to avoid
pregnancy for the entire study period and for up to 4 weeks after the last dose of
investigational product.
Women who are pregnant or breastfeeding.
Women with a positive pregnancy test on enrollment or prior to investigational
product administration.
Carcinosarcoma (malignant mixed mullerian tumor)
Endometrial leiomyosarcoma and endometrial stromal sarcomas.
Subjects with no prior chemotherapy (ie, cytotoxic) for locally advanced,
recurrent or metastatic endometrial cancer or subjects that received 2 or more
prior chemotherapy (ie, cytotoxic) regimens for locally advanced, recurrent or
metastatic endometrial cancer.
Subjects with known brain metastases. Note: brain scans are not required.
Receipt of prior ixabepilone therapy.
Concurrent active infection requiring antibiotics or other therapy.
Concurrent unstable disease or other debilitating illness that could jeopardize
participation such as congestive heart failure, unstable angina, myocardial
infarction or other cardiac disease within last 6 months.
For subjects whose prior therapy did not include an anthracycline (eg,
doxorubicin) and therefore may be randomized to doxorubicin, LVEF of < 50%
as measured by multi-gated radionuclide angiography (MUGA) or
echocardiography (ECHO).
History of prior malignancy within last 5 years except non-melanoma skin cancer,
carcinoma in situ of the cervix, or carcinoma in situ of the breast not treated with chemotherapy.
Known human immunodeficiency viral (HIV) infection.
Psychiatric disorders or other conditions rendering the subject incapable of
complying with the requirements of the protocol.
Absolute neutrophil count (ANC) < 1500/mm3.
Platelets < 100,000/ mm3.
Hemoglobin < 9 g/dL.
Total bilirubin > 1.5 times the institutional upper limit of normal (ULN), except for subjects with Gilbert’s disease.
AST or ALT > 2.5 times the institutional upper limit of normal (ULN).
Serum creatinine > 1.5 x institutional upper limit of normal (ULN).
Grade ? 2 neuropathy (sensory or motor).
Known allergy to any of the study drugs or their excipients such as, prior severe
HSR to agents containing Cremophor® EL.
No concurrent therapy directed at endometrial cancer (chemotherapy, hormonal,
or investigational during the study).
Subjects must not continue or institute treatment with the following strong
inhibitors of CYP3A4 from 72 hours prior to the initiation of study therapy until
end of treatment with ixabepilone or paclitaxel: Ketoconazole, itraconazole,
clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir,
amprenavir, indinavir, nelfinavir, delavirdine, or voriconazole (See IB1).
Other concurrent anti-tumor, chemotherapy, hormonal therapy, immunotherapy
regimens or radiation therapy, standard or investigational therapy (see
Section 5.5).
Prisoners or subjects who are involuntarily incarcerated.
Subjects who are compulsorily detained for treatment of either a psychiatric or
physical (eg, infectious disease) illness.

Age minimum: 18Y
Age maximum: 0Y
Gender: F

Health Condition(s) or Problem(s) studied

Advanced Endometrial Cancer
C54.1
C04.588.945.418.948.585

C00-D48

Intervention(s)

Comparison group: 250 patients will receive ixabepilone (40 mg/m2) administered IV over 3 hours every 21 days until disease progression or unacceptable toxicity. Control group: 250 patients will receive, depending on prior therapy received paclitaxel 175 mg/m2 administered intravenously for 3 hours or according to institutional guidelines every 21 days until progression or unacceptable toxicity or 60 mg/m2 of doxorubicin administered IV or according to institutional guidelines every 21 days until progression, cumulative dose of 500mg/m2 or unacceptable toxicity

Primary Outcome(s)

The primary analysis for this study will be a comparison of OS in all randomized subjects in the two treatment arms (ixabepilone vs control chemotherapy) using a two-sided, alpha = 0.05 level, log-rank test, stratified for measurable disease (yes versus no), prior anthracycline (yes versus no), and papillary serous or clear cell carcinoma (yes versus no) as established at the time of randomization.
The OS distribution of each randomized arm will be estimated using the Kaplan-Meier product-limit methods. A two-sided, 95% confidence interval for median OS in each arm will be computed using the Brookmeyer and Crowley method.
The hazard ratio of ixabepilone to control chemotherapy will be estimated using the Cox proportional hazard model stratified by prior anthracycline, and papillary serous or clear cell carcinoma with randomized treatment arm as the single covariate. A two-sided 95% confidence interval for the hazard ratio will be calculated.
A Cox proportional hazard model will be used to assess the association of potential prognostic factors with OS and to adjust the treatment comparison for these factors. This Cox model will be stratified for measurable disease (yes versus no), prior anthracycline use (yes versus no) and papillary serous or clear cell carcinoma (yes versus no) and will contain the following covariates: Karnofsky performance status (70 - 80 versus 90 - 100) and number of disease sites (<= 2 verses > 2). Estimates of the hazard ratio and its two-sided 95% confidence interval will be presented for each covariate, including randomized treatment.
In addition an unstratified log-rank test as well as an unstratified Cox proportional hazard model, using the stratification factors as covariates, will be performed.
The method of Gail and Simon38 will be used to test for a qualitative interaction between treatment and strata measurable disease (yes versus no), prior anthracycline (yes versus no), and papillary serous or clear cell carcinoma (yes or no). This test will be conducted at the alpha = 0.10 level.

Secondary Outcome(s)

PFS, overall response rate, duration of response and time to response are secondary endpoints for this study.
For these secondary endpoints, a hierarchical testing procedure will be used so that the overall experiment-wise Type I error rate is 0.05. Thus, if the primary efficacy analysis of OS shows a statistically significant difference between randomized arms, then testing of the treatment difference for PFS will proceed at the 0.05 two-sided significance level. If the overall survival analysis shows a significant difference between randomized treatment arms, then an analysis of overall response rate will proceed at the 0.05 two-sided significance level.
An interim analysis of overall survival will be performed when approximately 176 subjects will have death events
A comparison of PFS between the two randomized arms (ixabepilone verses control chemotherapy) using a two-sided, ? = 0.05 level, log-rank test, stratified for prior anthracycline use (yes versus no) and papillary serous or clear cell carcinoma (yes versus no) as established at the time of randomization will be performed. The PFS distribution of each randomized arm will be estimated using the Kaplan-Meier product-limit methods. A two-sided, 95% confidence interval for median survival in each arm will be computed. The hazard ratio and its 95% confidence interval of ixabepilone to control chemotherapy will be estimated using the same unadjusted and adjusted Cox proportional hazard model as described above for OS.
The analyses of tumor response will be based on the best overall response as determined by the investigators.
Overall response rate will be analyzed using the Cochran-Mantel-Haenszel (CMH) test, with an associated odds ratio estimate and 95% confidence interval, stratified by prior anthracycline, and papillary serous or clear cell carcinoma, to compare the response rates between the two randomized arms. The tumor response rate will be computed in each treatment arm for all randomized subjects. An exact two-sided 95% confidence interval for the response rate will be computed using the method of Clopper and Pearson.39 Time to response for each treatment arm will be summarized using descriptive statistics (median, minimum, and maximum). No formal statistical comparisons are planned.
The duration of overall response in each arm will be estimated using the Kaplan-Meier product limit method. Kaplan-Meier curves by randomized arm will be produced. A two-sided 95% confidence interval for median duration will be computed using the methods of Brookmeyer and Crowley. No formal statistical comparisons are planned.
For the primary OS endpoint, descriptive subset analyses will be performed for the following factors (as determined at baseline), measurable disease (yes, no), age (< 65, >= 65), race, prior anthracycline (yes, no); papillary serous or clear cell carcinoma (yes, no); Karnofsky performance status (70 - 80, 90 - 100), and number of disease sites (<= 2, > 2).
The above subset analyses will also be performed for PFS and response rate.

Secondary ID(s)

056/2010

1271/2009

NCT00883116

Source(s) of Monetary Support

Bristol-Myers Squibb - Brazil