A Study for Safety and Effectiveness of IMC-A12 by Itself or Combined With Antiestrogens to Treat Breast Cancer

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to determine whether IMC-A12 offers increased progression-free survival (PFS) associated with IMC-A12 monotherapy and IMC-A12 in combination with an antiestrogen therapy in patients with hormone receptor positive advanced or metastatic breast cancer that have experienced disease progression on antiestrogen therapy.

Detailed Description
-----------------
Breast cancer is the most common form of malignancy affecting women worldwide, with approximately 178,480 new cases of invasive breast cancer and 62,030 new cases of in situ breast cancer expected in the United States (US) in 2007. Approximately 40,460 women are expected to die of breast cancer in the coming year, making the disease the second leading cause of cancer-related mortality among women (trailing only cancers of the lung and bronchus). However, thanks in part to recent advances in treatment, mortality rates associated with breast cancer have declined consistently since 1990. Surgical resection and other treatments may particularly benefit patients whose disease is identified prior to metastasis; the 5-year survival rate for patients diagnosed with locoregionally advanced disease is 83%. However, women with distant metastases at diagnosis have a much poorer outlook, with a 5-year survival rate of only 26% and a median survival of approximately 2 years. Treatment of advanced disease may include first-line chemotherapy utilizing an anthracycline (eg, doxorubicin or epirubicin), antibody therapy, limited surgery, taxanes, and other cytotoxic agents. As complete responses are rare, these treatments are not generally employed as curative but in an effort to prolong life and provide symptom palliation. Approximately two-thirds of all breast cancers are positive for expression of the estrogen receptor.For patients whose tumors are positive for this receptor or the progesterone receptor, the preferred first-line treatment comprises blockade of estradiol synthesis or hormone receptor activity using aromatase inhibitors or antiestrogen agents. Although endocrine therapies are useful and well-tolerated, most patients respond to this form of treatment for about 12-18 months before developing refractory disease. New therapies able to provide additional benefit to patients with hormone receptor-positive, antiestrogen-refractory, advanced and metastatic breast cancer are required.

Official Title
-----------------
Phase 2 Randomized, Multicenter Study of IMC-A12 as a Single Agent or in Combination With Antiestrogens in Postmenopausal Women With Hormone Receptor-Positive Advanced or Metastatic Breast Cancer After Progression on Antiestrogen Therapy

Conditions
-----------------
Metastatic Breast Cancer

Intervention / Treatment
-----------------
* Biological: IMC-A12 (cixutumumab)
* Drug: tamoxifen
* Drug: Anastrozole
* Drug: Letrozole
* Drug: Exemestane
* Drug: Fulvestrant


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: The patient has histologically or cytologically-confirmed invasive breast cancer, which at the time of study entry is either stage III (locally advanced) disease not amenable to curative therapy or stage IV disease. Histological confirmation of recurrent/metastatic disease is not required if clinical evidence of stage IV disease recurrence is available Tumors are positive for estrogen receptors (ER), progesterone receptors (PgR), or both (ie, 10% or more of infiltrating cancer cells exhibit nuclear staining for ER and/or PgR; positive biochemical test results are also acceptable) The patient has received prior antiestrogen therapy: With at least one antiestrogen agent (with or without ovarian suppression) administered for ≥ 3 months in the adjuvant or metastatic setting; and Experienced disease progression while on or within 12 months after receiving the last dose of endocrine therapy The patient is postmenopausal and/or meets at least one of the following criteria: Age ≥ 18 years with an intact uterus and amenorrhea for ≥ 12 months, with estradiol and/or follicle-stimulating hormone (FSH) values in the postmenopausal range History of bilateral oophorectomy History of bilateral salpingo-oophorectomy History of radiation castration and amenorrheic for ≥ 3 months The patient has fasting serum glucose < 120 mg/dL or below the ULN Exclusion Criteria: The patient has received more than two regimens of prior chemotherapy in the metastatic (or locally advanced and inoperable breast cancer) and adjuvant setting The patient has poorly controlled diabetes mellitus. Patients with a history of diabetes mellitus are allowed to participate, provided that their blood glucose is within normal range (fasting glucose at study entry < 120 mg/dL or below ULN) and that they are on a stable dietary and/or therapeutic regimen for this condition The patient is known to be positive for infection with the human immunodeficiency virus

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: IMC-A12 (cixutumumab) + antiestrogen therapy<br>Participants will receive intravenous IMC-A12 10 mg/kg over 1 hour every 2 weeks, as well as the same dose and schedule of the last antiestrogen therapy to which their disease became refractory. | Biological: IMC-A12 (cixutumumab)<br>* 10 mg/kg I.V.<br>* Other names: LY3012217;Drug: tamoxifen<br>* Daily 20 mg, oral<br>Drug: Anastrozole<br>* Daily 1 mg, oral<br>Drug: Letrozole<br>* Daily 2.5 mg, oral<br>Drug: Exemestane<br>* Daily 25 mg, oral<br>Drug: Fulvestrant<br>* Monthly 250 mg, intramuscularly<br>|
| Experimental: IMC-A12 (cixutumumab)<br>Participants will receive only IMC-A12 (10 mg/kg over 1 hour every 2 weeks). | Biological: IMC-A12 (cixutumumab)<br>* 10 mg/kg I.V.<br>* Other names: LY3012217;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) | PFS is defined as the time from the date of randomization until date of objectively determined progressive disease (PD) or death due to any cause. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a ≥20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions unequivocal progression of non-target lesions. Participants without documentation of progression or death will be censored at the date of last tumor assessment. The PFS will be estimated following the Kaplan-Meier method. | From randomization up to 35.1 Months | 
| Overall Survival (OS) | OS is defined as the interval between date of randomization and the date of death due to any cause. Participants who are alive at the time of study completion will be censored at the time the participants was last known to be alive. | From randomization up to 36.5 Months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Complete Response (CR) and Partial Response (PR) (Objective Response Rate [ORR]) | Best overall response of CR or PR was defined using RECIST v 1.0 criteria. CR was defined as the disappearance of all lesions, pathological lymph node reduction in short axis to <10 mm, and normalization of tumor marker levels of non-target lesions. PR was defined as ≥30% decrease in sum of longest diameter (SOD) of target lesions taking as reference the baseline sum diameter. PD was defined as ≥20% increase in SOD of target lesions and short axes of target lymph nodes, taking as reference the smallest sum of the longest diameters recorded since treatment started and an absolute increase in sum diameter of ≥5 mm; appearance of ≥1 new lesions and/or unequivocal progression of existing non-target lesions. Participants who had no post baseline tumor assessments were considered non-responders and included in the denominator when calculating response rate. Percentage of participants=(number of participants with CR+PR/total number of participants)*100. | Randomization to PD up to 35.1 Months | 
| 12-Month Survival Rate | The 12-month survival rate is defined as the percentage of participants who have not died 12 months after the date of randomization. | From randomization to until the date of first documented date of death from any cause within 12 months, assessed up to 35.1 months | 
| Percentage of Participants With Complete Response (CR) and Partial Response (PR) or Stable Disease (SD) Disease Control Rate [DCR]) | DCR is defined as percentage of participants with CR, PR, or SD using RECIST v 1.0 criteria. CR: disappearance of all lesions, pathological lymph node reduction in short axis to <10 mm, and normalization of tumor marker levels of non-target lesions. PR: ≥30% decrease in SOD of target lesions taking as reference baseline sum diameter. PD: ≥20% increase in SOD of target lesions and short axes of target lymph nodes, taking as reference smallest sum of longest diameters recorded since treatment started and an absolute increase in sum diameter ≥5 mm; appearance of ≥1 new lesions and/or unequivocal progression of existing non-target lesions. SD: neither sufficient shrinkage to qualify for PR nor increase to qualify for PD. Participants who had no post baseline tumor assessments were considered non-responders and included in the denominator when calculating response rate. Percentage of participants=(number of participants with CR+PR+SD/total number of participants)*100. | Randomization to PD up to 35.1 Months | 
| Number of Participants Experiencing Adverse Events (AEs) in National Cancer Institute Common Toxicity Criteria for AE's (NCI-CTCAE) Version 3.0 Criteria for Adverse Events (NCI-CTCAE) | The NCI-CTCAE provides descriptive terminology for adverse event reporting. A grading (severity) scale is provided for each adverse event term. Severity will be graded as mild (grade 1), moderate (grade 2), severe (grade 3), or very severe (life threatening - grade 4). Clinically significant events were defined as serious and other non-serious adverse events related to study drug regardless of causality. A summary of serious and other non-serious adverse events is located in the Reported Adverse Event module. | Randomization to End of Study up to 36.5 Months | 
| Changes in Circulating Tumor Cell Counts (CTS) |  | Approximately 24 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
breast cancer, Postmenopausal, Hormones, Antiestrogen