Metastatic Breast Cancer
Conditions
Keywords
breast cancer, Postmenopausal, Hormones, Antiestrogen
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.
Interventions
BIOLOGICALIMC-A12 (cixutumumab)
10 mg/kg I.V.
DRUGtamoxifen
Daily 20 mg, oral
DRUGAnastrozole
Daily 1 mg, oral
DRUGLetrozole
Daily 2.5 mg, oral
DRUGExemestane
Daily 25 mg, oral
DRUGFulvestrant
Monthly 250 mg, intramuscularly
Sponsors
Eli Lilly and Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
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: 1. With at least one antiestrogen agent (with or without ovarian suppression) administered for ≥ 3 months in the adjuvant or metastatic setting; and 2. 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: 1. 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 2. History of bilateral oophorectomy 3. History of bilateral salpingo-oophorectomy 4. 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival (PFS) | From randomization up to 35.1 Months | 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. |
| Overall Survival (OS) | From randomization up to 36.5 Months | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Complete Response (CR) and Partial Response (PR) or Stable Disease (SD) Disease Control Rate [DCR]) | Randomization to PD up to 35.1 Months | 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. |
| Percentage of Participants With Complete Response (CR) and Partial Response (PR) (Objective Response Rate [ORR]) | Randomization to PD up to 35.1 Months | 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. |
| Changes in Circulating Tumor Cell Counts (CTS) | Approximately 24 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) | Randomization to End of Study up to 36.5 Months | 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. |
| 12-Month Survival Rate | From randomization to until the date of first documented date of death from any cause within 12 months, assessed up to 35.1 months | The 12-month survival rate is defined as the percentage of participants who have not died 12 months after the date of randomization. |
Countries
United States
Participant flow
Pre-assignment details
Participants who had progressive disease (PD) were considered to complete the study
Participants by arm
| Arm | Count |
|---|---|
| IMC-A12 (Cixutumumab) + Antiestrogen Therapy 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. | 62 |
| IMC-A12 (Cixutumumab) Participants will receive only IMC-A12 (10 mg/kg over 1 hour every 2 weeks). | 31 |
| Total | 93 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Abnormal Lab Results | 0 | 2 |
| Overall Study | Adverse Event | 8 | 0 |
| Overall Study | On treatment at cutoff date | 1 | 0 |
| Overall Study | Withdrawal by Subject | 2 | 2 |
Baseline characteristics
| Characteristic | IMC-A12 (Cixutumumab) + Antiestrogen Therapy | IMC-A12 (Cixutumumab) | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 25 Participants | 7 Participants | 32 Participants |
| Age, Categorical Between 18 and 65 years | 37 Participants | 24 Participants | 61 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 61 Participants | 30 Participants | 91 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants | 4 Participants | 9 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 55 Participants | 26 Participants | 81 Participants |
| Region of Enrollment United States | 62 Participants | 31 Participants | 93 Participants |
| Sex: Female, Male Female | 62 Participants | 31 Participants | 93 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 55 / 56 | 35 / 37 |
| serious Total, serious adverse events | 16 / 56 | 11 / 37 |
Outcome results
Primary
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.
Time frame: From randomization up to 36.5 Months
Population: Intent-to-treat (ITT) population: All randomized participants who were randomized regardless of actual treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| IMC-A12 (Cixutumumab) + Antiestrogen Therapy | Overall Survival (OS) | 20.3 months |
| IMC-A12 (Cixutumumab) | Overall Survival (OS) | NA months |
Primary
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.
Time frame: From randomization up to 35.1 Months
Population: Intent-to-treat (ITT) population: All randomized participants who were randomized regardless of actual treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| IMC-A12 (Cixutumumab) + Antiestrogen Therapy | Progression-Free Survival (PFS) | 2.0 months |
| IMC-A12 (Cixutumumab) | Progression-Free Survival (PFS) | 3.1 months |
Secondary
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.
Time frame: From randomization to until the date of first documented date of death from any cause within 12 months, assessed up to 35.1 months
Population: Intent-to-treat (ITT) population: All randomized participants who receive any drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IMC-A12 (Cixutumumab) + Antiestrogen Therapy | 12-Month Survival Rate | 15 percentage of participants |
| IMC-A12 (Cixutumumab) | 12-Month Survival Rate | 7.6 percentage of participants |
Secondary
Changes in Circulating Tumor Cell Counts (CTS)
Time frame: Approximately 24 months
Population: Zero participants analyzed. Circulating tumor cell counts were not collected for analysis.
Secondary
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.
Time frame: Randomization to End of Study up to 36.5 Months
Population: Safety population: All participants who received actual treatment of any drug. There is a difference of 6 participants for treatment groups of IMC-A12 (Cixutumumab) + Antiestrogen and IMC-A12 (Cixutumumab) of ITT population and Safety population due to planned treatment (based on randomization) differed from actual treatment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| IMC-A12 (Cixutumumab) + Antiestrogen Therapy | 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) | Participants with any AE | 55 Participants |
| IMC-A12 (Cixutumumab) + Antiestrogen Therapy | 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) | Participants with SAE's | 16 Participants |
| IMC-A12 (Cixutumumab) + Antiestrogen Therapy | 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) | AE of greater than Grade 3 | 22 Participants |
| IMC-A12 (Cixutumumab) + Antiestrogen Therapy | 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) | AE with outcome of Death | 3 Participants |
| IMC-A12 (Cixutumumab) + Antiestrogen Therapy | 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) | Study drug-related AE | 48 Participants |
| IMC-A12 (Cixutumumab) + Antiestrogen Therapy | 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) | Study drug-related SAE's | 5 Participants |
| IMC-A12 (Cixutumumab) + Antiestrogen Therapy | 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) | Study drug-related AE of greater than Grade 3 | 10 Participants |
| IMC-A12 (Cixutumumab) + Antiestrogen Therapy | 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) | AE leading to discontinuation of any study drug | 6 Participants |
| IMC-A12 (Cixutumumab) | 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) | AE leading to discontinuation of any study drug | 1 Participants |
| IMC-A12 (Cixutumumab) | 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) | Participants with any AE | 36 Participants |
| IMC-A12 (Cixutumumab) | 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) | Study drug-related AE | 31 Participants |
| IMC-A12 (Cixutumumab) | 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) | Participants with SAE's | 11 Participants |
| IMC-A12 (Cixutumumab) | 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) | Study drug-related AE of greater than Grade 3 | 7 Participants |
| IMC-A12 (Cixutumumab) | 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) | AE of greater than Grade 3 | 19 Participants |
| IMC-A12 (Cixutumumab) | 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) | Study drug-related SAE's | 2 Participants |
| IMC-A12 (Cixutumumab) | 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) | AE with outcome of Death | 2 Participants |
Secondary
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.
Time frame: Randomization to PD up to 35.1 Months
Population: Intent-to-treat (ITT) population: All randomized participants who were randomized regardless of actual treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IMC-A12 (Cixutumumab) + Antiestrogen Therapy | Percentage of Participants With Complete Response (CR) and Partial Response (PR) (Objective Response Rate [ORR]) | 1.6 percentage of participants |
| IMC-A12 (Cixutumumab) | Percentage of Participants With Complete Response (CR) and Partial Response (PR) (Objective Response Rate [ORR]) | 0 percentage of participants |
Secondary
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.
Time frame: Randomization to PD up to 35.1 Months
Population: Intent-to-treat (ITT) population: All randomized participants who were randomized regardless of actual treatment. Number of participants censored = 15 Cixutumumab + antiestrogen, 5 Cixutumumab only
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IMC-A12 (Cixutumumab) + Antiestrogen Therapy | Percentage of Participants With Complete Response (CR) and Partial Response (PR) or Stable Disease (SD) Disease Control Rate [DCR]) | 40.3 percentage of participants |
| IMC-A12 (Cixutumumab) | Percentage of Participants With Complete Response (CR) and Partial Response (PR) or Stable Disease (SD) Disease Control Rate [DCR]) | 51.6 percentage of participants |