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

• Sponsor: Eli Lilly and Company (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00728949
• Collaborator: (none)
• Enrollment: 93
• Locations: 9
• Arms: 2
• Duration (Months): 78
• Patients Per Site: 10.3
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Metastatic Breast Cancer	Biological: IMC-A12 (cixutumumab); Drug: tamoxifen; Drug: Anastrozole; Drug: Letrozole; Drug: Exemestane; Drug: Fulvestrant	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 93 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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
• Study Start Date: Aug 1, 2008
• Actual Primary Completion Date: Mar 1, 2012
• Actual Study Completion Date: Feb 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: 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.	Biological: IMC-A12 (cixutumumab); 10 mg/kg I.V.; Other Names: Cixutumumab LY3012217 ; Drug: tamoxifen; Daily 20 mg, oral; Drug: Anastrozole; Daily 1 mg, oral; Drug: Letrozole; Daily 2.5 mg, oral; Drug: Exemestane; Daily 25 mg, oral; Drug: Fulvestrant; Monthly 250 mg, intramuscularly
Experimental: IMC-A12 (cixutumumab) Participants will receive only IMC-A12 (10 mg/kg over 1 hour every 2 weeks).	Biological: IMC-A12 (cixutumumab); 10 mg/kg I.V.; Other Names: Cixutumumab LY3012217

Outcome Measures

Primary Outcome Measures

1. 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.

2. 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 Outcome Measures

1. 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.

2. 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.

3. 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.

4. 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.

5. Changes in Circulating Tumor Cell Counts (CTS) [Approximately 24 months]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: Female
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	ImClone Investigational Site	Scottsdale	Arizona	United States	85259
2	ImClone Investigational Site	Chicago	Illinois	United States	60611
3	ImClone Investigational Site	Westwood	Kansas	United States	66205
4	ImClone Investigational Site	Rochester	Minnesota	United States	55905-0002
5	ImClone Investigational Site	Lebanon	New Hampshire	United States	03756
6	ImClone Investigational Site	Bronx	New York	United States	10461
7	ImClone Investigational Site	New York	New York	United States	10021
8	ImClone Investigational Site	Columbus	Ohio	United States	43210
9	ImClone Investigational Site	Nashville	Tennessee	United States	37203

Sponsors and Collaborators

• Eli Lilly and Company

Investigators

• Study Director: Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 9 AM - 5 PM Eastern time (UTC/GMT - 5 hours, EST), Eli Lilly and Company

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Eli Lilly and Company
• ClinicalTrials.gov Identifier: NCT00728949
• Other Study ID Numbers: 13935; CP13-0604; I5A-IE-JAEK
• First Posted: Aug 6, 2008
• Last Update Posted: Jun 6, 2018
• Last Verified: May 1, 2018

• Keywords provided by Eli Lilly and Company: breast cancer; Postmenopausal; Hormones; Antiestrogen
• Additional relevant MeSH terms: Breast Neoplasms; Tamoxifen; Letrozole; Fulvestrant; Anastrozole; Exemestane; Antibodies, Monoclonal

Study Results

Participant Flow

Pre-assignment Detail	Participants who had progressive disease (PD) were considered to complete the study

Arm/Group Title	IMC-A12 (Cixutumumab) + Antiestrogen Therapy	IMC-A12 (Cixutumumab)
Arm/Group Description	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.	Participants will receive only IMC-A12 (10 mg/kg over 1 hour every 2 weeks).
Period Title: Overall Study
STARTED	62	31
COMPLETED	51	27
NOT COMPLETED	11	4

Baseline Characteristics

Arm/Group Title	IMC-A12 (Cixutumumab) + Antiestrogen Therapy	IMC-A12 (Cixutumumab)	Total
Arm/Group Description	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.	Participants will receive only IMC-A12 (10 mg/kg over 1 hour every 2 weeks).	Total of all reporting groups
Overall Participants	62	31	93
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	37 59.7%	24 77.4%	61 65.6%
>=65 years	25 40.3%	7 22.6%	32 34.4%
Sex: Female, Male (Count of Participants)
Female	62 100%	31 100%	93 100%
Male	0 0%	0 0%	0 0%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 1.6%	1 3.2%	2 2.2%
Not Hispanic or Latino	61 98.4%	30 96.8%	91 97.8%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	5 8.1%	4 12.9%	9 9.7%
White	55 88.7%	26 83.9%	81 87.1%
More than one race	2 3.2%	1 3.2%	3 3.2%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (Count of Participants)
United States	62 100%	31 100%	93 100%

Outcome Measures

1. Primary Outcome

Title	Progression-Free Survival (PFS)
Description	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

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) population: All randomized participants who were randomized regardless of actual treatment.

Arm/Group Title	IMC-A12 (Cixutumumab) + Antiestrogen Therapy	IMC-A12 (Cixutumumab)
Arm/Group Description	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.	Participants will receive only IMC-A12 (10 mg/kg over 1 hour every 2 weeks).
Measure Participants	62	31
Median (90% Confidence Interval) [months]	2.0	3.1

2. Secondary Outcome

Title	Percentage of Participants With Complete Response (CR) and Partial Response (PR) (Objective Response Rate [ORR])
Description	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

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) population: All randomized participants who were randomized regardless of actual treatment.

Arm/Group Title	IMC-A12 (Cixutumumab) + Antiestrogen Therapy	IMC-A12 (Cixutumumab)
Arm/Group Description	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.	Participants will receive only IMC-A12 (10 mg/kg over 1 hour every 2 weeks).
Measure Participants	62	31
Number (95% Confidence Interval) [percentage of participants]	1.6 2.6%	0 0%

3. Secondary Outcome

Title	12-Month Survival Rate
Description	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

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) population: All randomized participants who receive any drug.

Arm/Group Title	IMC-A12 (Cixutumumab) + Antiestrogen Therapy	IMC-A12 (Cixutumumab)
Arm/Group Description	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.	Participants will receive only IMC-A12 (10 mg/kg over 1 hour every 2 weeks).
Measure Participants	62	31
Number (90% Confidence Interval) [percentage of participants]	15 24.2%	7.6 24.5%

4. Secondary Outcome

Title	Percentage of Participants With Complete Response (CR) and Partial Response (PR) or Stable Disease (SD) Disease Control Rate [DCR])
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	IMC-A12 (Cixutumumab) + Antiestrogen Therapy	IMC-A12 (Cixutumumab)
Arm/Group Description	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.	Participants will receive only IMC-A12 (10 mg/kg over 1 hour every 2 weeks).
Measure Participants	62	31
Number (95% Confidence Interval) [percentage of participants]	40.3 65%	51.6 166.5%

5. Secondary Outcome

Title	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)
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	IMC-A12 (Cixutumumab) + Antiestrogen Therapy	IMC-A12 (Cixutumumab)
Arm/Group Description	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.	Participants will receive only IMC-A12 (10 mg/kg over 1 hour every 2 weeks).
Measure Participants	56	37
Participants with any AE	55 88.7%	36 116.1%
Participants with SAE's	16 25.8%	11 35.5%
AE of greater than Grade 3	22 35.5%	19 61.3%
AE with outcome of Death	3 4.8%	2 6.5%
Study drug-related AE	48 77.4%	31 100%
Study drug-related SAE's	5 8.1%	2 6.5%
Study drug-related AE of greater than Grade 3	10 16.1%	7 22.6%
AE leading to discontinuation of any study drug	6 9.7%	1 3.2%

6. Secondary Outcome

Title	Changes in Circulating Tumor Cell Counts (CTS)
Time Frame	Approximately 24 months

Outcome Measure Data

Analysis Population Description

Zero participants analyzed. Circulating tumor cell counts were not collected for analysis.

Arm/Group Title	IMC-A12 (Cixutumumab) + Antiestrogen Therapy	IMC-A12 (Cixutumumab)
Arm/Group Description	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.	Participants will receive only IMC-A12 (10 mg/kg over 1 hour every 2 weeks).
Measure Participants	0	0

7. Primary Outcome

Title	Overall Survival (OS)
Description	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

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) population: All randomized participants who were randomized regardless of actual treatment.

Arm/Group Title	IMC-A12 (Cixutumumab) + Antiestrogen Therapy	IMC-A12 (Cixutumumab)
Arm/Group Description	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.	Participants will receive only IMC-A12 (10 mg/kg over 1 hour every 2 weeks).
Measure Participants	62	31
Median (90% Confidence Interval) [months]	20.3	NA

Adverse Events

Adverse Event Reporting Description	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/Group Title	IMC-A12 (Cixutumumab) + Antiestrogen Therapy		IMC-A12 (Cixutumumab)
Arm/Group Description	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.		Participants will receive only IMC-A12 (10 mg/kg over 1 hour every 2 weeks).
All Cause Mortality
	IMC-A12 (Cixutumumab) + Antiestrogen Therapy		IMC-A12 (Cixutumumab)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	IMC-A12 (Cixutumumab) + Antiestrogen Therapy		IMC-A12 (Cixutumumab)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	16/56 (28.6%)		11/37 (29.7%)
Blood and lymphatic system disorders
Pancytopenia	0/56 (0%)	0	1/37 (2.7%)	2
Cardiac disorders
Pericarditis	0/56 (0%)	0	1/37 (2.7%)	1
Gastrointestinal disorders
Abdominal pain	1/56 (1.8%)	1	2/37 (5.4%)	2
Anal fissure	1/56 (1.8%)	1	0/37 (0%)	0
Ascites	1/56 (1.8%)	1	0/37 (0%)	0
Constipation	0/56 (0%)	0	1/37 (2.7%)	1
Diarrhoea	1/56 (1.8%)	1	1/37 (2.7%)	1
Nausea	0/56 (0%)	0	2/37 (5.4%)	2
Oesophageal pain	0/56 (0%)	0	1/37 (2.7%)	1
Vomiting	0/56 (0%)	0	2/37 (5.4%)	2
General disorders
Disease progression	2/56 (3.6%)	2	2/37 (5.4%)	2
Infusion related reaction	1/56 (1.8%)	1	0/37 (0%)	0
Pain	0/56 (0%)	0	1/37 (2.7%)	1
Hepatobiliary disorders
Hepatic cirrhosis	1/56 (1.8%)	1	0/37 (0%)	0
Infections and infestations
Gastroenteritis	0/56 (0%)	0	1/37 (2.7%)	1
Gastroenteritis viral	1/56 (1.8%)	1	0/37 (0%)	0
Pneumonia	1/56 (1.8%)	1	0/37 (0%)	0
Injury, poisoning and procedural complications
Wrong drug administered	1/56 (1.8%)	1	0/37 (0%)	0
Metabolism and nutrition disorders
Anorexia	0/56 (0%)	0	1/37 (2.7%)	1
Dehydration	2/56 (3.6%)	2	0/37 (0%)	0
Hyperglycaemia	2/56 (3.6%)	2	1/37 (2.7%)	1
Musculoskeletal and connective tissue disorders
Back pain	0/56 (0%)	0	1/37 (2.7%)	2
Pain in extremity	0/56 (0%)	0	1/37 (2.7%)	1
Pathological fracture	1/56 (1.8%)	1	1/37 (2.7%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Malignant pleural effusion	1/56 (1.8%)	1	0/37 (0%)	0
Nervous system disorders
Syncope	1/56 (1.8%)	1	0/37 (0%)	0
Respiratory, thoracic and mediastinal disorders
Dyspnoea	1/56 (1.8%)	1	1/37 (2.7%)	1
Pulmonary embolism	1/56 (1.8%)	1	0/37 (0%)	0
Other (Not Including Serious) Adverse Events
	IMC-A12 (Cixutumumab) + Antiestrogen Therapy		IMC-A12 (Cixutumumab)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	55/56 (98.2%)		35/37 (94.6%)
Blood and lymphatic system disorders
Anaemia	3/56 (5.4%)	3	1/37 (2.7%)	1
Neutropenia	0/56 (0%)	0	2/37 (5.4%)	2
Thrombocytopenia	0/56 (0%)	0	2/37 (5.4%)	2
Eye disorders
Photopsia	4/56 (7.1%)	4	1/37 (2.7%)	1
Vision blurred	0/56 (0%)	0	4/37 (10.8%)	5
Gastrointestinal disorders
Abdominal pain	9/56 (16.1%)	9	4/37 (10.8%)	6
Abdominal pain upper	0/56 (0%)	0	2/37 (5.4%)	2
Constipation	10/56 (17.9%)	11	4/37 (10.8%)	8
Diarrhoea	12/56 (21.4%)	14	14/37 (37.8%)	16
Dry mouth	3/56 (5.4%)	3	3/37 (8.1%)	3
Dysphagia	1/56 (1.8%)	1	2/37 (5.4%)	2
Eructation	0/56 (0%)	0	2/37 (5.4%)	2
Gastrooesophageal reflux disease	1/56 (1.8%)	1	3/37 (8.1%)	3
Nausea	18/56 (32.1%)	23	11/37 (29.7%)	11
Oral pain	0/56 (0%)	0	3/37 (8.1%)	3
Stomatitis	3/56 (5.4%)	3	3/37 (8.1%)	3
Vomiting	10/56 (17.9%)	14	9/37 (24.3%)	12
General disorders
Asthenia	2/56 (3.6%)	2	2/37 (5.4%)	2
Chills	0/56 (0%)	0	2/37 (5.4%)	2
Fatigue	22/56 (39.3%)	32	20/37 (54.1%)	28
Infusion related reaction	4/56 (7.1%)	4	1/37 (2.7%)	1
Mucosal inflammation	1/56 (1.8%)	1	3/37 (8.1%)	3
Oedema peripheral	5/56 (8.9%)	5	1/37 (2.7%)	1
Pyrexia	3/56 (5.4%)	3	3/37 (8.1%)	3
Thirst	0/56 (0%)	0	3/37 (8.1%)	4
Infections and infestations
Gastroenteritis viral	0/56 (0%)	0	2/37 (5.4%)	2
Upper respiratory tract infection	2/56 (3.6%)	2	3/37 (8.1%)	3
Urinary tract infection	2/56 (3.6%)	2	2/37 (5.4%)	2
Investigations
Alanine aminotransferase increased	3/56 (5.4%)	3	3/37 (8.1%)	7
Aspartate aminotransferase increased	2/56 (3.6%)	2	3/37 (8.1%)	8
Blood creatinine increased	0/56 (0%)	0	2/37 (5.4%)	2
Weight decreased	24/56 (42.9%)	32	18/37 (48.6%)	26
Metabolism and nutrition disorders
Anorexia	9/56 (16.1%)	10	10/37 (27%)	13
Decreased appetite	2/56 (3.6%)	2	5/37 (13.5%)	5
Hyperglycaemia	6/56 (10.7%)	10	8/37 (21.6%)	11
Hypokalaemia	2/56 (3.6%)	3	2/37 (5.4%)	2
Musculoskeletal and connective tissue disorders
Arthralgia	9/56 (16.1%)	12	3/37 (8.1%)	4
Back pain	11/56 (19.6%)	11	6/37 (16.2%)	6
Bone pain	2/56 (3.6%)	2	3/37 (8.1%)	4
Muscle spasms	7/56 (12.5%)	11	4/37 (10.8%)	7
Musculoskeletal chest pain	4/56 (7.1%)	4	3/37 (8.1%)	3
Musculoskeletal pain	4/56 (7.1%)	4	5/37 (13.5%)	5
Pain in extremity	4/56 (7.1%)	4	1/37 (2.7%)	2
Nervous system disorders
Dizziness	8/56 (14.3%)	9	3/37 (8.1%)	3
Dysgeusia	0/56 (0%)	0	5/37 (13.5%)	10
Headache	3/56 (5.4%)	3	3/37 (8.1%)	3
Peripheral sensory neuropathy	0/56 (0%)	0	2/37 (5.4%)	3
Psychiatric disorders
Anxiety	1/56 (1.8%)	1	2/37 (5.4%)	2
Depression	4/56 (7.1%)	4	2/37 (5.4%)	2
Insomnia	5/56 (8.9%)	5	0/37 (0%)	0
Renal and urinary disorders
Pollakiuria	1/56 (1.8%)	1	2/37 (5.4%)	2
Respiratory, thoracic and mediastinal disorders
Cough	4/56 (7.1%)	4	5/37 (13.5%)	5
Dyspnoea	7/56 (12.5%)	7	5/37 (13.5%)	6
Epistaxis	1/56 (1.8%)	1	3/37 (8.1%)	3
Nasal congestion	1/56 (1.8%)	1	2/37 (5.4%)	2
Rhinorrhoea	3/56 (5.4%)	3	1/37 (2.7%)	1
Sneezing	0/56 (0%)	0	2/37 (5.4%)	2
Skin and subcutaneous tissue disorders
Dry skin	2/56 (3.6%)	2	2/37 (5.4%)	2
Erythema	3/56 (5.4%)	3	1/37 (2.7%)	1
Nail disorder	3/56 (5.4%)	3	3/37 (8.1%)	3
Pruritus	2/56 (3.6%)	3	4/37 (10.8%)	7
Pruritus generalised	3/56 (5.4%)	3	1/37 (2.7%)	1
Rash	8/56 (14.3%)	10	4/37 (10.8%)	5
Vascular disorders
Hypertension	4/56 (7.1%)	4	1/37 (2.7%)	1

Limitations/Caveats

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.

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.