A Study of Ramucirumab (IMC-1121B) in Participants With Breast Cancer

• Sponsor: Eli Lilly and Company (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01256567
• Collaborator: (none)
• Enrollment: 7
• Locations: 4
• Arm: 1
• Duration (Months): 26.1
• Patients Per Site: 1.8
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The primary objective of this study is to investigate the safety and tolerability of the anti-VEGFR-2 monoclonal antibody ramucirumab drug product in combination with docetaxel in Japanese participants with metastatic, or locally advanced breast cancer, with the aim of confirming the recommended dose of ramucirumab drug product (DP) in combination with docetaxel.

Condition or Disease	Intervention/Treatment	Phase
Breast Cancer; Metastatic Breast Cancer	Biological: Ramucirumab; Drug: Docetaxel	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 7 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 1b Study of Docetaxel in Combination With Ramucirumab (IMC-1121B) Drug Product in Patients With Locally Advanced or Metastatic Breast Cancer
• Study Start Date: Dec 1, 2010
• Actual Primary Completion Date: Nov 1, 2012
• Actual Study Completion Date: Feb 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: ramucirumab and docetaxel combination	Biological: Ramucirumab; Ramucirumab administered as an intravenous (I.V.) infusion at a dose of 10 milligrams per kilogram (mg/kg) every 3 weeks.; Other Names: IMC-1121B LY3009806 ; Drug: Docetaxel; Docetaxel administered by intravenous (I.V.) infusion at a dose of 75 milligrams per square meter (mg/m^2) every 3 weeks.

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Adverse Events [Baseline up to data cut off (approximately 48.3 weeks)]

   Number participants with drug related dose-limiting toxicities (DLT) during Cycle 1; ramucirumab related: treatment-emergent adverse events (TEAE), serious adverse events (SAE), Grade 3 or higher TEAE, or TEAE leading to discontinuation or ramucirumab dose modification. DLT=G4 neutropenia >7days; G ≥3 neutropenia with fever ≥38.5°C requiring IV antibiotics or bacteriemia or sepsis; G4 thrombocytopenia; G ≥3 thrombocytopenia with bleeding requiring platelets; G≥3 prothrombin time and/or partial thromboplastin time in absence of anticoagulants; G≥2 hyperbilirubinemia ≥5 days; QTc >500 milliseconds (ms) or increase ≥100 ms or arrhythmia; G≥4 or uncontrollable hypertension; G≥3 nonhematologic toxicity (excluding G3: hypersensitivity, injection-site reaction, arthralgia/myalgia, asthenia/fatigue, diarrhea without loperamide therapy, nausea/vomiting without antiemetics, transient G3/4 elevation of aminotransferases); treatment delay >2 weeks due to toxicity.

Secondary Outcome Measures

1. Serum Anti-IMC-1121B Antibody Assessment (Immunogenicity) [Baseline up to data cut off (approximately 48.3 weeks)]

   The number of participants with a positive anti-IMC-1121B titer at any point during the study.

2. Maximum Concentration (Cmax) of Ramucirumab [Day 1 of Cycle 1 and Cycle 4 (cycle=21 days)]

   Cmax (Cycle 1) and Cmax at steady state (Cmax,ss, Cycle 4) of ramucirumab are provided.

3. Area Under the Curve (AUC) of Ramucirumab [Day 1 of Cycles 1 and 4 (cycle=21 days)]

   AUC from time zero to infinity (AUC[0-inf], Cycle 1) and at steady state (AUC tau, Cycle 4) of ramucirumab are provided.

4. Half Life (t 1/2) of Ramucirumab [Day 1 of Cycles 1 and 4 (cycle=21 days)]

5. Clearance (Cl) of Ramucirumab [Day 1 of Cycle 1 and Cycle 4 (cycle=21 days)]

   Clearance (Cycle 1) and at steady state (Clss, Cycle 4) of ramucirumab are provided.

6. Steady State Volume of Distribution (Vss) of Ramucirumab [Day 1 of Cycle 1 and 4 (cycle=21 days)]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 20 Years and Older
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• The participant is Japanese

• The participant has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

• The participant has a histopathologically or cytologically confirmed diagnosis of breast adenocarcinoma that is now metastatic or locally-recurrent and inoperable with curative intent

• The participant has measurable and/or non-measurable disease

• The participants' primary and/or metastatic tumor is Human Epidermal Growth Factor Receptor 2 (HER2) negative

• The participant received neo adjuvant or adjuvant taxane therapy ≥ 6 months prior to the study

• The participant received neo adjuvant or adjuvant biologic therapy ≥ 6 weeks prior to the study

• The participant completed all prior radiotherapy ≥ 3 weeks prior to the study registration date

• The participant received prior hormonal therapy for breast cancer in the neo adjuvant, adjuvant,and/or the metastatic setting ≥ 2 weeks prior to the study registration date

• The participant's left ventricular ejection fraction (LVEF) is within normal ranges

• The participant has adequate hematologic, hepatic, and coagulation function.

• Eligible participants of reproductive potential agree to use adequate contraceptive methods (hormonal or barrier methods) during the study period and for 12 weeks after the last dose of study medication

Exclusion Criteria:

• The participant has a concurrent active malignancy other than breast adenocarcinoma, adequately treated non-melanomatous skin cancer, or other non-invasive carcinoma or in situ neoplasm. Participants with previous treatment of malignancy is eligible, provided that she has been disease free for >3 years

• The participant has a known sensitivity to docetaxel

• The participant has a known sensitivity to agents of similar biologic composition as ramucirumab

• The participant has a history of chronic diarrheal disease within 6 months prior to the study registration date

• The participant has received irradiation to a major bone marrow area within 30 days prior to the study registration date

• The participant has received any experimental agents within 4 weeks prior to the study registration date

• The participant has a history of uncontrolled hereditary or acquired bleeding or thrombotic disorders

• The participant has Grade 3-4 bleeding within 3 months prior to the study registration date

• The participant has an ongoing or active infection requiring antibiotic, antifungal, or antiviral therapy

• The participant has uncontrolled hypertension, symptomatic congestive heart failure, psychiatric illness, or any other serious uncontrolled medical disorders

• The participant has brain metastases

• The participant has known human immunodeficiency virus infection or acquired immunodeficiency syndrome related illness

• The participant is pregnant or lactating

• The participant has not fully recovered from effects of prior chemotherapy

• The participant has undergone major surgery within 28 days prior to the study registration date

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	ImClone Investigational Site	Hidaka		Japan	350-1298
2	ImClone Investigational Site	Matsuyama		Japan	790-0007
3	Imclone Investigational Site	Nagoya		Japan	464-8681
4	ImClone Investigational Site	Osaka		Japan	540-0006

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: NCT01256567
• Other Study ID Numbers: 14200; CP12-1028; I4T-IE-JVBX
• First Posted: Dec 8, 2010
• Last Update Posted: Jun 18, 2014
• Last Verified: May 1, 2014

• Additional relevant MeSH terms: Breast Neoplasms; Docetaxel; Ramucirumab

Study Results

Participant Flow

Arm/Group Title	Ramucirumab and Docetaxel Combination
Arm/Group Description	Docetaxel: Docetaxel administered by intravenous infusion at a dose of 75 milligrams per square meter (mg/m^2) every 3 weeks. Ramucirumab: Ramucirumab (IMC-1121B) administered as an intravenous infusion at a dose of 10 milligrams per kilogram (mg/kg) every 3 weeks.
Period Title: Overall Study
STARTED	7
Received at Least 1 Dose of Study Drug	7
COMPLETED	6
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	Ramucirumab and Docetaxel Combination
Arm/Group Description	Docetaxel: Docetaxel administered by intravenous infusion at a dose of 75 milligrams per square meter (mg/m^2) every 3 weeks. Ramucirumab: Ramucirumab administered as an intravenous infusion at a dose of 10 milligrams per kilogram (mg/kg) every 3 weeks.
Overall Participants	7
Age, Customized (participants) [Number]
Between 20 and 65 years	6 85.7%
>=65 years	1 14.3%
Sex: Female, Male (Count of Participants)
Female	7 100%
Male	0 0%
Race/Ethnicity, Customized (participants) [Number]
Asian	7 100%
American Indian or Alaska Native	0 0%
Black or African American	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
White	0 0%
Other	0 0%
Region of Enrollment (participants) [Number]
Japan	7 100%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Adverse Events
Description	Number participants with drug related dose-limiting toxicities (DLT) during Cycle 1; ramucirumab related: treatment-emergent adverse events (TEAE), serious adverse events (SAE), Grade 3 or higher TEAE, or TEAE leading to discontinuation or ramucirumab dose modification. DLT=G4 neutropenia >7days; G ≥3 neutropenia with fever ≥38.5°C requiring IV antibiotics or bacteriemia or sepsis; G4 thrombocytopenia; G ≥3 thrombocytopenia with bleeding requiring platelets; G≥3 prothrombin time and/or partial thromboplastin time in absence of anticoagulants; G≥2 hyperbilirubinemia ≥5 days; QTc >500 milliseconds (ms) or increase ≥100 ms or arrhythmia; G≥4 or uncontrollable hypertension; G≥3 nonhematologic toxicity (excluding G3: hypersensitivity, injection-site reaction, arthralgia/myalgia, asthenia/fatigue, diarrhea without loperamide therapy, nausea/vomiting without antiemetics, transient G3/4 elevation of aminotransferases); treatment delay >2 weeks due to toxicity.
Time Frame	Baseline up to data cut off (approximately 48.3 weeks)

Outcome Measure Data

Analysis Population Description

All participants who received at least 1 dose of study drug.

Arm/Group Title	Ramucirumab and Docetaxel Combination
Arm/Group Description	Docetaxel: Docetaxel administered by intravenous infusion at a dose of 75 milligrams per square meter (mg/m^2) every 3 weeks. Ramucirumab: Ramucirumab administered as an intravenous infusion at a dose of 10 milligrams per kilogram (mg/kg) every 3 weeks.
Measure Participants	7
Dose Limiting Toxicity (DLT) during Cycle 1	2 28.6%
TEAE related to ramucirumab	7 100%
SAE related to ramucirumab	4 57.1%
TEAE of Grade ≥3 related to ramucirumab	6 85.7%
TEAE resulting in ramucirumab discontinuation	3 42.9%
TEAE with ramucirumab dose modification/delay	5 71.4%

2. Secondary Outcome

Title	Serum Anti-IMC-1121B Antibody Assessment (Immunogenicity)
Description	The number of participants with a positive anti-IMC-1121B titer at any point during the study.
Time Frame	Baseline up to data cut off (approximately 48.3 weeks)

Outcome Measure Data

Analysis Population Description

All participants with evaluable antibody assessment data.

Arm/Group Title	Ramucirumab and Docetaxel Combination
Arm/Group Description	Docetaxel: Docetaxel administered by intravenous infusion at a dose of 75 milligrams per square meter (mg/m^2) every 3 weeks. Ramucirumab: Ramucirumab administered as an intravenous infusion at a dose of 10 milligrams per kilogram (mg/kg) every 3 weeks.
Measure Participants	7
Number [participants]	0 0%

3. Secondary Outcome

Title	Maximum Concentration (Cmax) of Ramucirumab
Description	Cmax (Cycle 1) and Cmax at steady state (Cmax,ss, Cycle 4) of ramucirumab are provided.
Time Frame	Day 1 of Cycle 1 and Cycle 4 (cycle=21 days)

Outcome Measure Data

Analysis Population Description

All participants with evaluable Cmax data at the specified time points.

Arm/Group Title	Ramucirumab and Docetaxel Combination
Arm/Group Description	Docetaxel: Docetaxel administered by intravenous infusion at a dose of 75 milligrams per square meter (mg/m^2) every 3 weeks. Ramucirumab: Ramucirumab administered as an intravenous infusion at a dose of 10 milligrams per kilogram (mg/kg) every 3 weeks.
Measure Participants	7
Cmax at Cycle 1	261 (22)
Cmax,ss at Cycle 4 (n=6)	335 (22)

4. Secondary Outcome

Title	Area Under the Curve (AUC) of Ramucirumab
Description	AUC from time zero to infinity (AUC[0-inf], Cycle 1) and at steady state (AUC tau, Cycle 4) of ramucirumab are provided.
Time Frame	Day 1 of Cycles 1 and 4 (cycle=21 days)

Outcome Measure Data

Analysis Population Description

All participants with evaluable AUC data at the specified time points.

Arm/Group Title	Ramucirumab and Docetaxel Combination
Arm/Group Description	Docetaxel: Docetaxel administered by intravenous infusion at a dose of 75 milligrams per square meter (mg/m^2) every 3 weeks. Ramucirumab: Ramucirumab administered as an intravenous infusion at a dose of 10 milligrams per kilogram (mg/kg) every 3 weeks.
Measure Participants	7
AUC(0-inf) at Cycle 1	1700 (25)
AUC tau at Cycle 4 (n=6)	2320 (24)

5. Secondary Outcome

Title	Half Life (t 1/2) of Ramucirumab
Time Frame	Day 1 of Cycles 1 and 4 (cycle=21 days)

Outcome Measure Data

Analysis Population Description

All participants with evaluable t1/2 data at the specified time points.

Arm/Group Title	Ramucirumab and Docetaxel Combination
Arm/Group Description	Docetaxel: Docetaxel administered by intravenous infusion at a dose of 75 milligrams per square meter (mg/m^2) every 3 weeks. Ramucirumab: Ramucirumab administered as an intravenous infusion at a dose of 10 milligrams per kilogram (mg/kg) every 3 weeks.
Measure Participants	7
t1/2 at Cycle 1	6.57 (49)
t1/2 at Cycle 4 (n=6)	11.9 (26)

6. Secondary Outcome

Title	Clearance (Cl) of Ramucirumab
Description	Clearance (Cycle 1) and at steady state (Clss, Cycle 4) of ramucirumab are provided.
Time Frame	Day 1 of Cycle 1 and Cycle 4 (cycle=21 days)

Outcome Measure Data

Analysis Population Description

All participants with evaluable clearance data at the specified time points.

Arm/Group Title	Ramucirumab and Docetaxel Combination
Arm/Group Description	Docetaxel : Docetaxel administered by intravenous infusion at a dose of 75 milligrams per square meter (mg/m^2) every 3 weeks. Ramucirumab : Ramucirumab administered as an intravenous infusion at a dose of 10 milligrams per kilogram (mg/kg) every 3 weeks.
Measure Participants	7
Clearance at Cycle 1	13.6 (24)
Clearance at steady state (Clss) at Cycle 4 (n=6)	10.2 (24)

7. Secondary Outcome

Title	Steady State Volume of Distribution (Vss) of Ramucirumab
Time Frame	Day 1 of Cycle 1 and 4 (cycle=21 days)

Outcome Measure Data

Analysis Population Description

All participants with evaluable Vss data at the specified time points.

Arm/Group Title	Ramucirumab and Docetaxel Combination
Arm/Group Description	Docetaxel: Docetaxel administered by intravenous infusion at a dose of 75 milligrams per square meter (mg/m^2) every 3 weeks. Ramucirumab: Ramucirumab administered as an intravenous infusion at a dose of 10 milligrams per kilogram (mg/kg) every 3 weeks.
Measure Participants	7
Vss at Cycle 1	2.96 (32)
Vss at Cycle 4 (n=6)	3.92 (18)

Adverse Events

Arm/Group Title	Ramucirumab and Docetaxel Combination
Arm/Group Description	Docetaxel: Docetaxel administered by intravenous infusion at a dose of 75 milligrams per square meter (mg/m^2) every 3 weeks. Ramucirumab: Ramucirumab administered as an intravenous infusion at a dose of 10 milligrams per kilogram (mg/kg) every 3 weeks.
All Cause Mortality
	Ramucirumab and Docetaxel Combination
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Ramucirumab and Docetaxel Combination
	Affected / at Risk (%)	# Events
Total	7/7 (100%)
Blood and lymphatic system disorders
Febrile neutropenia	3/7 (42.9%)	3
Cardiac disorders
Cardiac failure	1/7 (14.3%)	1
Investigations
Neutrophil count decreased	1/7 (14.3%)	2
Musculoskeletal and connective tissue disorders
Muscular weakness	1/7 (14.3%)	1
Respiratory, thoracic and mediastinal disorders
Epistaxis	1/7 (14.3%)	1
Interstitial lung disease	1/7 (14.3%)	2
Pleural effusion	2/7 (28.6%)	2
Other (Not Including Serious) Adverse Events
	Ramucirumab and Docetaxel Combination
	Affected / at Risk (%)	# Events
Total	7/7 (100%)
Blood and lymphatic system disorders
Anaemia	1/7 (14.3%)	3
Febrile neutropenia	3/7 (42.9%)	9
Cardiac disorders
Palpitations	1/7 (14.3%)	1
Tachycardia	1/7 (14.3%)	1
Ear and labyrinth disorders
Ear pain	1/7 (14.3%)	1
Eye disorders
Asthenopia	1/7 (14.3%)	1
Conjunctivitis	1/7 (14.3%)	2
Lacrimation increased	3/7 (42.9%)	3
Myodesopsia	1/7 (14.3%)	1
Visual impairment	1/7 (14.3%)	2
Gastrointestinal disorders
Ascites	1/7 (14.3%)	1
Cheilitis	1/7 (14.3%)	1
Constipation	2/7 (28.6%)	6
Diarrhoea	2/7 (28.6%)	4
Gingival bleeding	1/7 (14.3%)	1
Gingivitis	2/7 (28.6%)	8
Haemorrhoids	2/7 (28.6%)	2
Nausea	2/7 (28.6%)	3
Periodontitis	1/7 (14.3%)	2
Stomatitis	3/7 (42.9%)	9
Vomiting	2/7 (28.6%)	2
General disorders
Chest discomfort	1/7 (14.3%)	2
Face oedema	4/7 (57.1%)	6
Fatigue	2/7 (28.6%)	4
Infusion related reaction	1/7 (14.3%)	1
Infusion site extravasation	1/7 (14.3%)	1
Injection site pain	1/7 (14.3%)	1
Malaise	4/7 (57.1%)	19
Mucosal inflammation	4/7 (57.1%)	9
Oedema peripheral	7/7 (100%)	16
Pyrexia	2/7 (28.6%)	3
Infections and infestations
Cystitis	1/7 (14.3%)	4
Nasopharyngitis	5/7 (71.4%)	8
Injury, poisoning and procedural complications
Fall	1/7 (14.3%)	1
Investigations
Alanine aminotransferase increased	2/7 (28.6%)	4
Aspartate aminotransferase increased	2/7 (28.6%)	3
Blood urine	1/7 (14.3%)	1
Haematocrit decreased	1/7 (14.3%)	1
Haemoglobin decreased	2/7 (28.6%)	2
Neutrophil count decreased	5/7 (71.4%)	17
Platelet count decreased	1/7 (14.3%)	4
Platelet count increased	1/7 (14.3%)	2
Weight increased	1/7 (14.3%)	1
White blood cell count decreased	1/7 (14.3%)	2
White blood cell count increased	1/7 (14.3%)	2
Metabolism and nutrition disorders
Anorexia	3/7 (42.9%)	10
Hyperuricaemia	1/7 (14.3%)	2
Musculoskeletal and connective tissue disorders
Arthralgia	1/7 (14.3%)	2
Arthritis	1/7 (14.3%)	1
Coccydynia	1/7 (14.3%)	1
Muscular weakness	1/7 (14.3%)	1
Myalgia	2/7 (28.6%)	3
Osteoporosis	1/7 (14.3%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Fibroma	1/7 (14.3%)	1
Nervous system disorders
Dysgeusia	4/7 (57.1%)	10
Headache	2/7 (28.6%)	3
Lacunar infarction	1/7 (14.3%)	1
Peripheral motor neuropathy	2/7 (28.6%)	3
Peripheral sensory neuropathy	3/7 (42.9%)	5
Presyncope	1/7 (14.3%)	1
Renal and urinary disorders
Proteinuria	3/7 (42.9%)	5
Reproductive system and breast disorders
Vaginal haemorrhage	1/7 (14.3%)	1
Respiratory, thoracic and mediastinal disorders
Cough	1/7 (14.3%)	2
Dyspnoea exertional	1/7 (14.3%)	1
Epistaxis	6/7 (85.7%)	8
Nasal congestion	1/7 (14.3%)	1
Oropharyngeal pain	1/7 (14.3%)	1
Pleural effusion	1/7 (14.3%)	1
Upper respiratory tract inflammation	1/7 (14.3%)	1
Skin and subcutaneous tissue disorders
Alopecia	6/7 (85.7%)	12
Dermatitis	2/7 (28.6%)	2
Dermatitis acneiform	1/7 (14.3%)	1
Dry skin	1/7 (14.3%)	1
Eczema	1/7 (14.3%)	1
Hyperkeratosis palmaris and plantaris	1/7 (14.3%)	2
Ingrowing nail	1/7 (14.3%)	1
Nail discolouration	1/7 (14.3%)	1
Nail disorder	5/7 (71.4%)	5
Palmar-plantar erythrodysaesthesia syndrome	2/7 (28.6%)	4
Rash	2/7 (28.6%)	5
Vascular disorders
Hypertension	1/7 (14.3%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

Investigators agreed to delay independently publishing or disclosing data, findings or conclusions from the study except as part of a multi-center publication. Upon study publication or if the draft publication is not produced within approximately 6 months of the final report of the study results, investigators may independently publish, subject to confidential information review/redaction by sponsor. The sponsor may request publication delay up to 90 days to seek patent protection.