Phase III Study of Docetaxel + Ramucirumab or Placebo in Breast Cancer

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
Eli Lilly and Company
ClinicalTrials.gov Identifier:
NCT00703326
First received: June 20, 2008
Last updated: May 16, 2014
Last verified: May 2014
  Purpose

The objective of this study is to compare the progression-free survival (PFS) of the drug combination ramucirumab plus docetaxel to placebo plus docetaxel in previously untreated participants with human epidermal growth factor receptor 2 (HER2)-negative, unresectable, locally-recurrent or metastatic breast cancer.


Condition Intervention Phase
Breast Cancer
Biological: ramucirumab (IMC-1121B)
Drug: docetaxel
Other: placebo
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: A Multicenter, Multinational, Randomized, Double-Blind, Phase III Study of IMC-1121B Plus Docetaxel Versus Placebo Plus Docetaxel in Previously Untreated Patients With HER2-Negative, Unresectable, Locally-Recurrent or Metastatic Breast Cancer

Resource links provided by NLM:


Further study details as provided by Eli Lilly and Company:

Primary Outcome Measures:
  • Progression-Free Survival (PFS) [ Time Frame: Randomization to disease progression or death or until data cutoff of 31 Mar 2013 (up to 48 months) ] [ Designated as safety issue: No ]
    PFS was defined as time from randomization until the first evidence of progression as defined by Response Evaluation Criteria in Solid Tumors (RECIST v1.0) or death from any cause; by Investigator assessment. Progressive disease (PD) was defined as at least a 20% increase in sum of longest diameter of target lesions taking as reference the smallest sum longest diameter since baseline, progression in non-target lesions or the appearance of 1 or more new lesion(s). Participants who neither progressed nor died were censored the day of their last radiographic tumor assessment if available or date of randomization if no post initiation radiographic assessment was available. If death or PD occurred after ≥2 missing radiographic visits, censoring occurred at date of the last radiographic visit prior to the missed visits. The symptomatic/clinical disease progression (deterioration) without documented radiologic progression did not constitute progression.


Secondary Outcome Measures:
  • Overall Survival (OS) [ Time Frame: Randomization to death or until data cutoff of 31-Mar-2013 (up to 49 months) ] [ Designated as safety issue: No ]
    OS was defined as the duration from randomization to death from any cause. Participants who were alive at data cut-off for the OS analysis or lost to follow-up were censored on the last date the participant was known to be alive.

  • Time to Progression (TTP) [ Time Frame: Randomization to disease progression or until data cutoff of 31-Mar-2013 (up to 48 months) ] [ Designated as safety issue: No ]
    TTP was defined as the time from the date of randomization to the first documented date of disease progression using Response Evaluation Criteria in Solid Tumors (RECIST v1.0) criteria; by Investigator assessment. Progressive disease (PD) was defined as at least a 20% increase in sum of longest diameter (LD) of target lesions taking as reference the smallest sum LD since baseline, progression in non-target lesions or the appearance of 1 or more new lesion(s). Participants who did not progress were censored at the last radiographic tumor assessment. If no post-baseline assessment was available censoring occurred at the date of randomization. If PD occurred after 2 or more missing radiographic visits, censoring occurred at the date of the last radiographic visit prior to the missed visits. The symptomatic/clinical disease progression (deterioration) without documented radiologic progression did not constitute progression.

  • Percentage of Participants With Complete Response (CR) or Partial Response (PR) (Objective Response Rate) [ Time Frame: Randomization to disease progression or until data cutoff of 31-Mar-2013 (up to 48 months) ] [ Designated as safety issue: No ]
    Objective response rate (ORR) was defined as the percentage of randomized participants achieving a best confirmed overall response of CR or PR using Response Evaluation Criteria in Solid Tumors (RECIST v1.0), based on the achievement of both measurement and confirmation criteria; by Investigator assessment. CR was defined as the disappearance of all target and non-target lesions. PR was defined as at least a 30% decrease in the sum of the longest diameters (LD) of target lesions, taking as reference the baseline sum LD and no progression in non-target lesions.

  • Duration of Response [ Time Frame: Date of first CR or PR to PD or death or until data cutoff date of 31-Mar-2013 (up to 35 months) ] [ Designated as safety issue: No ]
    Duration of complete response (CR) or partial response (PR) measured from time criteria were first met for CR or PR until first date of progressive disease (PD) or death from any cause defined using Response Evaluation Criteria in Solid Tumor (RECIST 1.0); by Investigator assessment. CR defined as disappearance of all target and non-target lesions. PR defined as ≥30% decrease in sum of longest diameter (LD) of target lesions and no progression in non-target lesions. PD defined as ≥20% increase in LD sum of target lesions taking as reference the smallest sum LD since baseline, progression in non-target lesions or the appearance of ≥1 new lesion(s). Participants who did not relapse or die censored at day of last radiographic tumor assessment. If death or PD was after ≥2 missing radiographic visits, censoring was at date of last radiographic visit prior to missed visits. Symptomatic/clinical disease progression without documented radiologic progression did not constitute progression.

  • Total Functional Assessment of Cancer Therapy-Breast (FACT-B): Change From Baseline to End of Therapy [ Time Frame: Baseline, End of Therapy or until data cutoff of 31-Mar-2013 (up to 42 months) ] [ Designated as safety issue: No ]
    FACT-B measures the following domains of health-related quality of life (HR-QL): physical well-being (PWB), social/family well-being (SFWB), emotional well-being (EWB), functional well-being (FWB), and additional concerns of breast cancer subscale (BCS) each with 6 or more items developed to measure problems specific to breast cancer symptoms plus additional items related to global QoL. Participants respond to each of the 36 questions on a 5-point scale from 0 (not at all) to 4 (very much) with a total scores range of 0-144. Higher scores indicate fewer symptoms and better HR-QoL.

  • Number of Participants With Adverse Events [ Time Frame: First dose to study completion (up to 49 months) plus 30-day safety follow-up ] [ Designated as safety issue: Yes ]
    Clinically significant events were defined as serious adverse events (SAE) and other treatment-emergent non-serious adverse events (NSAE). A summary of SAEs and other NSAEs is located in the Reported Adverse Event module.


Other Outcome Measures:
  • Serum Anti-Ramucirumab Antibody Assessment (Immunogenicity) [ Time Frame: Baseline, prior to cycle 3 infusion, prior to cycle 5 infusion, onset of infusion reaction, resolution of reaction and 30 days following the event until data cutoff of 31-Mar-2013 (up to 31 months) ] [ Designated as safety issue: No ]
    The overall percentage of participants with treatment-emergent positive for anti-ramucirumab (IMC-1121B) antibodies during the study. Participants were considered positive for anti-ramucirumab (IMC-1121B) antibodies if they exhibited a post-treatment antibody level that exceeded the positive upper cut point determined from the anti-ramucirumab (IMC-1121B) level seen in healthy untreated individuals.


Enrollment: 1144
Study Start Date: August 2008
Estimated Study Completion Date: August 2015
Primary Completion Date: March 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: ramucirumab (IMC-1121B) + docetaxel Biological: ramucirumab (IMC-1121B)
Ramucirumab (IMC-1121B) is administered at a dose of 10 milligrams per kilogram (mg/kg) as a 1-hour intravenous infusion on Day 1 of each 21-day cycle.
Other Names:
  • IMC-1121B
  • LY3009806
Drug: docetaxel
Docetaxel is administered at a dose of 75 milligrams per square meter (mg/m²) as a 1-hour intravenous infusion on Day 1 of each 21-day cycle.
Placebo Comparator: placebo + docetaxel Drug: docetaxel
Docetaxel is administered at a dose of 75 milligrams per square meter (mg/m²) as a 1-hour intravenous infusion on Day 1 of each 21-day cycle.
Other: placebo
Placebo comparator for ramucirumab (IMC-1121B) administered at a dose of 10 mg/kg as a 1-hour intravenous infusion on Day 1 of each 21-day cycle.
Other Name: placebo

Detailed Description:

Female participants at least 18 years of age with histologically or cytologically confirmed, human epidermal growth factor receptor 2 (HER2) negative breast adenocarcinoma that is metastatic or locally-recurrent and inoperable with curative intent will be randomized. Participants may not have received chemotherapy for metastatic or locally-recurrent, inoperable breast cancer.

It is anticipated that 1113 participants will be randomized with 371 participants in the docetaxel plus placebo arm and 742 participants in the docetaxel plus ramucirumab (IMC-1121B) arm. There will be approximately 250 centers in North and South America, Europe, Asia, Middle East, Africa, Australia, and New Zealand.

On Day 1 of each 21-day cycle, participants will receive docetaxel 75 mg/m² as a one-hour I.V. infusion followed by either ramucirumab (IMC-1121B) 10 mg/kg or placebo 10 mg/kg as a one-hour I.V. infusion. Each cycle is repeated every 21 days.

Treatment will continue until there is evidence of progressive disease, unacceptable toxicity, or other withdrawal criteria are met. Participants who discontinue study treatment with either ramucirumab (IMC-1121B) or placebo may continue to receive docetaxel. Similarly, participants who discontinue docetaxel therapy may continue to receive either ramucirumab (IMC-1121B) or placebo, whichever the participant was randomized to receive. All participants will be followed for survival at regularly scheduled intervals (every 6 weeks until progressive disease and every 6 months thereafter) for at least 36 months after discontinuing study therapy.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Participant is able to provide signed informed consent
  • Participant is female and ≥ 18 years of age or older if required by local laws or regulations
  • Participant has histologically or cytologically confirmed adenocarcinoma of the breast that is now metastatic or locally-recurrent and inoperable with curative intent. Every effort should be made to make paraffin-embedded tissue or slides from the diagnostic biopsy or surgical specimen available for confirmation of diagnosis
  • Participant has measurable and/or non-measurable disease
  • Participants' primary and/or metastatic tumor is human epidermal growth factor receptor 2 (HER2)-negative by fluorescence in-situ hybridization (FISH) or chromogenic in-situ hybridization (CISH) or 0, 1+ overexpression by immunohistochemistry (IHC)
  • Participant has not received prior chemotherapy for metastatic or locally-recurrent and inoperable breast cancer
  • Participant completed (neo) adjuvant taxane therapy at least 6 months prior to randomization
  • Participant completed (neo) adjuvant biologic therapy at least 6 weeks prior to randomization
  • Participant completed all prior radiotherapy with curative intent ≥ 3 weeks prior to randomization
  • Participant may have received prior hormonal therapy for breast cancer in the (neo) adjuvant and/or the metastatic setting ≥ 2 weeks prior to randomization
  • Participant's left ventricular ejection fraction is within normal institutional ranges
  • Participant has resolution to grade ≤ 1 by the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 3 (NCI-CTCAE v 3.0) of all clinically significant toxic effects of prior chemotherapy, surgery, radiotherapy, or hormonal therapy with the exception of peripheral neuropathy which must have resolved to grade ≤ 2
  • Participant has an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
  • Participant is amenable to compliance with protocol schedules and testing
  • Participant has adequate hematological functions [absolute neutrophil count (ANC) ≥ 1500 cells/microliter (mcL), hemoglobin ≥ 9 grams/deciliter (g/dL), and platelets ≥ 100,000 cells/mcL and ≤ 850,000 cells/mcL]
  • Participant has adequate hepatic function [bilirubin within normal limits (WNL), aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 2.5 times the upper limit of normal (ULN), or ≤ 5.0 times the ULN if the transaminase elevation is due to liver metastases, and alkaline phosphatase ≤ 5.0 times the ULN]
  • Participant has serum creatinine ≤ 1.5 x ULN. If serum creatinine > 1.5 x ULN the calculated creatinine clearance should be > 40 milliliters/minute (mL/min)
  • Participant's urinary protein is ≤ 1+ on dipstick or routine urinalysis (UA); if urine protein ≥ 2+, a 24-hour urine collection must demonstrate < 1000 milligrams (mg) of protein in 24 hours to allow participation in the study
  • Participant must have adequate coagulation function as defined by international normalized ratio (INR) ≤ 1.5 and a partial thromboplastin time (PTT) ≤ 1.5 X ULN if not receiving anticoagulation therapy. Participants on full-dose anticoagulation must be on a stable dose of oral anticoagulant or low molecular weight heparin and if on warfarin must have a INR between 2 and 3 and have no active bleeding (defined as within 14 days of randomization) or pathological condition that carries a high risk of bleeding (such as, tumor involving major vessels or known varices)
  • Women of childbearing potential must implement adequate contraception in the opinion of the investigator
  • Participant has not received prior biologic therapy for metastatic or locally recurrent and inoperable breast cancer

Exclusion Criteria:

  • 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. A participant with previous history of malignancy is eligible, provided that she has been disease free for > 3 years
  • Participant has a known sensitivity to docetaxel or other drugs formulated with polysorbate 80
  • Participant has a known sensitivity to agents of similar biologic composition as ramucirumab or other agents that specifically target vascular endothelial growth factor (VEGF)
  • Participant has a history of chronic diarrheal disease within 6 months prior to randomization
  • Participant has received irradiation to a major bone marrow area as defined as > 25% of bone marrow (such as, pelvic or abdominal radiation) within 30 days prior to randomization
  • Participant has participated in clinical trials of experimental agents within 4 weeks prior to randomization
  • Participant has a history of uncontrolled hereditary or acquired bleeding or thrombotic disorders
  • Participant has active, high risk bleeding (such as, via gastric ulcers or gastric varices) within 14 days prior to randomization
  • Participant has an ongoing or active infection requiring parenteral antibiotic, antifungal, or antiviral therapy
  • Participant has uncontrolled hypertension, symptomatic congestive heart failure, unstable angina pectoris, symptomatic or poorly controlled cardiac arrhythmia, psychiatric illness/social situations, or any other serious uncontrolled medical disorders in the opinion of the investigator
  • Participant has brain metastases, uncontrolled spinal cord compression, or carcinomatous meningitis, or new evidence of brain or leptomeningeal disease
  • Participant has known human immunodeficiency virus infection or acquired immunodeficiency syndrome-related illness
  • Participant has pulmonary lymphangitic involvement that results in pulmonary dysfunction requiring active treatment, including the use of oxygen.
  • Participant is pregnant or lactating
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00703326

  Show 234 Study Locations
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
  More Information

No publications provided

Responsible Party: Eli Lilly and Company
ClinicalTrials.gov Identifier: NCT00703326     History of Changes
Other Study ID Numbers: 13892, 2008-001727-65, TRIO-012, TRIO-CIRG-012, CP12-0606, I4T-IE-JVBC
Study First Received: June 20, 2008
Results First Received: May 16, 2014
Last Updated: May 16, 2014
Health Authority: Belgium: Federal Agency for Medicinal Products and Health Products
Brazil: Ministry of Health
Canada: Health Canada
Czech Republic: State Institute for Drug Control
Egypt: Ministry of Health and Population
Germany: Ethics Commission
Germany: Federal Institute for Drugs and Medical Devices
Germany: Paul-Ehrlich-Institut
Ireland: Irish Medicines Board
Israel: Ministry of Health
New Zealand: Medsafe
Peru: Instituto Nacional de Salud
Poland: Ethics Committee
Poland: Ministry of Health
Russia: Ministry of Health of the Russian Federation
Serbia and Montenegro: Agency for Drugs and Medicinal Devices
Slovakia: State Institute for Drug Control
South Africa: Medicines Control Council
South Korea: Korea Food and Drug Administration (KFDA)
Spain: Spanish Agency of Medicines
United Kingdom: Medicines and Healthcare Products Regulatory Agency
United States: Food and Drug Administration

Keywords provided by Eli Lilly and Company:
Metastatic breast cancer
HER2 negative breast cancer
locally recurrent breast cancer

Additional relevant MeSH terms:
Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Docetaxel
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions

ClinicalTrials.gov processed this record on July 22, 2014