Study of IMC-1121B (Ramucirumab) With Best Supportive Care in Participants With Gastric Cancer and Adenocarcinoma

Phase 3

Completed

• Conditions: Gastric Cancer; Adenocarcinoma
• Interventions: Biological: ramucirumab; Drug: Placebo; Other: Best Supportive Care (BSC)

• Registration Number: NCT00917384
• Lead Sponsor: Eli Lilly and Company

Brief Summary

The purpose of this study is to gather information about the use of an investigational drug called Ramucirumab in adenocarcinomas of the stomach or gastroesophageal junction.

Detailed Description

Placebo-controlled, multicenter Phase 3 study of participants with metastatic gastric cancer \[including adenocarcinomas of the gastroesophageal junction (GEJ)\] and disease progression on standard first-line chemotherapeutic regimens. Participants will be randomized on a 2:1 basis to receive best supportive care plus ramucirumab administered every 2 weeks or best supportive care plus placebo administered every 2 weeks, respectively. Participants will undergo radiographic assessment of disease status every 6 weeks. Participant will be treated until there is evidence of progressive disease, toxicity requiring cessation, withdrawal of consent, or until other withdrawal criteria are met.

Approximately 348 participants, with histologically- or cytologically-confirmed, metastatic gastric or GEJ adenocarcinoma, and radiographically measurable disease as defined by the Response Evaluation Criteria in Solid Tumors or evaluable, nonmeasurable disease, will be randomized. Participants will be enrolled from approximately 250 study centers in North America, South America, Central America, Asia, Australia, New Zealand, and Europe.

Study Timeline

• Study First Submitted: 2009-06-08
• Study First Submitted QC: 2009-06-09
• Study First Posted: 2009-06-10
• Study Start: 2009-08
• Disposition First Submitted: 2010-07-26
• Disposition First Submitted QC: 2010-07-26
• Disposition First Posted: 2010-07-29
• Primary Completion: 2012-07
• Results First Submitted: 2014-05-21
• Results First Submitted QC: 2014-10-09
• Results First Posted: 2014-10-16
• Study Completion: 2015-12
• Status Verified: 2019-09
• Last Update Submitted: 2019-09-10
• Last Update Posted: 2019-09-25

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 355

Inclusion Criteria

• Histologically or cytologically confirmed gastric carcinoma, including gastric adenocarcinoma or GEJ adenocarcinoma
• Metastatic disease or locally recurrent, unresectable disease with measurable lymph node metastases
• Measurable disease and/or evaluable disease. Measurable disease is defined as at least one unidimensionally-measurable target lesion [≥ 2 centimeter (cm) with conventional techniques or ≥ 1 cm by spiral computed tomography (CT)], as defined by Response using Response Evaluation Criteria in Solid Tumors (RECIST).

Examples of evaluable, nonmeasurable disease include gastric, peritoneal, or mesenteric thickening in areas of known disease, or peritoneal nodules that are too small to be considered measurable by RECIST

• Experienced disease progression during or within 4 months after the last dose of first-line therapy for metastatic disease, or during or within 6 months after the last dose of adjuvant therapy
• Disease is not amenable to potentially curative resection
• Participant is ≥ 18 years of age
• Participant has a life expectancy of ≥ 12 weeks
• Participant resolution to Grade ≤ 1 (or to Grade ≤ 2 in the case of neuropathy) by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), Version 3.0, of all clinically significant toxic effects of prior chemotherapy, surgery, radiotherapy, or hormonal therapy (with the exception of alopecia)
• Eastern Cooperative Oncology Group Performance Status (ECOG-PS) score of 0-1
• The participant has adequate hepatic function as defined by a total bilirubin ≤ 1.5 milligrams/deciliter (mg/dL) [25.65 micromole/liter (µmol/L)], and aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3.0 x the upper limit of normal (ULN) [or 5.0 x the ULN in the setting of liver metastases]
• The participant has adequate renal function as defined by a serum creatinine ≤ 1.5 x the ULN, or creatinine clearance (measured via 24-hour urine collection) ≥ 40 milliliters/minute (mL/min) (that is, if serum creatinine is > 1.5 x the ULN, a 24-hour urine collection to calculate creatinine clearance must be performed)
• The participant's urinary protein is ≤ 1+ on dipstick or routine urinalysis ([UA]; if urine dipstick or routine analysis is ≥ 2+, a 24-hour urine collection for protein must demonstrate < 1000 milligrams (mg) of protein in 24 hours to allow participation in the study)
• The participant has adequate hematologic function, as evidenced by an absolute neutrophil count (ANC) ≥ 1000 microliters (µL), hemoglobin ≥ 9 grams/deciliter (g/dL) [5.58 millimoles/liter (mmol/L)], and platelets ≥ 100,000/µL
• The participant must have adequate coagulation function as defined by International Normalized Ratio (INR) ≤ 1.5 and a partial thromboplastin time (PTT) ≤ 5 seconds above the ULN (unless receiving anticoagulation therapy). Participant on anticoagulation therapy with unresected primary tumors or local tumor recurrence following resection are not eligible
• If the participant has received prior anthracycline therapy as part of his or her first-line regimen, the participant is able to engage in ordinary physical activity without significant fatigue or dyspnea
• Because the teratogenicity of IMC-1121B is not known, the participant, if sexually active, must be postmenopausal, surgically sterile, or using effective contraception (hormonal or barrier methods)
• Female participant of childbearing potential must have a negative serum pregnancy test within 7 days prior to randomization
• Able to provide informed written consent and is amenable to compliance with protocol schedules and testing

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Exclusion Criteria

• Documented and/or symptomatic brain or leptomeningeal metastases
• Experienced any Grade 3-4 gastrointestinal bleeding within 3 months prior to randomization
• Experienced any arterial thromboembolic events, including but not limited to myocardial infarction, transient ischemic attack, cerebrovascular accident, or unstable angina, within 6 months prior to randomization
• Ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, symptomatic or poorly controlled cardiac arrhythmia, uncontrolled thrombotic or hemorrhagic disorder, or any other serious uncontrolled medical disorders in the opinion of the investigator
• Ongoing or active psychiatric illness or social situation that would limit compliance with study requirements
• Uncontrolled or poorly-controlled hypertension despite standard medical management
• Participant has a serious or nonhealing wound, ulcer, or bone fracture
• Received chemotherapy, radiotherapy, immunotherapy, or targeted therapy for gastric cancer within 2 weeks prior to randomization
• Received any investigational therapy within 30 days prior to randomization
• Undergone major surgery within 28 days prior to randomization, or subcutaneous venous access device placement within 7 days prior to randomization
• Received prior therapy with an agent that directly inhibits vascular endothelial growth factor (VEGF) or VEGF receptor 2 (R-2) activity (including bevacizumab), or any antiangiogenic agent
• Receiving chronic antiplatelet therapy, including aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs, including ibuprofen, naproxen, and others), dipyridamole or clopidogrel, or similar agents. Once-daily aspirin use [maximum dose 325 milligram/day (mg/day)] is permitted
• Participant has elective or planned major surgery to be performed during the course of the clinical trial
• Participant has a known allergy to any of the treatment components
• Pregnant or lactating
• Known to be positive for infection with the human immunodeficiency virus
• Known alcohol or drug dependency
• Participant has a concurrent active malignancy other than adequately-treated nonmelanomatous skin cancer, other noninvasive carcinoma, or in situ neoplasm. A participant with previous history of malignancy is eligible, provided that he/she has been free of disease for > 3 years

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
ramucirumab	ramucirumab	Participants receive ramucirumab, administered via intravenous infusion every 2 weeks at a dose of 8 milligrams/kilogram (mg/kg), and best supportive care (BSC) as determined appropriate by the investigator(s). Treatment will continue until there is evidence of progressive disease (PD), the development of unacceptable toxicity, protocol noncompliance, or withdrawal of consent.
ramucirumab	Best Supportive Care (BSC)	Participants receive ramucirumab, administered via intravenous infusion every 2 weeks at a dose of 8 milligrams/kilogram (mg/kg), and best supportive care (BSC) as determined appropriate by the investigator(s). Treatment will continue until there is evidence of progressive disease (PD), the development of unacceptable toxicity, protocol noncompliance, or withdrawal of consent.
Placebo	Placebo	Participants receive injection for intravenous infusion every 2 weeks plus BSC as determined appropriate by the investigator(s). Because investigators and ancillary medical personnel will be blinded as to assignment to active therapy versus placebo, the volume of placebo to be administered will be calculated as if it were active product with a dose of 8 mg/kg. Treatment will continue until there is evidence of PD, the development of unacceptable toxicity, protocol noncompliance, or withdrawal of consent.
Placebo	Best Supportive Care (BSC)	Participants receive injection for intravenous infusion every 2 weeks plus BSC as determined appropriate by the investigator(s). Because investigators and ancillary medical personnel will be blinded as to assignment to active therapy versus placebo, the volume of placebo to be administered will be calculated as if it were active product with a dose of 8 mg/kg. Treatment will continue until there is evidence of PD, the development of unacceptable toxicity, protocol noncompliance, or withdrawal of consent.

Primary Outcome Measures

Name	Time	Method
Overall Survival (OS)	Randomization up to 28 months post-randomization	Overall survival is defined as the time from the date of randomization to the date of death from any cause. Participants who were alive at the date of data cut-off or who were lost to follow-up were censored on the last date the participant was known to be alive

Secondary Outcome Measures

Name	Time	Method
Progression-Free Survival (PFS)	Randomization up to 17 months	PFS is defined as the time from date of randomization until date of objectively determined progressive disease (PD) or death due to any cause, whichever is first. Participants alive and without PD were censored at the time of last adequate objective tumor assessment (that is, response other than unevaluable).
Percentage of Participants Who Are Progression-Free at Week 12 (PFS Rate)	Week 12 post-randomization	The percentage of participants alive and progression-free 12 weeks after randomization. Progression-free survival (PFS) is defined as the time from the date of randomization until the date of objectively determined progressive disease (PD) or death due to any cause whichever comes first. Participants alive and without PD were censored at the time of the last adequate objective tumor assessment.
Percentage of Participants With Objective Response (Objective Response Rate [ORR])	Randomization up to 17 months post-randomization	ORR is equal to the percentage of participants achieving a best overall response of complete response (CR) or partial response (PR). CR and PR were defined using the Response Evaluation Criteria in Solid Tumors (RECIST v1.0). CR is defined as the disappearance of all target and non-target lesions, no appearance of new lesions and confirmed at the consecutive tumor assessment. PR is 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), no progression of non-target lesions, no appearance of new lesions and confirmed at a subsequent tumor assessment.
Duration of Response (DOR)	Randomization up to 17 months post-randomization	DOR is the interval from date of initial documented response (complete response \[CR\] or partial response \[PR\]) to first documented date of disease progression (PD) or death as a result of any cause. CR and PR were defined using the Response Evaluation Criteria in Solid Tumors (RECIST v1.0). CR is defined as the disappearance of all target and non-target lesions, no appearance of new lesions and confirmed at the consecutive tumor assessment. PR is 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), no progression of non-target lesions, no appearance of new lesions and confirmed at a subsequent tumor assessment. Participants who did not relapse or die were censored at the time of the last adequate objective tumor assessment.
Change From Baseline in Quality of Life (QoL) as Measured by the European Organisation for Research and Treatment of Cancer Questionnaire (EORTC-QLQ-C30)	Baseline up to Cycle 10 (18 weeks [1 cycle=2 weeks])	EORTC QLQ-C30 v3.0 is a self-administered questionnaire with multidimensional scales that measures 5 functional domains (physical, role, cognitive, emotional, and social), global health status, and symptom scales of fatigue, pain, nausea and vomiting, dyspnea, loss of appetite, insomnia, constipation and diarrhea, and financial difficulties. A linear transformation is applied to standardize the raw scores to range between 0 and 100 per developer guidelines. For functional domains and global health status, higher scores represent a better level of functioning. For symptoms scales, higher scores represented a greater degree of symptoms. Best change from baseline results determined by Least Square (LS) mean estimated with randomization stratification factors and baseline value as continuous covariate.
Number of Participants With Adverse Events	Randomization up to 18 months	Clinically significant events were defined as serious adverse events (SAE) and other treatment-emergent non-serious adverse events (NSAE). A summary of SAEs and all other NSAEs is located in the Reported Adverse Event module.
Maximum Concentration (Cmax) of IMC-1121B	6 weeks post-randomization	Cmax was not analyzed as only pre-dose samples were collected.
Number of Participants Who Developed Antibodies Against IMC-1121B	Baseline, 12 Weeks	The number of participants who developed treatment emergent antibody responses to IMC-1121B after baseline.

Trial Locations

Locations (1)

ImClone Investigational Site; 🇬🇧 Wolverhampton, United Kingdom