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

• Proportion of Participants Who are Progression-free (PFS) at Week 12 [ Time Frame: Week 12 ] [ Designated as safety issue: No ]
  The 12-week progression-free survival (PFS) rate is defined as the proportion of participants that are alive and progression-free 12 weeks after randomization.
• Proportion of Participants with Objective Response (Objective Response Rate) [ Time Frame: Approximately 30 months ] [ Designated as safety issue: No ]
  The objective response rate (ORR) is equal to the proportion of participants achieving a best overall response of partial or complete response (PR + CR).
• Duration of Response [ Time Frame: Approximately 30 Months ] [ Designated as safety issue: No ]
  Duration of response is the interval from date of initial documented response (complete response or partial response) to the first documented date of disease progression or death.
• Change from Baseline in Quality of Life (QoL) as measured by the European Organisation for Research and Treatment of Cancer (EORTC-QLQ-C30) Survey [ Time Frame: 18 Weeks ] [ Designated as safety issue: No ]
• Number of Participants with Adverse Events [ Time Frame: Approximately 30 Months ] [ Designated as safety issue: Yes ]
• Maximum concentration (Cmax) of IMC-1121B [ Time Frame: 6 weeks ] [ Designated as safety issue: No ]
• Change from Baseline in Antibodies against IMC-1121B [ Time Frame: 12 Weeks ] [ Designated as safety issue: Yes ]
• Progression-free Survival (PFS) [ Time Frame: Approximately 30 Months ] [ Designated as safety issue: No ]
  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 is first.

• To evaluate the progression-free survival (PFS), including 12-week PFS rate, associated with IMC-1121B versus placebo [ Time Frame: 40 months ] [ Designated as safety issue: No ]
• To evaluate the objective response rate (ORR) [ Time Frame: 40 months ] [ Designated as safety issue: No ]
• To evaluate the duration of response [ Time Frame: 40 Months ] [ Designated as safety issue: No ]
• To evaluate the quality of life (QoL) [ Time Frame: 40 Months ] [ Designated as safety issue: No ]
• To evaluate the safety profile of IMC-1121B [ Time Frame: 40 months ] [ Designated as safety issue: Yes ]
• To examine the pharmacodynamic profile of IMC-1121B [ Time Frame: 40 Months ] [ Designated as safety issue: No ]
• To assess the immunogenicity of IMC-1121B [ Time Frame: 40 Months ] [ Designated as safety issue: Yes ]

The purpose of this study is to gather information about the use of an investigational drug called IMC-1121B (Ramucirumab) in adenocarcinomas of the gastroesophageal junction.

Placebo-controlled, multicenter Phase 3 study of patients with metastatic gastric cancer (including adenocarcinomas of the gastroesophageal junction) and disease progression on standard first-line chemotherapeutic regimens. Patients will be randomized on a 2:1 basis to receive best supportive care (BSC) plus IMC-1121B administered every 2 weeks or best supportive care (BSC) plus placebo administered every 2 weeks, respectively. Patients will undergo radiographic assessment of disease status every 6 weeks. Patients will be treated until there is evidence of progressive disease (PD), toxicity requiring cessation, withdrawal of consent, or until other withdrawal criteria are met.

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

• Gastric Cancer
• Adenocarcinoma

• Biological: IMC-1121B (ramucirumab)
  Administered via intravenous (I.V.) infusion every 2 weeks at a dose of 8 mg/kg
  Other Name: 1121B
• Drug: Placebo
  Placebo comparator for IMC-1121B(ramucirumab) 8 mg/kg as intravenous (I.V.) infusion every 2 weeks
• Other: Best Supportive Care
  Best supportive care (BSC) as determined appropriate by the investigator(s). BSC may include but are not limited to antiemetic agents, opiate and nonopiate analgesic agents, appetite stimulants, and granulocyte and erythroid growth factors.

• Experimental: IMC-1121B (ramucirumab )
  Participants receive IMC-1121B (ramucirumab), administered via intravenous (I.V.) infusion every 2 weeks at a dose of 8 mg/kg, and best supportive care (BSC) as determined appropriate by the investigator(s). Treatment will continue until there is evidence of PD, the development of unacceptable toxicity, protocol noncompliance, or withdrawal of consent.
  Interventions:

  • Biological: IMC-1121B (ramucirumab)
  • Other: Best Supportive Care
• Placebo Comparator: Placebo
  Participants receive injection for intravenous infusion every 2 weeks plus best supportive care 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.
  Interventions:

  • Drug: Placebo
  • Other: Best Supportive Care

Inclusion Criteria:

• Histologically or cytologically confirmed gastric carcinoma, including gastric adenocarcinoma or Gastroesophageal Junction (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 cm with conventional techniques or ≥ 1 cm by spiral CT), as defined by 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
• Patient is ≥ 18 years of age
• Patient has a life expectancy of ≥ 12 weeks
• Patient 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 score of 0-1
• The patient has adequate hepatic function as defined by a total bilirubin ≤ 1.5 mg/dL (25.65 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 patient 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 mL/minute (ie, if serum creatinine is > 1.5 x the ULN, a 24-hour urine collection to calculate creatinine clearance must be performed)
• The patient'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 mg of protein in 24 hours to allow participation in the study)
• The patient has adequate hematologic function, as evidenced by an absolute neutrophil count (ANC) ≥ 1000/µL, hemoglobin ≥ 9 g/dL (5.58 mmol/L), and platelets ≥ 100,000/µL
• The patient 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). Patients on anticoagulation therapy with unresected primary tumors or local tumor recurrence following resection are not eligible
• If the patient has received prior anthracycline therapy as part of his or her first-line regimen, the patient is able to engage in ordinary physical activity without significant fatigue or dyspnea
• Because the teratogenicity of IMC-1121B is not known, the patient, if sexually active, must be postmenopausal, surgically sterile, or using effective contraception (hormonal or barrier methods)
• Female patients 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

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
• Patient 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 VEGF or VEGFR-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 mg/day) is permitted
• Patient has elective or planned major surgery to be performed during the course of the clinical trial
• Patient 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
• Patient has a concurrent active malignancy other than adequately-treated nonmelanomatous skin cancer, other noninvasive carcinoma, or in situ neoplasm. A patient with previous history of malignancy is eligible, provided that he/she has been free of disease for > 3 years