Study of Ramucirumab, Trastuzumab and Paclitaxel in Patients With HER2-positive Recurrent/Metastatic Gastric Cancer (HER-RAM Study)

Study Overview
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Brief Summary
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Human epidermal growth factor receptor 2 (HER2) is overexpressed or amplified in 10-20% of gastric or gastroesophageal junction cancer. Trastuzumab combined with fluorouracil and platinum has been established as first-line treatment for patients with HER2-positive gastric cancer. The role of trastuzumab in second-line treatment for HER2-positive gastric cancer has not yet been addressed. Here, we evaluated the safety and efficacy of adding trastuzumab to ramucirumab and paclitaxel combination as a second-line treatment in HER2-positive gastric cancer progressed after trastuzumab-containing chemotherapy.

Official Title
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An Open-label, Multicenter Phase Ib/II Study of Ramucirumab in Combination With Trastuzumab and Weekly Paclitaxel in Patients With HER2-positive Recurrent/Metastatic Gastric Cancer

Conditions
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Recurrent/Metastatic Gastric Cancer

Intervention / Treatment
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* Drug: Trastuzumab + Ramucirumab + Paclitaxel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically proven metastatic or locally advanced HER2-positive gastric cancer Documented disease progression after receiving prior line of trastuzumab-containing chemotherapy for gastric cancer Able and willing to give written informed consent and has signed the informed consent form (ICF), prior to performance of any trial activities. Eligible male and female subjects aged ≥19 years. Has measurable disease as determined by RECIST 1.1. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Has baseline left ventricular ejection fraction (LVEF) ≥ 55%. Adequate organ function as demonstrated by laboratory test results within 14 days prior to first dose of study treatment. Have urinary protein that is <2 on dipstick or routine urinalysis. Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to first dose of study treatment. Female subjects of childbearing potential and male subjects should be willing to use methods of birth control for the course of the study and up to 120 days after the last dose of study treatment. Exclusion Criteria: Received prior anticancer treatment with targeted agents, chemotherapy, or radiotherapy within 14 days, with monoclonal antibodies within 28 days, has previously received treatment with ramucirumab, or has participated in another clinical trial within 14 days prior to start of study treatment. Has experienced any Grade 3-4 gastrointestinal bleeding within 3 months prior to treatment. Has experienced any arterial thromboembolic events, including but not limited to myocardial infarction, transient ischemic attack, cerebrovascular accident, or unstable angina, within 3 months prior to treatment. Has history of severe thromboembolism, including deep vein thrombosis and pulmonary embolism within 6 months prior to treatment. Has an active or ongoing infection, symptomatic congestive heart failure, uncontrolled angina pectoris, symptomatic or poorly controlled arrhythmia, uncontrolled thrombotic or hemorrhagic disorder, or any other serious uncontrolled medical disorders in the opinion of the investigator. Has ongoing or active psychiatric illness or social situation that would limit compliance with study requirements. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Has evidence of active, non-infectious pneumonitis. Has a known history of Human Immunodeficiency Virus (HIV). Has known active hepatitis B or hepatitis C. Have an elective or a planned major surgery during the course of the trial or has undergone major surgery within 4 weeks prior to enrollment. Has history of GI perforation and/or fistula within 6 months prior to treatment. Is pregnant or breastfeeding, or possibly pregnant. Has history of Child-Pugh Class B or more of liver cirrhosis or hepatic encephalopathy, or cirrhosis with clinically meaningful ascites. Is undergoing long-term antiplatelet therapy within 7 days prior to treatment. Has known history of hypersensitivity to one or more of the study treatments or their substances, or known severe hypersensitivity to monoclonal antibodies. Has a known additional malignancy that is progressing or has required active treatment within the past 3 years.

Ages Eligible for Study
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Minimum Age: 19 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Study treatment<br>(Phase Ib part) Trastuzumab 4 mg/kg (loading dose) followed by 2 mg/kg IV, ramucirumab 8 mg/kg IV, and paclitaxel 80 or 70 mg/m2 IV (according to dose level) (Phase II part) Trastuzumab 4 mg/kg (loading dose) followed by 2 mg/kg IV, ramucirumab 8 mg/kg IV, and paclitaxel at RP2D (80 or 70 mg/m2 IV) | Drug: Trastuzumab + Ramucirumab + Paclitaxel<br>* For both Phase Ib and II: Trastuzumab 4 mg/kg (loading dose) followed by 2 mg/kg on Days 1, 8, 15 and 22, and ramucirumab 8 mg/kg on Days 1 and 15, as well as paclitaxel will be administered intravenously in a 4-week cycle (every 28 days) For Phase Ib, Paclitaxel 80 or 70 mg/m2 (according to dose level) will be administered on Days 1, 8, 15 For Phase II, paclitaxel at RP2D (80 or 70 mg/m2) will be administered on Days 1, 8, 15 of each cycle<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1b: Maximum tolerated dose of trastuzumab, ramucirumab, and paclitaxel combination treatment in patients with HER2-positive gastric cancer |  | Phase 1b: During the first 4 weeks of treatment | 
| Phase 2: Progression-free survival in patients with HER2-positive gastric cancer receiving trastuzumab, ramucirumab, and paclitaxel combination treatment |  | Phase 2: At 24 weeks after start of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival |  | through study completion, an average of 2 years | 
| Objective response rate according to RECIST 1.1 |  | through study completion, an average of 2 years | 
| Disease control rate according to RECIST 1.1 |  | through study completion, an average of 2 years | 
| Safety and tolerability based on incidence of treatment-emergent adverse events as assessed by CTCAE v4.02 |  | Throughout the overall study period as well as up to 3 months after the last dose study treatment for each subject |