Elsevier

Clinical Lung Cancer

Volume 13, Issue 6, November 2012, Pages 505-509
Clinical Lung Cancer

Current trial
A Randomized, Double-Blind, Phase III Study of Docetaxel and Ramucirumab Versus Docetaxel and Placebo in the Treatment of Stage IV Non–Small-Cell Lung Cancer After Disease Progression After 1 Previous Platinum-Based Therapy (REVEL): Treatment Rationale and Study Design

https://doi.org/10.1016/j.cllc.2012.06.007Get rights and content

Abstract

This article describes the treatment rationale and study-related procedures for the A Randomized, Double-Blind, Phase 3 Study of Docetaxel and Ramucirumab Versus Docetaxel and Placebo in the Treatment of Stage IV Non-Small-Cell Lung Cancer Following Disease Progression after One Prior Platinum-Based Therapy (REVEL) study (I4T-MC-JVBA; ClinicalTrials.gov NCT01168973). This international, randomized, placebo-controlled, double-blinded phase III trial examines the efficacy and safety of ramucirumab treatment administered in combination with docetaxel, as compared with docetaxel administered with placebo, in patients with stage IV non–small-cell lung cancer (NSCLC) whose disease progressed during or after first-line platinum-based chemotherapy with or without maintenance treatment. The primary end point is overall survival; secondary end points include progression-free survival, objective response rate, disease control rate, patient-reported outcomes, and assessment of safety and tolerability of ramucirumab. Eligible patients (enrollment N = 1242) are randomized at a 1:1 ratio to receive either docetaxel (75 mg/m2) plus ramucirumab (10 mg/kg) (Arm A) or docetaxel (75 mg/m2) plus placebo (Arm B). Both drugs are administered via intravenous infusion once every 3 weeks until evidence of disease progression, unacceptable toxicity, noncompliance, or patient's consent withdrawal. Efficacy and safety will be compared between the study arms and in patient subgroups including patients with nonsquamous versus squamous tumor histology and patients who received prior bevacizumab treatment. Multiple blood and tumor tissue biomarker samples are collected during the study. The goal of the REVEL study is to demonstrate that ramucirumab in combination with docetaxel improves overall survival of patients with NSCLC with progressive disease after first-line therapy, and to advance our knowledge of the role of angiogenesis blockade in patients with NSCLC by identifying patients who are likely to experience maximum benefit based on extensive clinical biomarker correlative analysis.

Introduction

A promising approach to the treatment of patients with cancer is inhibition of angiogenesis which is driven by several receptors and multiple ligands present on tumor cells and surrounding cells supporting growth of tumor microvasculature. Vascular endothelial growth factor (VEGF), a potent endothelial cell mitogen produced by solid tumors, is the predominant ligand contributing to angiogenesis and resultant tumor growth and metastatic activity.1, 2, 3, 4, 5, 6 VEGF receptor (VEGFR)-2, which is present mostly on endothelial cells, binds VEGF and other ligands involved in angiogenesis, serving as the principal receptor responsible for many of the VEGF-induced biological changes, including modification of blood vessel structure and function, proliferation, and migration.7

The variety of targeted receptors and ligands and the complexity of receptor-ligand interactions present an opportunity for differentiation between efficacy and safety of different monoclonal antibodies and small molecules based on their specific targets and mechanisms of action. Bevacizumab, a monoclonal antibody targeting VEGF-A, has been approved by the Food and Drug Administration in several types of cancer including first-line treatment in combination with standard chemotherapy in patients with non–small-cell lung cancer (NSCLC) with nonsquamous tumor histology.6, 8, 9, 10 Many small-molecule tyrosine-kinase inhibitors (TKIs) which target the intracellular portion of the VEGF receptor inhibit other intracellular signaling pathways and thus have distinctly different mechanisms of anticancer activity. These differences are often reflected in distinctly different results from studies with monoclonal antibodies versus small molecule TKIs.6

Ramucirumab (IMC-1121B, LY3009806) is a recombinant human monoclonal antibody that binds with high affinity to the extracellular domain of VEGFR-2. Unlike all approved angiogenesis inhibitors, the antiangiogenic activity of this fully human monoclonal antibody is because of exclusive binding to human VEGFR-2. Mouse models suggest that when DC101, a mouse-specific monoclonal antibody used in preclinical studies to demonstrate the effects of VEGFR-2 blockade, is administered to tumors in mice it prevents VEGF binding and blocks VEGFR-2 signaling and VEGF-induced endothelial cell growth in vitro. The resulting antiangiogenic and antitumor activity11, 12 includes inhibition of metastases after the removal of the primary tumor.12, 13, 14

Phase I clinical trials provided initial safety data and evidence of antitumor activity in a variety of tumor types.7 Promising preliminary efficacy results have been reported in phase II studies in patients with metastatic renal cancer after VEGFR-2 TKI-therapy,15 first-line metastatic colorectal cancer,16 metastatic castration resistant prostate cancer,17 breast cancer previously treated with anthracycline and taxane therapy,18 and first-line stage IIIB/IV non–small-cell lung cancer.19 Large randomized phase III studies are ongoing in patients with gastric cancer (http://ClinicalTrials.gov Identifier: NCT01170663), metastatic gastric or gastroesophageal junction adenocarcinoma (http://ClinicalTrials.gov Identifier: NCT00917384), hepatocellular carcinoma (http://ClinicalTrials.gov Identifier: NCT01140347), recurrent colorectal cancer (http://ClinicalTrials.gov Identifier: NCT01183780), and metastatic breast cancer (http://ClinicalTrials.gov Identifier: NCT00703326).20

New strategies against NSCLC include early use of multiple potentially active agents before initial progression of disease, which can result in very few available options at the time of disease progression.21 Currently, there is no approved antiangiogenic therapy in second-line treatment. Docetaxel has been established in multiple clinical trials as an effective second-line chemotherapy treatment for NSCLC.22 Addition of ramucirumab, a novel antiangiogenic compound, to current standard chemotherapy with docetaxel in this study, A Randomized, Double-Blind, Phase 3 Study of Docetaxel and Ramucirumab Versus Docetaxel and Placebo in the Treatment of Stage IV NSCLC Following Disease Progression after One Prior Platinum-Based Therapy (REVEL), may address an important medical need for patients with progressive NSCLC after first-line platinum-based therapy. Eligibility criteria for this study have been designed to minimize the risk of severe pulmonary hemorrhage and other serious complications based on prior experience with antiangiogenic antibody therapy. Given evidence that risk for hemorrhage is likely secondary to anatomic factors and not histology,23, 24 patients are not excluded based on squamous tumor histology or prior bevacizumab therapy, while patients with clinically significant pulmonary cavitation and major blood vessel involvement are excluded.

A large number of clinical trials with antiangiogenic agents, while demonstrating activity in some patients, failed to demonstrate significant clinical efficacy in unselected patients. These disappointing results underscore the importance of biomarker analysis to establish predictive factors of clinical efficacy to guide future patient selection. Plasma samples will be evaluated for VEGF isoforms and other soluble factors implicated in angiogenesis. Archival tumor tissue samples will be collected to assess VEGFR-2 expression by immunohistochemistry, single nucleotide polymorphisms, DNA mutations, and copy number variation.

Section snippets

Objectives

The REVEL (14T-MC-JVBA, ClinicalTrial.gov identifyer NCT01168973) study is an international, randomized, placebo-controlled, double-blinded phase III trial to evaluate the efficacy and safety of ramucirumab treatment administered in combination with docetaxel, as compared with docetaxel administered with placebo, in patients with stage IV NSCLC whose disease progressed during or after first-line platinum-based chemotherapy with or without maintenance treatment. The primary end point of this

Summary

The current, ongoing REVEL trial is designed to examine the efficacy and safety of ramucirumab treatment administered in combination with docetaxel, as compared with docetaxel plus placebo, in patients with advanced NSCLC whose disease progressed during or after 1 previous first-line platinum-based chemotherapy with or without maintenance treatment. Patients with all NSCLC tumor histologies are allowed to participate in this study, as are patients who received prior bevacizumab treatment.

Disclosure

Dr Yurasov, Dr Cao, Dr Alexandris, and Dr John are employees of and stockholders in Eli Lilly and Company or 1 of its subsidiaries. Dr Perol has a consultant or advisory role for Eli Lilly, F Hoffmann-La Roche, Boehringer-Ingelheim, and Genentech. Dr Garon has no conflicts of interest.

Acknowledgments

This study is sponsored by Eli Lilly and Company or 1 of its subsidiaries. Assistance with manuscript preparation was provided by Danette Hann, INC Research.

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