Elsevier

Clinical Colorectal Cancer

Volume 12, Issue 3, September 2013, Pages 218-222
Clinical Colorectal Cancer

Current trial
Treatment Rationale and Study Design for a Randomized, Double-Blind, Placebo-Controlled Phase II Study Evaluating Onartuzumab (MetMAb) in Combination With Bevacizumab Plus mFOLFOX-6 in Patients With Previously Untreated Metastatic Colorectal Cancer

https://doi.org/10.1016/j.clcc.2013.04.001Get rights and content

Background

Dysregulation of the hepatocyte growth factor (HGF)/MET pathway is associated with poor prognosis, more aggressive biological characteristics of the tumor, and shortened survival in patients with metastatic colorectal cancer (mCRC). Onartuzumab (MetMAb) is a recombinant humanized monovalent monoclonal antibody directed against MET. We present the treatment rationale and protocol for an ongoing randomized multicenter placebo-controlled phase II study designed to evaluate the efficacy and safety of MetMAb combined with bevacizumab and mFOLFOX-6 (5-fluoruracil, leucovorin, and oxaliplatin).

Patients and Methods

Eligible patients with previously untreated mCRC are randomized 1:1 to either mFOLFOX-6 combined with bevacizumab and placebo followed by 5-fluorouracil/leucovorin plus bevacizumab and placebo or mFOLFOX6, bevacizumab plus MetMAb followed by 5 FU/LV, bevacizumab, and MetMAb. The primary end point of this study is progression-free survival (PFS) in the intent-to-treat (ITT) population. Secondary end points include overall survival (OS), objective response rate, and safety. Subanalyses will be performed to evaluate the effect of MET receptor expression on study primary and secondary end points. Correlative studies will be performed on tissue- and blood-derived biomarkers related to both HGF/MET signaling and other associated pathway markers.

Introduction

Colorectal cancer (CRC) is a leading cause of cancer-related death in the Western world.1 Oxaliplatin or irinotecan-based regimens (with fluoropyrimidine) are standard palliative treatments used in the metastatic setting. Biological agents targeting vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) pathways in association with expanded use and improved techniques of hepatic metastectomy have significantly improved survival for patients with metastatic CRC (mCRC).2 Bevacizumab plus an oxaliplatin-based doublet is a commonly used first-line therapy for mCRC.3 Despite advances in treatment, 5-year survival rates remain < 10%, necessitating the need for additional therapeutic options.

The MET tyrosine kinase, a high-affinity receptor for hepatocyte growth factor (HGF), is considered an attractive target for cancer intervention owing to the important role it plays in tumor formation, progression, metastasis, angiogenesis, and drug resistance. On HGF binding, MET undergoes dimerization and autophosphorylation, leading to the activation of a number of canonical signaling pathways.4 MET can also be activated by HGF-independent mechanisms such as receptor overexpression, gene amplification, or mutation.

Dysregulation of the HGF/MET axis is associated with poor prognosis, more aggressive biological characteristics of the tumor, and shortened survival in patients with mCRC, making the MET pathway an attractive target (http://www.vai.org/met).5, 6, 7, 8 Onartuzumab (MetMAb) is a recombinant humanized monovalent monoclonal antibody directed against MET. By binding the MET extracellular domain, MetMAb blocks ligand binding and subsequent activation by HGF. The unique monovalent design of MetMAb eliminates the potential for MET activation through receptor dimerization, which is thought to occur with a bivalent antibody. Phase I testing indicated that onartuzumab was generally safe and well tolerated, both alone and in combination with bevacizumab.9

In a randomized phase II study, Spigel et al10 evaluated the efficacy and safety profile of onartuzumab combined with erlotinib in patients with stage IIIb/IV non–small-cell lung cancer with progressive disease after first-line treatment. Tissue was used to determine MET expression status by immunohistochemistry (IHC). “MET-positive” tumors were those in which > 50% of tumor cells stained with an intensity of 2 or 3 on an IHC scale of 0 to 3. Approximately 50% of patients were categorized as MET-positive. No treatment effect was found in the ITT population; however, in patients with MET-positive tumors, the combination resulted in improved overall survival (OS) (hazard ratio [HR], 0.37; P = .042) and progression-free survival (PFS) (HR, 0.53, P = .002) compared with the control arm. Somewhat unexpectedly, the converse was observed in patients with “MET-negative” tumors, ie, worsened OS and PFS. MetMAb did not exacerbate erlotinib-related toxicity, and the most frequent MetMAb-related toxicity was peripheral edema, occurring in approximately 20% of all MetMAb-treated patients.10 It remains to be seen whether MET expression status is a determinant of treatment outcome with MetMAb in other tumor types in combination with non-EGFR backbone regimens.

The MET pathway plays a key role in angiogenesis through interaction with the VEGF pathway. MET is expressed on both normal and tumor vascular endothelial cells, and MET pathway activation leads to migration and branching of endothelial cells, as well as increased production of multiple angiogenic factors, including VEGF and interleukin-8. Conversely, VEGF expression on endothelial cells can lead to increased expression of HGF and subsequent activation of MET on tumor cells, resulting in a paracrine feedback loop between tumor and vasculature (Figure 1). In xenograft models, the combination of MetMAb and bevacizumab leads to greater tumor growth inhibition compared with treatment with either agent alone. Knockdown of MET results in suppressed levels of multiple angiogenic factors, including decreased VEGF levels (unpublished observations).

HGF/MET and VEGF pathway interaction may also be an important determinant of tumor invasion and metastasis. VEGF inhibitors initially inhibit tumor growth, but resistance invariably occurs when tumors adopt a more invasive phenotype and metastasize away from regions of hypoxia.11, 12 MET expression is increased by hypoxia and contributes to the aggressiveness of hypoxic tumors.13 Hypoxia-induced c-MET expression can be triggered by VEGF inhibitors, resulting in the selection of migratory invasive tumor cells predisposed to metastasize.14 Upregulation of serum HGF levels has also been linked to resistance to bevacizumab in patients with mCRC.15 Collectively, these data indicate that HGF/MET and VEGF pathway cross talk occurs and suggests that targeting the MET/VEGF axis could result in improved clinical benefit in mCRC.

Based on these considerations, the current randomized phase II trial is designed to evaluate whether the addition of MetMAb to mFOLFOX-6 (modified 5-fluorouracil, leucovorin, oxaliplatin) plus bevacizumab could improve PFS compared with mFOLFOX-6 plus bevacizumab alone (ClinicalTrials.gov Identifier: NCT01418222).

Section snippets

Objectives

The primary objective of this study is to evaluate the efficacy of MetMAb in combination with bevacizumab and mFOLFOX-6 compared with placebo plus bevacizumab/mFOLFOX-6 as measured by PFS in patients with previously untreated mCRC. Secondary objectives include objective response rate, time to treatment failure, OS, and evaluation of safety. Correlative biomarker studies using blood and archival tumor tissue to identify biomarkers that might be predictive of clinical efficacy, adverse events, or

Eligibility Criteria

Study entry was limited to patients aged ≥ 18 years with histologically or cytologically confirmed metastatic adenocarcinoma of the colon or rectum. Patients were required to have an Eastern Cooperative Oncology Group performance status of 0 or 1, measureable disease by Response Evaluation Criteria in Solid Tumors, version 1.1, and adequate bone marrow, renal, and liver function.

Key exclusions include previous radiation therapy or systemic treatment for mCRC, adjuvant

Treatment Plan

This is a multicenter open-label randomized phase II trial currently randomizing eligible patients in a 1:1 ratio to 1 of 2 treatment arms (Figure 2). Randomization will be stratified according to previous adjuvant treatment. Patients in the experimental arm will receive treatment in 2-week cycles composed of MetMAb (10 mg/kg, intravenously [IV], on day 1, every 14 days) combined with bevacizumab (5 mg/kg, IV, on day 1, every 14 days) and mFOLFOX-6 (oxaliplatin: 85 mg/m2, IV, day 1; leucovorin:

Statistical Analysis Plan

Primary and secondary efficacy end point analyses will be performed on the intent-to-treat (ITT) population, defined as all consenting patients randomized to trial treatment. The study will enroll approximately 188 patients, allowing for a 5% dropout rate. Accrual and follow-up will last 25 months. The final analysis will occur after 120 PFS events have occurred. Using a 1-sided log-rank test, this study has a 90% power at a 10% significance level to detect an HR of 0.625 assuming the median

Conclusion

This randomized phase II study is designed to evaluate the efficacy and safety of MetMAb in combination with standard-of-care treatment (bevacizumab plus mFOLFOX-6) in patients with newly diagnosed mCRC. The primary end point is duration of PFS in the ITT population, with additional analysis of results according to MET expression status.

Acknowledgments

This study is sponsored by F. Hoffmann-La Roche. F. Hoffmann-La Roche provided support for manuscript submission.

References (15)

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