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Phase I Dose-Escalation Study of Onartuzumab As a Single Agent and in Combination with Bevacizumab in Patients with Advanced Solid Malignancies

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Phase I Dose-Escalation Study of Onartuzumab As a Single Agent and in Combination with Bevacizumab in Patients with Advanced Solid Malignancies Published OnlineFirst February 3, 2014; DOI: 10.1158/1078-0432.CCR-13-2070 Clinical Cancer Cancer Therapy: Clinical Research Phase I Dose-Escalation Study of Onartuzumab as a Single Agent and in Combination with Bevacizumab in Patients with Advanced Solid Malignancies Ravi Salgia1, Premal Patel2, John Bothos2, Wei Yu2, Steve Eppler2, Priti Hegde2, Shuang Bai2, Surinder Kaur2, Ihsan Nijem2, Daniel V.T. Catenacci1, Amy Peterson2, Mark J. Ratain1, Blase Polite1, Janice M. Mehnert3, and Rebecca A. Moss3 Abstract Purpose: This first-in-human study evaluated the safety, immunogenicity, pharmacokinetics, and antitumor activity of onartuzumab, a monovalent antibody against the receptor tyrosine kinase MET. Experimental Design: This 3þ3 dose-escalation study comprised three stages: (i) phase Ia dose escalation of onartuzumab at doses of 1, 4, 10, 20, and 30 mg/kg intravenously every 3 weeks; (ii) phase Ia cohort expansion at the recommended phase II dose (RP2D) of 15 mg/kg; and (iii) phase Ib dose escalation of onartuzumab at 10 and 15 mg/kg in combination with bevacizumab (15 mg/kg intravenously every 3 weeks). Serum samples were collected for evaluation of pharmacokinetics, potential pharmaco- dynamic markers, and antitherapeutic antibodies. Results: Thirty-four patients with solid tumors were treated in phase Ia and 9 in phase Ib. Onartuzumab was generally well tolerated at all dose levels evaluated; the maximum tolerated dose was not reached. The most frequent drug-related adverse events included fatigue, peripheral edema, nausea, and hypoalbumi- nemia. In the phase Ib cohort, onartuzumab at the RP2D was combined with bevacizumab and no dose- limiting toxicities were seen. Onartuzumab showed linear pharmacokinetics in the dose range from 4 to 30 mg/kg. The half-life was approximately 8 to 12 days. There were no apparent pharmacokinetic interactions between onartuzumab and bevacizumab, and antitherapeutic antibodies did not seem to affect the safety or pharmacokinetics of onartuzumab. A patient with gastric carcinoma in the 20-mg/kg dose cohort achieved a durable complete response for nearly 2 years. Conclusions: Onartuzumab was generally well tolerated as a single agent and in combination with bevacizumab in patients with solid tumors. Clin Cancer Res; 20(6); 1–10. Ó2014 AACR. Introduction poor prognosis in several cancers, including non–small cell MET, a receptor tyrosine kinase, initiates branching mor- lung cancer (NSCLC), breast cancer, gastric cancer, head phogenesis in normal cells upon binding of its only known and neck cancer, and glioblastoma (3). Components of the ligand, hepatocyte growth factor (HGF; also known as MET signaling pathway have emerged as attractive thera- scatter factor). Branching morphogenesis involves cell pro- peutic targets (5–7). liferation, transformation, and migration (1, 2). Dysregula- Onartuzumab (formerly called MetMAb and PRO143966) tion of HGF and MET plays a key role in tumorigenesis (3, is a humanized, monovalent (one-armed) monoclonal anti- 4). Clinically, MET receptor expression is associated with body that blocks HGF binding and prevents downstream cellularsignaling (8). Onartuzumab was designed asa mono- valent antibody to avoid the agonistic activity that may occur when a bivalent antibody binds two MET molecules (9). Authors' Affiliations: 1Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois; 2Genentech, Inc., Onartuzumab demonstrated antitumor activity in various South San Francisco, California; and 3Rutgers Cancer Institute of New animal tumor models (6, 8, 10). MET and its downstream Jersey, Rutgers, The State University of New Jersey, New Brunswick, New Jersey effectors interact with other tumorigenic pathways; MET activation functions as a potent regulator of the angiogenic Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). switch by increasing expression of angiogenic molecules such as vascular endothelial growth factor (VEGF) (11). Hypoxia Corresponding Author: Rebecca A. Moss, Rutgers Cancer Institute of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08903-2681. can induce expression of MET on tumor cells, which may Phone: 1-732-235-8663; Fax: 1-732-235-8808; E-mail: enable improved tumor cell survival and/or migration [email protected] toward regions of normoxia (12). Enhanced antitumor activ- doi: 10.1158/1078-0432.CCR-13-2070 ity has been observed when combining onartuzumab with Ó2014 American Association for Cancer Research. an anti-VEGF antibody in preclinical models (10). These www.aacrjournals.org OF1 Downloaded from clincancerres.aacrjournals.org on October 3, 2021. © 2014 American Association for Cancer Research. Published OnlineFirst February 3, 2014; DOI: 10.1158/1078-0432.CCR-13-2070 Salgia et al. Patients were generally excluded if they had received Translational Relevance antitumor therapies or undergone a major surgical proce- Aberrant upregulation of the MET pathway is frequent dure within 4 weeks of the start of the study. Patients were in human malignancies, and leads to branching mor- excluded from the bevacizumab cohort in phase Ib if they phogenesis and invasion. MET activation may also occur had inadequately controlled hypertension as defined by during states of hypoxia, which may enable migration/ systolic blood pressure >150 mmHg and/or diastolic blood invasion toward regions of normoxia. This phase Ia and pressure >100 mmHg, a history of cardiovascular disease or Ib study shows onartuzumab—a humanized, monova- significant vascular disease within 6 months before enroll- lent (one-armed) monoclonal antibody that blocks ment, or major surgery within 28 days before start of dosing. hepatocyte growth factor binding—is well tolerated as single agent and in combination with bevacizumab. In Study design and treatments this setting of good safety, we show how pharmacoki- The study involved three stages: (1) the phase Ia dose- netic/pharmacodynamic (PK-PD) modeling may be escalation phase was designed to determine the safety, used to derive a recommended phase II dose. One tolerability, and pharmacokinetics of single-agent onartu- patient with clinically relevant exposure and with auto- zumab (supplied by Genentech, Inc.) at dose levels of 1, 4, crine MET gastric cancer achieved a complete response. 10, 20, and 30 mg/kg administered by i.v. Q3W, and to identify the RP2D; (2) in the phase Ia expansion, additional patients were enrolled to study safety and pharmacokinetics of single-agent onartuzumab at the RP2D; and (3) the phase observations justify evaluation of combination therapies that Ib stage evaluated the combination of onartuzumab [10 target both angiogenesis and MET signaling. mg/kg (one dose level below the RP2D) or 15 mg/kg i.v. We conducted a phase I dose-escalation study of onartu- Q3W (RP2D)] with bevacizumab (15 mg/kg i.v. Q3W; zumab to identify the maximum tolerated dose (MTD) and supplied by Genentech, Inc.). Patients without progressive recommended phase II dose (RP2D), and to characterize disease or significant toxicity could continue treatment with the safety, tolerability, and pharmacokinetics of onartuzu- study drug(s) for a maximum of 16 cycles or 1 year. mab, alone and in combination with bevacizumab, in Patients were discontinued from the study for any of the patients with advanced solid malignancies. following reasons: dose-limiting toxicity (DLT), disease progression, noncompliance, change in eligibility, or if the Materials and Methods investigator felt it was in their best interest. Patients in phase Onartuzumab was administered by intravenous (i.v.) Ib who experienced bevacizumab-related adverse events infusion every 3 weeks (Q3W), either alone or in combi- (AE) discontinued bevacizumab, but could continue with nation with bevacizumab (15 mg/kg i.v. Q3W) in patients onartuzumab treatment. with advanced solid malignancies refractory to standard of Astandard3þ3 dose-escalation design applied for care therapy or for which standard of care therapy did not onartuzumab until the maximum administered dose of exist. This study was conducted at two U.S. sites (The 30 mg/kg was reached in the phase Ia escalation and until University of Chicago, IL, and Cancer Institute of New the RP2D of 15 mg/kg was reached in phase Ib with Jersey, NJ). The protocol was approved by the Institutional bevacizumab. The dose of onartuzumab for each patient Review Boards before patient recruitment and was con- was dependent on dose level assignment and patient ducted in accordance with the International Conference on weight on or within 14 days of day 1 of cycle 1. Onartu- Harmonisation E6 Guideline for Good Clinical Practice. zumab was administered over 90 Æ 10 minutes for the first two doses. Subsequent doses were administered over Eligibility criteria 30 Æ 10 minutes (for dose levels <10 mg/kg) or 60 Æ 10 Key inclusion criteria were adults with histologically minutes (for dose levels 10 mg/kg). In phase Ib, onar- confirmed solid malignancy that was incurable, locally tuzumab was given before bevacizumab. advanced, or metastatic and that had failed to respond to at least one prior regimen or for which standard of Safety, tolerability, and response assessments care therapy did not exist; measurable or evaluable dis- The primary outcome measure was the safety and toler- ease defined by Response Evaluation Criteria in Solid ability of onartuzumab alone or in combination with Tumors (RECIST; ref. 13); Eastern Cooperative
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