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Safety and Pharmacokinetics of Ganitumab (AMG 479) Combined with Sorafenib, Panitumumab, Erlotinib, Or Gemcitabine in Patients with Advanced Solid Tumors

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Safety and Pharmacokinetics of Ganitumab (AMG 479) Combined with Sorafenib, Panitumumab, Erlotinib, Or Gemcitabine in Patients with Advanced Solid Tumors Published OnlineFirst April 17, 2012; DOI: 10.1158/1078-0432.CCR-11-3369 Clinical Cancer Cancer Therapy: Clinical Research Safety and Pharmacokinetics of Ganitumab (AMG 479) Combined with Sorafenib, Panitumumab, Erlotinib, or Gemcitabine in Patients with Advanced Solid Tumors Lee S. Rosen1, Igor Puzanov2, Gregory Friberg3, Emily Chan2, Yuying C. Hwang3, Hongjie Deng3, Jill Gilbert2, Devalingam Mahalingam4, Ian McCaffery3, Shaunita A. Michael2, Alain C. Mita4, Monica M. Mita4, Marilyn Mulay1, Poornima Shubhakar3, Min Zhu3, and John Sarantopoulos4 Abstract Purpose: This phase 1b dose-escalation study assessed safety, tolerability, and pharmacokinetics of ganitumab, a fully human monoclonal antibody against the insulin-like growth factor 1 (IGF1) receptor, combined with targeted agents or cytotoxic chemotherapy in patients with advanced solid tumors. Experimental Design: Patients with treatment-refractory advanced solid tumors were sequentially enrolled at 2 ganitumab dose levels (6 or 12 mg/kg i.v. every 2 weeks) combined with either sorafenib 400 mg twice daily, panitumumab 6 mg/kg every 2 weeks, erlotinib 150 mg once daily, or gemcitabine 1,000 mg/m2 on days 1, 8, and 15 of each 4-week cycle. The primary end points were safety and pharmacokinetics of ganitumab. Results: Ganitumab up to 12 mg/kg appeared well tolerated combined with sorafenib, panitumumab, erlotinib, or gemcitabine. Treatment-emergent adverse events were generally mild and included fatigue, nausea, vomiting, and chills. Three patients had dose-limiting toxicities: grade 3 hyperglycemia (ganitumab 6 mg/kg and panitumumab), grade 4 neutropenia (ganitumab 6 mg/kg and gemcitabine), and grade 4 thrombocytopenia (ganitumab 12 mg/kg and erlotinib). Ganitumab-binding and panitumumab-binding antibodies were detected in 5 and 2 patients, respectively; neutralizing antibodies were not detected. The pharmacokinetics of ganitumab and each cotherapy did not appear affected by coadministration. Circu- lating total IGF1 and IGF binding protein 3 increased from baseline following treatment. Four patients (9%) had partial responses. Conclusions: Ganitumab up to 12 mg/kg was well tolerated, without adverse effects on pharmaco- kinetics in combination with either sorafenib, panitumumab, erlotinib, or gemcitabine. Ganitumab is currently under investigation in combination with some of these and other agents. Clin Cancer Res; 18(12); 3414–27. Ó2012 AACR. Introduction are several lines of evidence that implicate the IGF1R The insulin-like growth factor 1 receptor (IGF1R) is a type signaling axis in the development of human malignancies 1 transmembrane tyrosine kinase receptor that, with its (6). Not only have constitutive IGF1R expression, IGF1R ligands insulin-like growth factor 1 (IGF1) and 2 (IGF2), overexpression, and autocrine or paracrine signaling via regulates cell proliferation and apoptosis (1–4). The activity IGF1R been proposed as mechanisms of transformation in of IGFs is modulated by 6 IGF binding proteins (IGFBP), several tumor types (7–11), but studies using gene knock- which may affect tumor growth and IGF function (5). There out mice have shown that IGF1R is required for transfor- mation (12, 13). In early-phase clinical trials, IGF1R inhibitors have Authors' Affiliations: 1Premiere Oncology, Santa Monica, California; 2Van- shown acceptable toxicity profiles and evidence of antitu- derbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nash- mor activity (14). Several lines of evidence suggest that these ville, Tennessee; 3Amgen Inc., Thousand Oaks, California; and 4Institute for Drug Development, Cancer Therapy and Research Center, The University agents might be combined with other anticancer agents in of Texas Health Science Center at San Antonio, San Antonio, Texas the treatment of solid tumors. Interactions between IGF1R Note: Supplementary data for this article are available at Clinical Cancer and epidermal growth factor receptor (EGFR) have been Research Online (http://clincancerres.aacrjournals.org/). reported in different cell types, and IGF1R may induce EGFR Corresponding Author: Lee S. Rosen, UCLA Hematology/Oncology, phosphorylation via autocrine or paracrine mechanisms 2020 Santa Monica Blvd, Suite 600, Santa Monica, CA 90404. Phone: involving EGF-like ligands (15–17). It was therefore pos- 310-633-8400; Fax: 310-633-8419; E-mail: [email protected] tulated that combined inhibition of IGF1R and vascular doi: 10.1158/1078-0432.CCR-11-3369 endothelial growth factor (VEGF) or EGFR would be of Ó2012 American Association for Cancer Research. therapeutic benefit. This rationale was further supported by 3414 Clin Cancer Res; 18(12) June 15, 2012 Downloaded from clincancerres.aacrjournals.org on September 29, 2021. © 2012 American Association for Cancer Research. Published OnlineFirst April 17, 2012; DOI: 10.1158/1078-0432.CCR-11-3369 Safety of Ganitumab Plus Targeted or Cytotoxic Agents Patients and Methods Translational Relevance Patients Ganitumab (AMG 479) is a fully human immuno- Patients aged 18 years or more with pathologically or globulin G1 monoclonal antibody against the insulin- cytologically documented advanced solid tumors or renal like growth factor 1 receptor (IGF1R). In early-stage cell carcinoma (sorafenib cohorts) refractory to at least 1 trials, ganitumab had acceptable toxicity and evidence line of therapy or for which no standard or curative therapy of activity in patients with advanced solid tumors and was available; measurable or evaluable disease per World increased overall survival when combined with gemci- Health Organization (WHO) guidelines; an Eastern Coop- tabine in patients with previously untreated metastatic erative Oncology Group performance status of 2 or less; life pancreatic cancer. Combinations of IGF1R inhibitors expectancy of 3 months or more; and adequate hemato- and targeted or cytotoxic agents may improve treatment logic, renal, and hepatic function were eligible to enroll. efficacy. We assessed the safety, pharmacokinetics, and Exclusion criteria included unresolved toxicities from antitumor activity of ganitumab combined with the prior anticancer therapy; primary or metastatic central ner- multikinase inhibitor sorafenib, the fully human anti– vous system tumors (sorafenib cohorts only; controlled epidermal growth factor receptor (EGFR) monoclonal central nervous system tumors were allowed in other antibody panitumumab, the EGFR small-molecule cohorts); uncontrolled hypertension; ascites or pleural effu- inhibitor erlotinib, or the nucleoside analogue gemci- sion requiring treatment; abnormal pulmonary function, tabine. Ganitumab in combination with these agents including impaired carbon monoxide diffusion capacity was generally well tolerated, had favorable pharmaco- (gemcitabine cohorts); magnesium below the lower limit kinetics, and resulted in partial responses and tumor of normal (panitumumab cohorts); myocardial infarction, reductions in some patients. Ganitumab is currently arterial thrombosis, or venous thrombosis within the pre- under investigation in combination with targeted and vious 6 months; clinically significant hypoglycemia or cytotoxic agents for the treatment of several tumor types. hyperglycemia per investigator assessment; symptomatic congestive heart failure; unstable angina; unstable cardiac arrhythmia requiring treatment; peptic ulcer disease (sor- afenib cohorts); major surgery within the previous 4 weeks (8 weeks for the sorafenib cohorts); anticoagulation therapy preclinical studies reporting additive or synergistic inhibi- (except low-dose warfarin) within the previous week; active tion of tumor cell growth, induction of apoptosis, and infection within the previous 2 weeks; and history of chron- regression of tumor xenografts in several models when ic hepatitis. Diabetes (type 1 or 2) and existence or risk for small-molecule tyrosine kinase inhibitors of IGF1R were primary hepatic tumors were added as exclusion criteria combined with either of the EGFR inhibitors erlotinib or after enrollment had begun. gefitinib (18–20). Similarly, combined treatment with an Previous treatment with ganitumab or gemcitabine was IGF1R inhibitor and the multikinase inhibitor sorafenib not permitted. Prior treatment with cetuximab, panitumu- was also associated with additive inhibition of cholangio- mab, sorafenib, bevacizumab, or erlotinib was allowed. carcinoma cell growth (21). Furthermore, combination Patients were excluded for anticancer therapy, radiation treatment with an IGF1R inhibitor and the cytotoxic che- therapy, antibody therapy, retinoid therapy, hormonal motherapy gemcitabine was associated with additive inhi- therapy, or participation in clinical trials within the previ- bition of human pancreatic tumor xenograft growth (22). ous 4 weeks before enrollment (within the previous 6 weeks Ganitumab (AMG 479) is a fully human immunoglob- for nitrosoureas and mitomycin C). Concurrent hormone ulin G1 monoclonal antibody against IGF1R that inhibits replacement therapy or gonadotropin-releasing hormone tumor cell proliferation, promotes tumor cell death, and modulators were allowed for prostate cancer. Concomitant causes regression of established tumor xenografts (23, 24). medications that interfered with cytochrome P450 3A In a phase 1, first-in-human study, ganitumab as mono- metabolism were prohibited in the sorafenib and erlotinib therapy had acceptable toxicity up to the maximum tested cohorts. Institutional Review Board approval was obtained dose (20 mg/kg i.v. every 2 weeks) and
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