Safety and pharmacokinetics of ganitumab (AMG 479) combined with sorafenib, panitumumab, erlotinib, or gemcitabine in patients with advanced solid tumors

Lee S. Rosen, Igor Puzanov, Gregory Friberg, Emily Chan, Yuying C. Hwang, Hongjie Deng, Jill Gilbert, Devalingam Mahalingam, Ian McCaffery, Shaunita A. Michael, Alain C. Mita, Monica M. Mita, Marilyn Mulay, Poornima Shubhakar, Min Zhu, John Sarantopoulos

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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. Circulating 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 pharmacokinetics in combination with either sorafenib, panitumumab, erlotinib, or gemcitabine. Ganitumab is currently under investigation in combination with some of these and other agents.

Original languageEnglish (US)
Pages (from-to)3414-3427
Number of pages14
JournalClinical Cancer Research
Volume18
Issue number12
DOIs
StatePublished - Jun 15 2012

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gemcitabine
Pharmacokinetics
Safety
Neoplasms
Insulin-Like Growth Factor Binding Protein 3
sorafenib
AMG 479
Erlotinib Hydrochloride
panitumumab
Somatomedin Receptors
Chills

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Safety and pharmacokinetics of ganitumab (AMG 479) combined with sorafenib, panitumumab, erlotinib, or gemcitabine in patients with advanced solid tumors. / Rosen, Lee S.; Puzanov, Igor; Friberg, Gregory; Chan, Emily; Hwang, Yuying C.; Deng, Hongjie; Gilbert, Jill; Mahalingam, Devalingam; McCaffery, Ian; Michael, Shaunita A.; Mita, Alain C.; Mita, Monica M.; Mulay, Marilyn; Shubhakar, Poornima; Zhu, Min; Sarantopoulos, John.

In: Clinical Cancer Research, Vol. 18, No. 12, 15.06.2012, p. 3414-3427.

Research output: Contribution to journalArticle

Rosen, LS, Puzanov, I, Friberg, G, Chan, E, Hwang, YC, Deng, H, Gilbert, J, Mahalingam, D, McCaffery, I, Michael, SA, Mita, AC, Mita, MM, Mulay, M, Shubhakar, P, Zhu, M & Sarantopoulos, J 2012, 'Safety and pharmacokinetics of ganitumab (AMG 479) combined with sorafenib, panitumumab, erlotinib, or gemcitabine in patients with advanced solid tumors', Clinical Cancer Research, vol. 18, no. 12, pp. 3414-3427. https://doi.org/10.1158/1078-0432.CCR-11-3369
Rosen, Lee S. ; Puzanov, Igor ; Friberg, Gregory ; Chan, Emily ; Hwang, Yuying C. ; Deng, Hongjie ; Gilbert, Jill ; Mahalingam, Devalingam ; McCaffery, Ian ; Michael, Shaunita A. ; Mita, Alain C. ; Mita, Monica M. ; Mulay, Marilyn ; Shubhakar, Poornima ; Zhu, Min ; Sarantopoulos, John. / Safety and pharmacokinetics of ganitumab (AMG 479) combined with sorafenib, panitumumab, erlotinib, or gemcitabine in patients with advanced solid tumors. In: Clinical Cancer Research. 2012 ; Vol. 18, No. 12. pp. 3414-3427.
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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. Circulating 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 pharmacokinetics in combination with either sorafenib, panitumumab, erlotinib, or gemcitabine. Ganitumab is currently under investigation in combination with some of these and other agents.",
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T1 - Safety and pharmacokinetics of ganitumab (AMG 479) combined with sorafenib, panitumumab, erlotinib, or gemcitabine in patients with advanced solid tumors

AU - Rosen, Lee S.

AU - Puzanov, Igor

AU - Friberg, Gregory

AU - Chan, Emily

AU - Hwang, Yuying C.

AU - Deng, Hongjie

AU - Gilbert, Jill

AU - Mahalingam, Devalingam

AU - McCaffery, Ian

AU - Michael, Shaunita A.

AU - Mita, Alain C.

AU - Mita, Monica M.

AU - Mulay, Marilyn

AU - Shubhakar, Poornima

AU - Zhu, Min

AU - Sarantopoulos, John

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Y1 - 2012/6/15

N2 - 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. Circulating 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 pharmacokinetics in combination with either sorafenib, panitumumab, erlotinib, or gemcitabine. Ganitumab is currently under investigation in combination with some of these and other agents.

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