Cancer Chemother Pharmacol (2015) 75:993–1004 DOI 10.1007/s00280-015-2694-y
ORIGINAL ARTICLE
Motesanib with or without panitumumab plus FOLFIRI or FOLFOX for the treatment of metastatic colorectal cancer Niall Tebbutt · Dusan Kotasek · Howard A. Burris · Lee S. Schwartzberg · Herbert Hurwitz · Joe Stephenson · Douglas J. Warner · Lisa Chen · Cheng‑Pang Hsu · David Goldstein
Received: 10 December 2014 / Accepted: 26 January 2015 / Published online: 15 March 2015 © Springer-Verlag Berlin Heidelberg 2015
Abstract Purpose This study assessed the safety, efficacy, and pharmacokinetics of motesanib, a multitargeted small molecule angiogenesis inhibitor, with and without panitumumab, in combination with FOLFIRI or FOLFOX in patients with metastatic colorectal cancer (mCRC). Methods This open-label, phase 1b, two-part, multicenter study in patients with mCRC and ≤1 prior treatment evaluated escalating doses (50, 75, 100, or 125 mg QD, 75 mg BID) of motesanib with panitumumab and chemotherapy
The results of this study have not been previously published or submitted for publication elsewhere. The results were presented in part at the Gastrointestinal Cancers Symposium, Orlando, FL, January 23–24, 2010; the American Society of Clinical Oncology, Chicago IL, June 4–8, 2010; the European Society of Medical Oncology, Stockholm, Sweden, September 12–16, 2008; and the American Society of Clinical Oncology-Gastrointestinal Cancers, 2007. ClinicalTrials.gov Registration Number: NCT00101894. Electronic supplementary material The online version of this article (doi:10.1007/s00280-015-2694-y) contains supplementary material, which is available to authorized users. N. Tebbutt (*) Department of Medical Oncology, Austin Health, Heidelberg, VIC 3084, Australia e-mail: [email protected] D. Kotasek Ashford Cancer Centre, Ashford, SA, Australia H. A. Burris Sarah Cannon Research Institute, Nashville, TN, USA L. S. Schwartzberg The West Clinic, Memphis, TN, USA
(Part 1) and the target dose of motesanib with chemotherapy (Part 2). Results At 17 sites in the USA and Australia, 119 patients were enrolled between December 2004 and February 2010. In Part 1 [motesanib plus panitumumab/FOLFIRI (n = 36) or plus panitumumab/FOLFOX (n = 17)], all motesanib doses tested were tolerated and 125 mg QD was deemed the target dose. Following toxicity results for combination therapy in other trials, panitumumab was withdrawn from the study. Part 2 evaluated motesanib 125 mg with chemotherapy [FOLFIRI (n = 37); FOLFOX (n = 29)]. The primary endpoint, objective response rate in patients with measurable disease by RECIST, was 20 % overall and was higher among patients receiving first-line (27 % overall; FOLFOX, 24 %; FOLFIRI, 27 %) compared with second-line therapy (14 % overall; FOLFOX, 0 %; FOLFIRI, 20 %). The most common adverse events were diarrhea, nausea, fatigue, and hypertension. We observed a low rate of cholecystitis [3 of 119 (2.5 %)], a known adverse event of motesanib and other small molecule VEGF inhibitors. Conclusions Motesanib 125 mg QD in combination with FOLFIRI or FOLFOX chemotherapy was tolerated and demonstrated modest efficacy in first-/second-line mCRC. H. Hurwitz Duke University Medical Center, Durham, NC, USA J. Stephenson Cancer Center of the Carolinas, Greenville, SC, USA D. J. Warner · L. Chen · C.‑P. Hsu Amgen Inc., Thousand Oaks, CA, USA D. Goldstein Prince of Wales Clinical School, University of New South Wales, Prince of Wales Hospital, Sydney, NSW, Australia
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994
Keywords Anti-angiogenic · Targeted agent · Metastatic colorectal cancer · Dose-escalation · Motesanib · Panitumumab
Introduction Colorectal cancer is more common in developed countries with an incidence rate of 29.2 per 100,000 compared with 11.7 in less developed countries [1]. Australia ranks eighth highest in the world for the incidence of colorectal cancer by country, with 38.4 cases per 100,000. Although the USA did not rank in the top 20 as estimated by Globocan, colorectal cancer also presents a considerable burden, with over 140,000 new cases of colorectal cancer expected annually [2]. Approximately 50 % of patients diagnosed with colorectal cancer develop metastatic disease (mCRC) for which oxaliplatin- or irinotecan-based chemotherapy is standard [3–5]. Integration of targeted biologic agents (bevacizumab, cetuximab, and panitumumab) with chemotherapy has improved survival and offered additional treatment options. In attempts to further improve outcome, numerous novel targeted agent candidates are currently under investigation [6–8]. Motesanib diphosphate (motesanib; AMG 706) is an oral small molecule angiogenesis inhibitor of multiple targets including vascular endothelial growth factor receptors (VEGFR) 1, 2, and 3, platelet-derived growth factor receptor (PDGFR), and stem cell factor receptor (c-Kit) [9]. Thus, motesanib has a potential clinical advantage over bevacizumab as an angiogenesis inhibitor due to its broader mechanism of action with more complete inhibition of VEGF targets. Motesanib has been investigated in a variety of tumor types and has shown activity both as monotherapy [10–12] and in combination with chemotherapy [13–16]. Panitumumab is a monoclonal antibody against EGFR that has been studied as monotherapy and in combination with chemotherapy as well as with bevacizumab and chemotherapy in patients with mCRC [17–21]. Combining VEGF- and EGFR-targeted agents may provide more complete inhibition of tumor growth by potentially overcoming resistance to single pathway inhibition [22]. The present study assessed the safety, efficacy, and pharmacokinetics of motesanib with and without panitumumab in combination with FOLFIRI or FOLFOX in patients with mCRC.
Methods Patients Eligible patients were adults with a diagnosis of metastatic colorectal adenocarcinoma with ≤1 prior systemic chemotherapy regimen for mCRC, an Eastern Cooperative
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Cancer Chemother Pharmacol (2015) 75:993–1004
Oncology Group (ECOG) performance status of 0 or 1, adequate organ function, life expectancy ≥3 months, and no systemic chemotherapy within 28 days or prior radiotherapy to the target lesion unless disease progression of the target lesion within 6 weeks could be documented. Those who had received prior irinotecan-containing chemotherapy were only eligible for participation in FOLFOX cohorts, while those who had received prior oxaliplatin-containing chemotherapy were only eligible for FOLFIRI cohorts. This trial was conducted in accordance with the Declaration of Helsinki and good clinical practice, as well as all local regulations. The protocol was approved by the institutional ethics committee at each site, and written informed consent was obtained before any study procedures were performed. Study design and treatment This was an open-label, phase 1b, two-part, multicenter, sequential dose-escalation (or de-escalation) study of motesanib with or without panitumumab plus either FOLFIRI or FOLFOX chemotherapy as first- or second-line treatment in patients with mCRC. In Part 1, motesanib was to be evaluated in escalating doses (50 mg QD, 75 mg QD, 100 mg QD, 125 mg QD, and 75 mg BID) with panitumumab and FOLFIRI or FOLFOX chemotherapy. Six patients were initially enrolled in the first dose cohort (50 mg QD), and safety data were reviewed after at least six evaluable patients had completed the dose-limiting toxicity (DLT) period (2 cycles; 28 days). A new cohort at the next dose level was then initiated until the maximum tolerated dose (MTD; defined as the highest well-tolerated dose), or target dose (125 mg QD) was reached. More patients were to be added in any cohort to acquire additional safety data. Part 1 commenced before kras was known as a predictive biomarker for panitumumab, and hence, k-ras testing was not undertaken. A DLT was defined as any motesanib-related, grade 4 hematological (anemia was not considered a DLT) or nonhematological toxicity, or grade 3 non-hematological toxicity that was unacceptable in duration, during the DLT period. DLT definition modifications were as follows: grade 3 fatigue persistent for more than 7 days or grade 4 fatigue; grade 3 or 4 nausea, diarrhea, or vomiting despite maximum supportive care; grade 3 or 4 neutropenia with fever >38.5 °C; grade 4 neutropenia (absolute neutrophil count
ORIGINAL ARTICLE
Motesanib with or without panitumumab plus FOLFIRI or FOLFOX for the treatment of metastatic colorectal cancer Niall Tebbutt · Dusan Kotasek · Howard A. Burris · Lee S. Schwartzberg · Herbert Hurwitz · Joe Stephenson · Douglas J. Warner · Lisa Chen · Cheng‑Pang Hsu · David Goldstein
Received: 10 December 2014 / Accepted: 26 January 2015 / Published online: 15 March 2015 © Springer-Verlag Berlin Heidelberg 2015
Abstract Purpose This study assessed the safety, efficacy, and pharmacokinetics of motesanib, a multitargeted small molecule angiogenesis inhibitor, with and without panitumumab, in combination with FOLFIRI or FOLFOX in patients with metastatic colorectal cancer (mCRC). Methods This open-label, phase 1b, two-part, multicenter study in patients with mCRC and ≤1 prior treatment evaluated escalating doses (50, 75, 100, or 125 mg QD, 75 mg BID) of motesanib with panitumumab and chemotherapy
The results of this study have not been previously published or submitted for publication elsewhere. The results were presented in part at the Gastrointestinal Cancers Symposium, Orlando, FL, January 23–24, 2010; the American Society of Clinical Oncology, Chicago IL, June 4–8, 2010; the European Society of Medical Oncology, Stockholm, Sweden, September 12–16, 2008; and the American Society of Clinical Oncology-Gastrointestinal Cancers, 2007. ClinicalTrials.gov Registration Number: NCT00101894. Electronic supplementary material The online version of this article (doi:10.1007/s00280-015-2694-y) contains supplementary material, which is available to authorized users. N. Tebbutt (*) Department of Medical Oncology, Austin Health, Heidelberg, VIC 3084, Australia e-mail: [email protected] D. Kotasek Ashford Cancer Centre, Ashford, SA, Australia H. A. Burris Sarah Cannon Research Institute, Nashville, TN, USA L. S. Schwartzberg The West Clinic, Memphis, TN, USA
(Part 1) and the target dose of motesanib with chemotherapy (Part 2). Results At 17 sites in the USA and Australia, 119 patients were enrolled between December 2004 and February 2010. In Part 1 [motesanib plus panitumumab/FOLFIRI (n = 36) or plus panitumumab/FOLFOX (n = 17)], all motesanib doses tested were tolerated and 125 mg QD was deemed the target dose. Following toxicity results for combination therapy in other trials, panitumumab was withdrawn from the study. Part 2 evaluated motesanib 125 mg with chemotherapy [FOLFIRI (n = 37); FOLFOX (n = 29)]. The primary endpoint, objective response rate in patients with measurable disease by RECIST, was 20 % overall and was higher among patients receiving first-line (27 % overall; FOLFOX, 24 %; FOLFIRI, 27 %) compared with second-line therapy (14 % overall; FOLFOX, 0 %; FOLFIRI, 20 %). The most common adverse events were diarrhea, nausea, fatigue, and hypertension. We observed a low rate of cholecystitis [3 of 119 (2.5 %)], a known adverse event of motesanib and other small molecule VEGF inhibitors. Conclusions Motesanib 125 mg QD in combination with FOLFIRI or FOLFOX chemotherapy was tolerated and demonstrated modest efficacy in first-/second-line mCRC. H. Hurwitz Duke University Medical Center, Durham, NC, USA J. Stephenson Cancer Center of the Carolinas, Greenville, SC, USA D. J. Warner · L. Chen · C.‑P. Hsu Amgen Inc., Thousand Oaks, CA, USA D. Goldstein Prince of Wales Clinical School, University of New South Wales, Prince of Wales Hospital, Sydney, NSW, Australia
13
994
Keywords Anti-angiogenic · Targeted agent · Metastatic colorectal cancer · Dose-escalation · Motesanib · Panitumumab
Introduction Colorectal cancer is more common in developed countries with an incidence rate of 29.2 per 100,000 compared with 11.7 in less developed countries [1]. Australia ranks eighth highest in the world for the incidence of colorectal cancer by country, with 38.4 cases per 100,000. Although the USA did not rank in the top 20 as estimated by Globocan, colorectal cancer also presents a considerable burden, with over 140,000 new cases of colorectal cancer expected annually [2]. Approximately 50 % of patients diagnosed with colorectal cancer develop metastatic disease (mCRC) for which oxaliplatin- or irinotecan-based chemotherapy is standard [3–5]. Integration of targeted biologic agents (bevacizumab, cetuximab, and panitumumab) with chemotherapy has improved survival and offered additional treatment options. In attempts to further improve outcome, numerous novel targeted agent candidates are currently under investigation [6–8]. Motesanib diphosphate (motesanib; AMG 706) is an oral small molecule angiogenesis inhibitor of multiple targets including vascular endothelial growth factor receptors (VEGFR) 1, 2, and 3, platelet-derived growth factor receptor (PDGFR), and stem cell factor receptor (c-Kit) [9]. Thus, motesanib has a potential clinical advantage over bevacizumab as an angiogenesis inhibitor due to its broader mechanism of action with more complete inhibition of VEGF targets. Motesanib has been investigated in a variety of tumor types and has shown activity both as monotherapy [10–12] and in combination with chemotherapy [13–16]. Panitumumab is a monoclonal antibody against EGFR that has been studied as monotherapy and in combination with chemotherapy as well as with bevacizumab and chemotherapy in patients with mCRC [17–21]. Combining VEGF- and EGFR-targeted agents may provide more complete inhibition of tumor growth by potentially overcoming resistance to single pathway inhibition [22]. The present study assessed the safety, efficacy, and pharmacokinetics of motesanib with and without panitumumab in combination with FOLFIRI or FOLFOX in patients with mCRC.
Methods Patients Eligible patients were adults with a diagnosis of metastatic colorectal adenocarcinoma with ≤1 prior systemic chemotherapy regimen for mCRC, an Eastern Cooperative
13
Cancer Chemother Pharmacol (2015) 75:993–1004
Oncology Group (ECOG) performance status of 0 or 1, adequate organ function, life expectancy ≥3 months, and no systemic chemotherapy within 28 days or prior radiotherapy to the target lesion unless disease progression of the target lesion within 6 weeks could be documented. Those who had received prior irinotecan-containing chemotherapy were only eligible for participation in FOLFOX cohorts, while those who had received prior oxaliplatin-containing chemotherapy were only eligible for FOLFIRI cohorts. This trial was conducted in accordance with the Declaration of Helsinki and good clinical practice, as well as all local regulations. The protocol was approved by the institutional ethics committee at each site, and written informed consent was obtained before any study procedures were performed. Study design and treatment This was an open-label, phase 1b, two-part, multicenter, sequential dose-escalation (or de-escalation) study of motesanib with or without panitumumab plus either FOLFIRI or FOLFOX chemotherapy as first- or second-line treatment in patients with mCRC. In Part 1, motesanib was to be evaluated in escalating doses (50 mg QD, 75 mg QD, 100 mg QD, 125 mg QD, and 75 mg BID) with panitumumab and FOLFIRI or FOLFOX chemotherapy. Six patients were initially enrolled in the first dose cohort (50 mg QD), and safety data were reviewed after at least six evaluable patients had completed the dose-limiting toxicity (DLT) period (2 cycles; 28 days). A new cohort at the next dose level was then initiated until the maximum tolerated dose (MTD; defined as the highest well-tolerated dose), or target dose (125 mg QD) was reached. More patients were to be added in any cohort to acquire additional safety data. Part 1 commenced before kras was known as a predictive biomarker for panitumumab, and hence, k-ras testing was not undertaken. A DLT was defined as any motesanib-related, grade 4 hematological (anemia was not considered a DLT) or nonhematological toxicity, or grade 3 non-hematological toxicity that was unacceptable in duration, during the DLT period. DLT definition modifications were as follows: grade 3 fatigue persistent for more than 7 days or grade 4 fatigue; grade 3 or 4 nausea, diarrhea, or vomiting despite maximum supportive care; grade 3 or 4 neutropenia with fever >38.5 °C; grade 4 neutropenia (absolute neutrophil count
