Invest New Drugs (2015) 33:241–246 DOI 10.1007/s10637-014-0169-3
PHASE II STUDIES
A phase II trial of bevacizumab plus temsirolimus in patients with advanced hepatocellular carcinoma Jennifer J. Knox & Rui Qin & Jonathan R. Strosberg & Benjamin Tan & Andreas Kaubisch & Anthony B. El-Khoueiry & Tanios S. Bekaii-Saab & Steven R. Rousey & Helen X. Chen & Charles Erlichman
Received: 29 July 2014 / Accepted: 1 October 2014 / Published online: 16 October 2014 # Springer Science+Business Media New York 2014
Summary Background There is strong rationale to combine temsirolimus (TEM) with Bevacizumab (BEV) for patients with advanced HCC. Methods A modified two-stage Simon phase II trial was performed with plans to advance to stage 2 if more than 2 patients had confirmed PR or >18 patients were progression free at 6 months out of 25 in stage 1. Toxicity, PFS and overall survival were secondary endpoints. Eligible pts had advanced HCC, Child Pugh A liver status and no prior
Presented in abstract form at ASCO 2012 annual meeting, abstract # 4099 J. J. Knox (*) Staff Medical Oncologist, Gastrointestinal Oncology Lead, Princess Margaret Cancer Centre, University of Toronto, 5-210, 610 University Ave, Toronto, ON M5G 2 M9, USA e-mail: [email protected] R. Qin : C. Erlichman Mayo Clinic, Rochester, MN, USA J. R. Strosberg H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA B. Tan Washington University School of Medicine, St Louis, MO, USA A. Kaubisch Montefiore Medical Center, Bronx, NY, USA A. B. El-Khoueiry University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA, USA T. S. Bekaii-Saab The Wexner Medical Center at the Ohio State University, Columbus, OH, USA S. R. Rousey Metro Minnesota CCOP, St Louis Park, MN, USA H. X. Chen National Cancer Institute, Bethesda, MD, USA
systemic therapy involving the VEGF or m-TOR targeted agents. Patients were treated with temsirolimus 25 mg IV on Days 1, 8, 15, and 22 of a 28 day cycle and bevacizumab 10 mg/kg IV on Days 1 and 15 of the cycle. Results Twentyeight eligible patients were enrolled, 26 evaluable receiving a median of 6.5 cycles (range 1–18). Drug related toxicities were common including cytopenias, fatigue, mucositis, diarrhea and mild bleeds. Dose reductions or discontinuation of TEM were common. Accrual closed for presumed futility after interim analysis of the first 25 evaluable patients showed only one PR and 16/25 were progression-free at 6 months. However, the final data update in March 2013 demonstrated 4 confirmed PRs, a 5th unconfirmed PR and 16 /26 progressionfree at 6 months. Median PFS and OS were 7 and 14 months respectively. Conclusion This first-line HCC trial evaluating the BEV/TEM doublet reports an ORR of 19 % and OS of 14 months which is favorable but requires further study at a more optimized dose and schedule. Keywords Hepatocellular carcinoma . Bevacizumab . Temsirolimus . Phase II
Introduction Hepatocellular carcinoma (HCC) is the 5th most common cancer worldwide with a rising incidence over the past three decades [1, 2]. Worldwide, HCC is the third leading cause of cancer death. At presentation, the majority of patients (70– 85 %) already have unresectable disease and those with localised disease have high rates of recurrence as high as 50 % in 2 years in surgical series. For patients who relapse or progress, and for those patients who present with advanced disease, the prognosis is poor with median survival rates of less than 12 months. Poor underlying liver function and the lack of
242
effective systemic therapies are the main factors leading to poor survival in these patients [2–4]. Potential for progress in systemic therapy for advanced HCC patients may lie with targeted agents. It is well recognized that many mutations and aberrant cell pathways drive primary liver tumorigenesis. HCCs have tremendous molecular heterogeneity, suggesting that therapeutic advancements may require simultaneous targeting of more than one molecular pathway [5]. Vascular endothelial growth factor (VEGF) and the mammalian target of rapamycin (mTOR) pathways are two promising targets for HCC drug development. VEGF is over-expressed in HCC, and the level of expression correlates with tumor grade. [6] Anti-angiogenic drugs such as sorafenib or bevacizumab have already demonstrated activity in advanced HCC. Sorafenib is a multikinase inhibitor with anti-angiogenic, proapoptotic and Raf kinase inhibitory activity. A phase III randomized trial in patients with advanced HCC with preserved liver function (Child-Pugh A) demonstrated that sorafenib was associated with a statistically significant improvement in overall survival (10.7 versus 7.9 months, HR 0.69, p
PHASE II STUDIES
A phase II trial of bevacizumab plus temsirolimus in patients with advanced hepatocellular carcinoma Jennifer J. Knox & Rui Qin & Jonathan R. Strosberg & Benjamin Tan & Andreas Kaubisch & Anthony B. El-Khoueiry & Tanios S. Bekaii-Saab & Steven R. Rousey & Helen X. Chen & Charles Erlichman
Received: 29 July 2014 / Accepted: 1 October 2014 / Published online: 16 October 2014 # Springer Science+Business Media New York 2014
Summary Background There is strong rationale to combine temsirolimus (TEM) with Bevacizumab (BEV) for patients with advanced HCC. Methods A modified two-stage Simon phase II trial was performed with plans to advance to stage 2 if more than 2 patients had confirmed PR or >18 patients were progression free at 6 months out of 25 in stage 1. Toxicity, PFS and overall survival were secondary endpoints. Eligible pts had advanced HCC, Child Pugh A liver status and no prior
Presented in abstract form at ASCO 2012 annual meeting, abstract # 4099 J. J. Knox (*) Staff Medical Oncologist, Gastrointestinal Oncology Lead, Princess Margaret Cancer Centre, University of Toronto, 5-210, 610 University Ave, Toronto, ON M5G 2 M9, USA e-mail: [email protected] R. Qin : C. Erlichman Mayo Clinic, Rochester, MN, USA J. R. Strosberg H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA B. Tan Washington University School of Medicine, St Louis, MO, USA A. Kaubisch Montefiore Medical Center, Bronx, NY, USA A. B. El-Khoueiry University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA, USA T. S. Bekaii-Saab The Wexner Medical Center at the Ohio State University, Columbus, OH, USA S. R. Rousey Metro Minnesota CCOP, St Louis Park, MN, USA H. X. Chen National Cancer Institute, Bethesda, MD, USA
systemic therapy involving the VEGF or m-TOR targeted agents. Patients were treated with temsirolimus 25 mg IV on Days 1, 8, 15, and 22 of a 28 day cycle and bevacizumab 10 mg/kg IV on Days 1 and 15 of the cycle. Results Twentyeight eligible patients were enrolled, 26 evaluable receiving a median of 6.5 cycles (range 1–18). Drug related toxicities were common including cytopenias, fatigue, mucositis, diarrhea and mild bleeds. Dose reductions or discontinuation of TEM were common. Accrual closed for presumed futility after interim analysis of the first 25 evaluable patients showed only one PR and 16/25 were progression-free at 6 months. However, the final data update in March 2013 demonstrated 4 confirmed PRs, a 5th unconfirmed PR and 16 /26 progressionfree at 6 months. Median PFS and OS were 7 and 14 months respectively. Conclusion This first-line HCC trial evaluating the BEV/TEM doublet reports an ORR of 19 % and OS of 14 months which is favorable but requires further study at a more optimized dose and schedule. Keywords Hepatocellular carcinoma . Bevacizumab . Temsirolimus . Phase II
Introduction Hepatocellular carcinoma (HCC) is the 5th most common cancer worldwide with a rising incidence over the past three decades [1, 2]. Worldwide, HCC is the third leading cause of cancer death. At presentation, the majority of patients (70– 85 %) already have unresectable disease and those with localised disease have high rates of recurrence as high as 50 % in 2 years in surgical series. For patients who relapse or progress, and for those patients who present with advanced disease, the prognosis is poor with median survival rates of less than 12 months. Poor underlying liver function and the lack of
242
effective systemic therapies are the main factors leading to poor survival in these patients [2–4]. Potential for progress in systemic therapy for advanced HCC patients may lie with targeted agents. It is well recognized that many mutations and aberrant cell pathways drive primary liver tumorigenesis. HCCs have tremendous molecular heterogeneity, suggesting that therapeutic advancements may require simultaneous targeting of more than one molecular pathway [5]. Vascular endothelial growth factor (VEGF) and the mammalian target of rapamycin (mTOR) pathways are two promising targets for HCC drug development. VEGF is over-expressed in HCC, and the level of expression correlates with tumor grade. [6] Anti-angiogenic drugs such as sorafenib or bevacizumab have already demonstrated activity in advanced HCC. Sorafenib is a multikinase inhibitor with anti-angiogenic, proapoptotic and Raf kinase inhibitory activity. A phase III randomized trial in patients with advanced HCC with preserved liver function (Child-Pugh A) demonstrated that sorafenib was associated with a statistically significant improvement in overall survival (10.7 versus 7.9 months, HR 0.69, p
