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A randomized phase II efficacy and correlative studies of cetuximab with or without sorafenib in recurrent and/or metastatic head and neck squamous cell carcinoma.
Gilbert J, Schell MJ, Zhao X, Murphy B, Tanvetyanon T, Leon ME, Neil Hayes D, Haigentz M, Saba N, Nieva J, Bishop J, Sidransky D, Ravi R, Bedi A, Chung CH
(2015) Oral Oncol 51: 376-82
MeSH Terms: Adult, Aged, Antineoplastic Agents, Carcinoma, Squamous Cell, Cetuximab, Female, Head and Neck Neoplasms, Humans, Male, Middle Aged, Neoplasm Metastasis, Niacinamide, Phenylurea Compounds, Recurrence, Sorafenib
Show Abstract · Added February 17, 2015
INTRODUCTION - A combination of cetuximab and sorafenib in patients with recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) were assessed for potential benefit.
MATERIAL AND METHODS - In a randomized phase II study, R/M HNSCC patients were treated with cetuximab 400mg/m(2) IV on day 1 followed by 250mg/m(2) IV weekly (Arm A), or cetuximab at the same dose/schedule plus sorafenib 400mg PO twice-a-day (Arm B). Each cycle was 21days. Tumor p16 and HPV status, and plasma immunomodulatory cytokine levels were assessed.
RESULTS - Of 55 patients enrolled (Arm A-27, Arm B-28), 52 patients received assigned treatments and 43 were evaluable for response. Overall response rate was 8% for both arms. Median overall survival (OS) and progression-free survival (PFS) were 9.0 and 3.0months in Arm A, and 5.7 and 3.2months in Arm B, respectively. Forty-four patients had tumors available for p16 staining (35-negative, 9-positive). Three of nine p16-positive tumors were also HPV positive. The p16-negative patients had significantly better PFS compared to the p16-positive patients (3.7 vs. 1.6months; p-value: 0.03), regardless of study arms. Twenty-four plasma samples were tested for 12 cytokine levels and patients with higher TGFβ1 levels had inferior PFS compared to lower levels (1.9 vs. 4.7months; adjusted p-value: 0.015), regardless of study arms.
CONCLUSIONS - A subset of R/M patients with p16-negative tumors or lower plasma TGFβ1 levels had longer PFS given the cetuximab-based therapy. However, both arms showed only modest response and sorafenib given with cetuximab did not demonstrate clinical benefit.
Copyright © 2014 Elsevier Ltd. All rights reserved.
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15 MeSH Terms
Phase II trial of sorafenib and erlotinib in advanced pancreatic cancer.
Cardin DB, Goff L, Li CI, Shyr Y, Winkler C, DeVore R, Schlabach L, Holloway M, McClanahan P, Meyer K, Grigorieva J, Berlin J, Chan E
(2014) Cancer Med 3: 572-9
MeSH Terms: Adult, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols, Disease-Free Survival, Drug-Related Side Effects and Adverse Reactions, ErbB Receptors, Erlotinib Hydrochloride, Female, Humans, Male, Middle Aged, Molecular Targeted Therapy, Neoplasm Staging, Niacinamide, Pancreatic Neoplasms, Phenylurea Compounds, Quinazolines, Sorafenib
Show Abstract · Added March 11, 2014
This trial was designed to assess efficacy and safety of erlotinib with sorafenib in the treatment of patients with advanced pancreatic adenocarcinoma. An exploratory correlative study analyzing pretreatment serum samples using a multivariate protein mass spectrometry-based test (VeriStrat®), previously shown to correlate with outcomes in lung cancer patients treated with erlotinib, was performed. Patients received sorafenib 400 mg daily along with erlotinib 150 mg daily with a primary endpoint of 8-week progression free survival (PFS) rate. Pretreatment serum sample analysis by VeriStrat was done blinded to clinical and outcome data; the endpoints were PFS and overall survival (OS). Difference between groups (by VeriStrat classification) was assessed using log-rank P values; hazard ratios (HR) were obtained from Cox proportional hazards model. Thirty-six patients received study drug and were included in the survival analysis. Eight-week PFS rate of 46% (95% confidence interval (CI): 0.32-0.67) did not meet the primary endpoint of a rate ≥70%. Thirty-two patients were included in the correlative analysis, and VeriStrat "Good" patients had superior PFS (HR = 0.18, 95% CI: 0.06-0.57; P = 0.001) and OS (HR = 0.31 95% CI: 0.13-0.77, P = 0.008) compared to VeriStrat "Poor" patients. Grade 3 toxicities of this regimen included fever, anemia, diarrhea, dehydration, rash, and altered liver function. This study did not meet the primary endpoint, and this combination will not be further pursued. In this small retrospective analysis, the proteomic classification was significantly associated with clinical outcomes and is being further evaluated in ongoing studies.
© 2014 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.
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19 MeSH Terms
Oncogenic and sorafenib-sensitive ARAF mutations in lung adenocarcinoma.
Imielinski M, Greulich H, Kaplan B, Araujo L, Amann J, Horn L, Schiller J, Villalona-Calero MA, Meyerson M, Carbone DP
(2014) J Clin Invest 124: 1582-6
MeSH Terms: Adenocarcinoma, Adenocarcinoma of Lung, Aged, Amino Acid Substitution, Antineoplastic Agents, Cell Transformation, Neoplastic, DNA, Neoplasm, Female, Humans, Lung Neoplasms, Molecular Targeted Therapy, Mutation, Missense, Niacinamide, Oncogenes, Phenylurea Compounds, Proto-Oncogene Proteins A-raf, Proto-Oncogene Proteins B-raf, Proto-Oncogene Proteins c-raf, Sorafenib
Show Abstract · Added June 26, 2014
Targeted cancer therapies often induce "outlier" responses in molecularly defined patient subsets. One patient with advanced-stage lung adenocarcinoma, who was treated with oral sorafenib, demonstrated a near-complete clinical and radiographic remission for 5 years. Whole-genome sequencing and RNA sequencing of primary tumor and normal samples from this patient identified a somatic mutation, ARAF S214C, present in the cancer genome and expressed at high levels. Additional mutations affecting this residue of ARAF and a nearby residue in the related kinase RAF1 were demonstrated across 1% of an independent cohort of lung adenocarcinoma cases. The ARAF mutations were shown to transform immortalized human airway epithelial cells in a sorafenib-sensitive manner. These results suggest that mutant ARAF is an oncogenic driver in lung adenocarcinoma and an indicator of sorafenib response.
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19 MeSH Terms
Crizotinib induces PUMA-dependent apoptosis in colon cancer cells.
Zheng X, He K, Zhang L, Yu J
(2013) Mol Cancer Ther 12: 777-86
MeSH Terms: Animals, Antineoplastic Agents, Apoptosis, Apoptosis Regulatory Proteins, Cell Line, Tumor, Colonic Neoplasms, Crizotinib, Drug Synergism, Female, Gefitinib, Gene Expression Regulation, Neoplastic, Humans, Mice, Niacinamide, Phenylurea Compounds, Protein Kinase Inhibitors, Proto-Oncogene Proteins, Pyrazoles, Pyridines, Quinazolines, Sorafenib, Tumor Suppressor Protein p53, Xenograft Model Antitumor Assays
Show Abstract · Added July 28, 2015
Oncogenic alterations in MET or anaplastic lymphoma kinase (ALK) have been identified in a variety of human cancers. Crizotinib (PF02341066) is a dual MET and ALK inhibitor and approved for the treatment of a subset of non-small cell lung carcinoma and in clinical development for other malignancies. Crizotinib can induce apoptosis in cancer cells, whereas the underlying mechanisms are not well understood. In this study, we found that crizotinib induces apoptosis in colon cancer cells through the BH3-only protein PUMA. In cells with wild-type p53, crizotinib induces rapid induction of PUMA and Bim accompanied by p53 stabilization and DNA damage response. The induction of PUMA and Bim is mediated largely by p53, and deficiency in PUMA or p53, but not Bim, blocks crizotinib-induced apoptosis. Interestingly, MET knockdown led to selective induction of PUMA, but not Bim or p53. Crizotinib also induced PUMA-dependent apoptosis in p53-deficient colon cancer cells and synergized with gefitinib or sorafenib to induce marked apoptosis via PUMA in colon cancer cells. Furthermore, PUMA deficiency suppressed apoptosis and therapeutic responses to crizotinib in xenograft models. These results establish a critical role of PUMA in mediating apoptotic responses of colon cancer cells to crizotinib and suggest that mechanisms of oncogenic addiction to MET/ALK-mediated survival may be cell type-specific. These findings have important implications for future clinical development of crizotinib.
©2013 AACR
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23 MeSH Terms
Cardiac side effects of anticancer treatments: new mechanistic insights.
Geisberg C, Pentassuglia L, Sawyer DB
(2012) Curr Heart Fail Rep 9: 211-8
MeSH Terms: Anthracyclines, Antibiotics, Antineoplastic, Antibodies, Monoclonal, Humanized, Antineoplastic Agents, Benzenesulfonates, Daunorubicin, Doxorubicin, Heart Failure, Humans, Indoles, Myocardial Contraction, Myocytes, Cardiac, Niacinamide, Phenylurea Compounds, Pyridines, Pyrroles, Sorafenib, Sunitinib, Trastuzumab
Show Abstract · Added March 5, 2014
Damage to heart cells leading to heart failure is a known complication of well-established cancer therapies including anthracycline antibiotics and radiation therapy, and the cardiovascular complications of these therapies has been controlled in large part through dose limitations and modifications of delivery methods. Recent research into the cellular and molecular mechanisms for the cardiovascular effects of these therapies may lead to other cardioprotective strategies that improve effectiveness of cancer treatments. Newer cancer therapies that have been developed based upon specifically targeting oncogene signaling also have been associated with heart failure. Rapid development of a detailed understanding of how these agents cause cardiac dysfunction promises to improve outcomes in cancer patients, as well as stimulate concepts of cardiovascular homeostasis that will likely accelerate development of cardiovascular therapies.
1 Communities
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19 MeSH Terms
Primary renal cell carcinoma: relationship between 18F-FDG uptake and response to neoadjuvant sorafenib.
Khandani AH, Cowey CL, Moore DT, Gohil H, Rathmell WK
(2012) Nucl Med Commun 33: 967-73
MeSH Terms: Adult, Aged, Aged, 80 and over, Benzenesulfonates, Biological Transport, Carcinoma, Renal Cell, Feasibility Studies, Female, Fluorodeoxyglucose F18, Humans, Kidney Neoplasms, Male, Middle Aged, Multimodal Imaging, Neoadjuvant Therapy, Niacinamide, Phenylurea Compounds, Positron-Emission Tomography, Pyridines, Safety, Sorafenib, Survival Analysis, Tomography, X-Ray Computed, Treatment Outcome, Young Adult
Show Abstract · Added October 17, 2015
OBJECTIVE - The objective of this study was to collect preliminary data on the predictive value of pretherapy 18F-fluorodeoxyglucose positron emission tomography in primary renal cell carcinoma (RCC) patients undergoing neoadjuvant therapy with sorafenib.
METHODS - As part of a clinical trial to assess the safety and feasibility of using neoadjuvant sorafenib in patients with RCC, 26 patients [19 with clear cell RCC (ccRCC), seven with non-clear cell RCC (non-ccRCC)] underwent 18F-fluorodeoxyglucose positron emission tomography with concurrent computed tomography (CT) before commencing sorafenib therapy and 17 (13 ccRCC, four non-ccRCC) of them also at the end of sorafenib therapy. The maximal standard uptake value at baseline (SUV base) and its change from baseline after therapy (SUV diff and SUV rel) were recorded and correlated with therapy response, measured as percentage size change on CT, using Spearman's rank and Pearson's correlation coefficients.
RESULTS - SUV base and size change on CT showed a strong inverse correlation (Spearman's rank correlation coefficient=-0.72, P=0.0003; Pearson's correlation coefficient=-0.64, P=0.002) in ccRCC. There was no statistically significant correlation in non-ccRCC (Spearman's rank correlation coefficient=0.67, P=0.098; Pearson's correlation coefficient=0.46, P=0.32). In neither group was there a statistically significant correlation between change in SUV and size after commencement of treatment. All findings were limited by the small number of samples included in this analysis.
CONCLUSION - Primary ccRCC tumors with lower SUV base are more likely to respond to neoadjuvant sorafenib, whereas this trend was not observed for non-ccRCC tumors.
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25 MeSH Terms
Skin toxicity and efficacy of sunitinib and sorafenib in metastatic renal cell carcinoma: a national registry-based study.
Poprach A, Pavlik T, Melichar B, Puzanov I, Dusek L, Bortlicek Z, Vyzula R, Abrahamova J, Buchler T, Czech Renal Cancer Cooperative Group
(2012) Ann Oncol 23: 3137-3143
MeSH Terms: Aged, Angiogenesis Inhibitors, Antineoplastic Agents, Carcinoma, Renal Cell, Disease-Free Survival, Exanthema, Female, Hand-Foot Syndrome, Humans, Indoles, Kidney Neoplasms, Male, Middle Aged, Neoplasm Metastasis, Niacinamide, Phenylurea Compounds, Protein Kinase Inhibitors, Pyrroles, Registries, Retrospective Studies, Skin, Sorafenib, Sunitinib, Treatment Outcome
Show Abstract · Added March 5, 2014
BACKGROUND - A retrospective, registry-based analysis to assess the outcomes of metastatic renal cell cancer (mRCC) patients treated with sunitinib and sorafenib who developed dermatologic adverse events was performed.
PATIENTS AND METHODS - Data on mRCC patients treated with sunitinib or sorafenib were obtained from the Czech Clinical Registry of Renal Cell Cancer Patients. Outcomes of patients who developed hand-foot syndrome (HFS) of any grade and/or grade 3/4 rash during the treatment were compared with patients without HFS and no, mild, or moderate rash.
RESULTS - The cohort included 705 patients treated with sunitinib and 365 patients treated with sorafenib. For sunitinib, the median overall survival (OS) was 43.0 months versus 31.0 months (P = 0.027) and median progression-free survival (PFS) 20.8 months versus 11.1 months (P = 0.007) for patients with versus without dermatologic toxicity, respectively. For sorafenib, the median OS and PFS were 27.9 and 24.6 months (P = 0.244), and 12.2 and 8.8 months (P = 0.050), respectively. In multivariable Cox regression, the skin toxicity was significantly associated with longer OS in the sunitinib cohort.
CONCLUSION - The presence of skin toxicity is associated with improved OS and PFS in patients with mRCC treated with sunitinib.
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24 MeSH Terms
Safety and pharmacokinetics of ganitumab (AMG 479) combined with sorafenib, panitumumab, erlotinib, or gemcitabine in patients with advanced solid tumors.
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) Clin Cancer Res 18: 3414-27
MeSH Terms: Adult, Aged, Antibodies, Monoclonal, Antibodies, Monoclonal, Humanized, Antineoplastic Combined Chemotherapy Protocols, Benzenesulfonates, Biomarkers, Tumor, Deoxycytidine, Erlotinib Hydrochloride, Female, Humans, Male, Middle Aged, Neoplasms, Niacinamide, Panitumumab, Phenylurea Compounds, Pyridines, Quinazolines, Receptor, IGF Type 1, Sorafenib
Show Abstract · Added March 5, 2014
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/m(2) 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.
©2012 AACR.
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21 MeSH Terms
Randomized phase II trial of sorafenib with temsirolimus or tipifarnib in untreated metastatic melanoma (S0438).
Margolin KA, Moon J, Flaherty LE, Lao CD, Akerley WL, Othus M, Sosman JA, Kirkwood JM, Sondak VK
(2012) Clin Cancer Res 18: 1129-37
MeSH Terms: Adult, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols, Benzenesulfonates, Female, Humans, Male, Melanoma, Middle Aged, Neoplasm Metastasis, Neoplasm Staging, Niacinamide, Phenylurea Compounds, Pyridines, Quinolones, Sirolimus, Sorafenib, Survival Analysis, Treatment Outcome
Show Abstract · Added March 20, 2014
PURPOSE - Signaling pathway stimulation by activating mutations of oncogenes occurs in most melanomas and can provide excellent targets for therapy, but the short-term therapeutic success is limited by intrinsic and acquired resistance. The mitogen-activated protein kinase and phosphoinositide 3-kinase/AKT/mTOR pathways are activated in most cutaneous melanomas. The purpose of this trial was to prospectively evaluate 2 molecularly targeted drug combinations in patients with untreated metastatic melanoma.
EXPERIMENTAL DESIGN - This randomized phase II study enrolled patients between May 2008 and November 2009 with nonocular melanoma, no prior systemic chemotherapy, and no history of brain metastasis. Arm A received oral sorafenib 200 mg twice daily plus i.v. temsirolimus 25 mg weekly; and arm B received oral sorafenib 400 mg every morning, 200 mg every night daily plus oral tipifarnib 100 mg twice daily, 3 weeks of every 4. The primary objectives were to evaluate progression-free survival (PFS), objective response rate, and toxicity for the 2 regimens.
RESULTS - On arm A (63 evaluable patients), the median PFS was 2.1 months and median overall survival (OS) was 7 months. Three patients achieved partial response (PR). Thirty-nine evaluable patients were accrued to arm B, which closed after first-stage accrual; the median PFS was 1.8 months and OS was 7 months, with 1 patient achieving PR.
CONCLUSIONS - The combinations of molecularly targeted agents tested did not show sufficient activity to justify further use. Newer agents and improved patient selection by characterization of the molecular targets in individual tumors show great promise and should be incorporated into future studies, along with appropriate laboratory correlates.
©2012 AACR.
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20 MeSH Terms
Reversible cardiomyopathy associated with sunitinib and sorafenib.
Uraizee I, Cheng S, Moslehi J
(2011) N Engl J Med 365: 1649-50
MeSH Terms: Aged, Antineoplastic Agents, Benzenesulfonates, Cardiomyopathies, Female, Humans, Indoles, Male, Middle Aged, Niacinamide, Phenylurea Compounds, Protein-Tyrosine Kinases, Pyridines, Pyrroles, Sorafenib, Sunitinib, Vascular Endothelial Growth Factor A
Added March 4, 2015
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17 MeSH Terms