An Intergroup Randomized Phase II Study of Bevacizumab or Cetuximab in Combination with Gemcitabine and in Combination with Chemoradiation in Patients with Resected Pancreatic Carcinoma: A Trial of the ECOG-ACRIN Cancer Research Group (E2204).
ABSTRACT: OBJECTIVES:Evaluate toxicity of two treatment arms, A (cetuximab) and B (bevacizumab), when combined with gemcitabine, and chemoradiation in patients with completely resected pancreatic carcinoma. Secondary objectives included overall survival (OS) and disease-free survival (DFS). METHODS:Patients with R0/R1 resection were randomized 1:1 to cetuximab or bevacizumab administered in combination with gemcitabine for two treatment cycles. Next three cycles included concurrent cetuximab/bevacizumab plus chemoradiation, followed by one cycle of cetuximab/bevacizumab. Cycles 7-12 included cetuximab/bevacizumab with gemcitabine. Cycles were 2 weeks. Frequency of specific toxicities was summarized for each treatment arm at two times during the study, after chemotherapy but prior to chemoradiation and after all therapy. RESULTS:A total of 127 patients were randomized (A, n = 65; B, n = 62). Prior to chemoradiation, the overall rate for toxicities of interest was 10% for arm A and 2% for arm B. After all therapy, the overall rates for toxicities of interest were 30 and 25% for arms A and B, respectively. Overall median OS and DFS were 17 and 11 months, respectively, which is not a significant improvement over expected survival rates for historical controls. CONCLUSIONS:Both treatments were tolerable with manageable toxicities, and were safe enough for a phase III trial had this been indicated.
Project description:Adjuvant gemcitabine with or without chemoradiation is a standard therapeutic option for patients with resected pancreatic cancer. The feasibility and toxicity of gemcitabine with docetaxel before and after 5-fluorouracil (5FU)-based chemoradiation in the adjuvant pancreatic and biliary cancer setting were investigated.After a curative-intent resection, eligible patients with pancreaticobiliary cancers were treated with two cycles of gemcitabine and docetaxel followed by 5FU-based chemoradiation. Four weeks after completing chemoradiation, two cycles of gemcitabine and docetaxel were administered. The primary endpoint was the incidence of severe toxicities. Secondary endpoints included disease-free survival (DFS) and overall survival (OS).Fifty patients with pancreaticobiliary cancers were enrolled. Twenty-nine patients had pancreatic cancer whereas 21 patients had biliary tract or ampullary cancers. There was one death as a result of pneumonia, and 15% of patients experienced grade 3 or greater non-haematological toxicities. The median DFS and OS for patients with pancreatic cancer were 9.6 and 17 months, respectively, and for those with resected biliary tract cancer were 12 and 23 months, respectively.This combination of gemcitabine and docetaxel with chemoradiation is feasible and tolerable in the adjuvant setting. Future studies utilizing a different gemcitabine/taxane combination and schedule may be appropriate in the adjuvant treatment of both pancreatic cancer and biliary tumours.
Project description:We conducted a phase I clinical trial for patients with advanced cancer and predominant liver disease.Patients were treated with HAI nab-paclitaxel (120-210 mg/m(2); day 1); intravenous bevacizumab (10 mg/kg; day 1); and intravenous gemcitabine (600-800 mg/m(2); days 1 and 8). A conventional "3 + 3" study design was used.Fifty patients with advanced cancer and predominant liver metastases were treated (median age, 58 years; 27 women, 23 men; median number of prior therapies, 3 [range 0-12]). The most common cancers were breast (n = 9) and pancreatic (n = 9). Overall, 264 cycles were administered (median/patient, 4; range 1-17). No dose-limiting toxicities were noted during the escalation phase. On dose level 4, 3 patients were unable to receive gemcitabine on day 8 because of severe thrombocytopenia. Dose level 3 was selected as the maximum-tolerated dose (HAI nab-paclitaxel 180 mg/m(2) and intravenous gemcitabine 800 mg/m(2) and bevacizumab 10 mg/kg); 32 patients were treated in the expansion phase. The most common treatment-related toxicities were thrombocytopenia (n = 17), neutropenia (n = 10), and fatigue (n = 12). Of 46 patients evaluable for response, 9 (20 %) had a partial response (PR) and 9 (20 %) had stable disease for ?6 months. The median overall survival duration was 7.0 months (95 % CI: 4, 22 months), and the median progression-free survival duration was 4.2 months (95 % CI: 2.7, 8.6 months).HAI nab-paclitaxel in combination with gemcitabine and bevacizumab was well tolerated and had antitumor activity in selected patients with advanced cancer and liver metastases.
Project description:To evaluate the benefit with the addition of paclitaxel to cisplatin-based concurrent chemoradiotherapy (C-CRT) for the treatment of locally advanced carcinoma of the uterine cervix in terms of local control, disease free survival (DFS) and overall survival (OS).From 1/7/2011 to 31/5/2012, 81 women (median age of 50 years) with newly diagnosed, histopathologically proven carcinoma cervix with FIGO stages IIA to IIIB were randomized to two arms-cisplatin 40 mg/m(2)/week for 5 weeks was given in single agent cisplatin (control arm), while cisplatin 30 mg/m(2)/week and paclitaxel 50 mg/m(2)/week for 5 weeks were given in cisplatin and paclitaxel (study arm). External beam radiotherapy (EBRT) was delivered to a total dose of 50 Gray (Gy) in 25 fractions (#) followed by intracavitary (I/C) brachytherapy or supplement EBRT at 20 Gy/10# with 2 cycles of respective chemotherapy. This prospective trial was registered with clinicaltrials.gov (NCT01593306).Patients (n=81) had a maximum follow up of 36 months with a median follow up of 29 months. At first follow up study arm showed complete response in 84% vs. 75.6% in control arm (P=0.4095). An increase in toxicities was observed in the study arm in comparison to the control arm in terms of haematological grade II (35% vs. 12.2%), gastrointestinal (GI) grade III (20% vs. 7.4%) and GI grade IV (12.5% vs. 2.4%) toxicities. At median follow-up, the study arm demonstrated enhanced outcomes over the control arm in terms of DFS (79.5% vs. 64.3%; P=0.07) and OS (87.2% vs. 78.6%; P=0.27).Despite the expected increase in manageable toxicities, these early results reveal promise with the inclusion of paclitaxel into the standard cisplatin based chemoradiation regime. Larger multi-institutional studies are justified to confirm a potential for the enhancement of response rates and survival.
Project description:Bevacizumab is a humanized monoclonal antibody targeting vascular endothelial growth factor (VEGF). Recurrence after resection of colorectal liver metastases (CRLMs), presumably caused by VEGF-mediated outgrowth of micrometastases, might decrease when VEGF is inhibited. This study examines the efficacy and safety of adding bevacizumab to an adjuvant regimen of CAPOX in patients undergoing radical resection for their CRLMs. Patients with resected CRLMs were randomized after surgery to receive CAPOX and bevacizumab (arm A) or CAPOX alone (arm B) as adjuvant treatment. CAPOX was given in both arms for a total of eight cycles. Bevacizumab was administered for 16 cycles. The primary end point was disease-free survival (DFS). Secondary outcomes were overall survival (OS), toxicity, and quality of life (QoL). In total, 79 patients were randomized. At the time of analysis, 23 events were encountered in arm A and 20 in arm B. One-year DFS rate was 79% [95% confidence interval (CI): 68%-93%] and 68% (95% CI: 55%-85%) for arm A and B, respectively (P=.89). Toxicity was evaluated for 75 patients. No significant differences in toxicity between the two arms were found. QoL scores were higher in arm A, of which emotional functioning and global QoL scores were significant. Adding bevacizumab to a CAPOX regimen in patients undergoing a resection for their CLM is safe and showed higher QoL scores compared with CAPOX alone. Because of premature closure of the study, conclusions about the effect on DFS of additional VEGF inhibition in this setting could not yet be made.
Project description:The role of adjuvant chemoradiotherapy (CRT) in resectable pancreatic cancer is still debated. This randomized phase II intergroup study explores the feasibility and tolerability of a gemcitabine-based CRT regimen after R0 resection of pancreatic head cancer.Within 8 weeks after surgery, patients were randomly assigned to receive either four cycles of gemcitabine (control arm) or gemcitabine for two cycles followed by weekly gemcitabine with concurrent radiation (50.4 Gy; CRT arm). The primary objective was to exclude a < 60% treatment completion and a > 40% rate of grade 4 hematologic or GI toxicity in the CRT arm with type I and II errors of 10%. Secondary end points were late toxicity, disease-free survival (DFS), and overall survival (OS).Between September 2004 and January 2007, 90 patients were randomly assigned (45:45). Patient characteristics were similar in both arms. Treatment was completed per protocol by 86.7% and 73.3% (80% CI, 63.1% to 81.9%; 95% CI, 58.1% to 85.4%) in the control and CRT arms, respectively, and grade 4 toxicity was 0% and 4.7% (two of 43; 80% CI, 1.2% to 11.9%), respectively. In the CRT arm, three patients experienced grade 3-related late toxicity. Median DFS was 12 months in the CRT arm and 11 months in the control arm. Median OS was 24 months in both arms. First local recurrence was less frequent in the CRT arm (11% v 24%).Adjuvant gemcitabine-based CRT is feasible, well-tolerated, and not deleterious; adding this treatment to full-dose adjuvant gemcitabine after resection of pancreatic cancer should be evaluated in a phase III trial.
Project description:Cetuximab and bevacizumab have each been demonstrated to prolong survival when added to chemotherapy in patients with advanced non-small-cell lung cancer (NSCLC). However, the potential benefit of combining cetuximab and bevacizumab together with a platinum-based doublet had not been explored. We designed this phase II trial to evaluate the safety, tolerability, and efficacy of the combination of carboplatin, paclitaxel, cetuximab, and bevacizumab in chemotherapy-naive patients with advanced, nonsquamous NSCLC.Patients received with up to six cycles of carboplatin (area under curve 6), paclitaxel (200 mg/m(2)), cetuximab (400 mg/m(2) day 1 then 250 mg/m(2) weekly), and bevacizumab (15 mg/kg) every 21 days. Patients with an objective response or stable disease received maintenance cetuximab (250 mg/m(2) weekly) and bevacizumab (15 mg/kg every 21 days) until disease progression. The primary endpoint was safety as defined by the frequency and severity of hemorrhagic toxicities. Secondary endpoints included response rate, progression-free survival, overall survival, and toxicity. Molecular biomarkers were assessed in an exploratory manner.The primary endpoint of grade 4 or higher hemorrhage of 2% (95% confidence interval: 0%-7%) met prespecified criteria for safety. One hundred ten patients were enrolled. There were four treatment-related deaths including lung hemorrhage (2), infection (1), and unknown (1). Median progression-free survival was 7 months and median overall survival was 15 months. The response rate was 56% with an overall disease control rate of 77%.This regimen was safe, feasible, and effective as a frontline treatment of advanced NSCLC, providing the basis for the ongoing phase III trial S0819.
Project description:Bevacizumab and temsirolimus are active agents in advanced solid tumors. Temsirolimus inhibits mTOR in the PI3 kinase/AKT/mTOR pathway as well as CYP2A, which may be a resistance mechanism for cetuximab. In addition, temsirolimus attenuates upregulation of HIF-1? levels, which may be a resistance mechanism for bevacizumab.We analyzed safety and responses in 21 patients with advanced solid tumors treated with bevacizumab, cetuximab, and temsirolimus.The median age of patients was 60 years (range, 23-80 years). The median number of prior systemic therapies was 3 (range, 1-6). The maximum tolerated dose (MTD) was determined to be bevacizumab 10 mg/kg biweekly, temsirolimus 5 mg weekly and cetuximab 100/75 mg/m2 weekly. Grade 3 or 4 toxicities were seen in 52% of patients with the highest prevalence being hyperglycemia (14%) and hypophosphatemia (14%). Eighteen of the 21 patients were evaluable for response. Three patients were taken off the study before restaging for toxicities. Partial response (PR) was observed in 2/18 patients (11%) and stable disease (SD) lasting ? 6 months was observed in 4/18 patients (22%) (total = 6/18 (33%)). In 8 evaluable patients with squamous cell carcinoma of the head and neck (HNSCC) there were partial responses in 2/8 (25%) patients and SD ? 6 months in 1/8 (13%) patients (total = 3/8, (38%)).The combination of bevacizumab, cetuximab, and temsirolimus showed activity in HNSCC; however, there were numerous toxicities reported, which will require careful management for future clinical development.
Project description:Patients with a newly diagnosed glioblastoma multiforme (GBM) have a high risk of recurrent disease with a dismal outcome despite intensive treatment of sequential surgery and chemoradiotherapy with temozolomide (TMZ), followed by TMZ as a single agent. Bevacizumab (BV) may increase response rates to chemotherapy in the recurrent treatment setting of GBM. We hypothesized that a neoadjuvant treatment strategy for patients with newly diagnosed GBM using chemoradiotherapy plus BV would improve resectability and thus survival. We performed a phase II trial of the treatment strategy of BV plus chemoradiation to determine the safety of this combination in patients who had already undergone primary surgery for their GBM.After a biopsy (6 patients) or a resection (13 patients) of a newly diagnosed GBM, 19 patients received radiotherapy (30 fractions of 2 Gy) in combination with daily TMZ 75 mg/m(2) and BV 10 mg/kg on days 1, 14, and 28, followed by 6 monthly cycles of TMZ 150-200 mg/m(2) on days 1-5.The overall response rate was 26%. Three patients had a complete response after resection, and in two patients, a complete response after resection followed by chemoradiation plus BV was seen. No grade 3-4 toxicities were observed during combination treatment. The median progression-free survival was 9.6 months (95% confidence interval [CI]: 4.3-14.4 months). The median overall survival was 16 months (95% CI: 8.1-26.3 months), similar to a matched control group that received standard chemoradiotherapy from our institution.Combination of bevacizumab with radiotherapy and TMZ is safe and feasible in patients with newly diagnosed GBM, but because of low response rates, this treatment strategy does not favor a neoadjuvant approach.
Project description:BACKGROUND:Even clearly resectable pancreatic cancer still has an unfavorable prognosis. Neoadjuvant or perioperative therapies might improve the prognosis of these patients. Thus, evaluation of perioperative chemotherapy in resectable pancreatic cancer in a prospective, randomized trial is warranted. A substantial improvement in overall survival of patients with metastatic pancreatic cancer with FOLFIRINOX and nab-paclitaxel/gemcitabine vs standard gemcitabine has been demonstrated in phase III-trials. Indeed nab-paclitaxel/gemcitabine has a more favorable toxicity profile compared to the FOLFIRINOX protocol and appears applicable in a perioperative setting. METHODS:NEONAX is an interventional, prospective, randomized, controlled, open label, two sided phase II study with an unconnected analysis of the results in both experimental arms against a fixed survival probability (38% at 18?months with adjuvant gemcitabine), NCT02047513. NEONAX will enroll 166 patients with resectable pancreatic ductal adenocarcinoma (? cT3, N0 or N1, cM0) in two arms: Arm A (perioperative arm): 2?cycles nab-paclitaxel (125?mg/m2)/gemcitabine (1000?mg/m2, d1, 8 and 15 of an 28?day-cycle) followed by tumor surgery followed by 4?cycles nab-paclitaxel/gemcitabine, Arm B (adjuvant arm): tumor surgery followed by 6?cycles nab-paclitaxel/gemcitabine. The randomization (1:1) is eminent to avoid allocation bias between the groups. Randomization is stratified for tumor stage (ct1/2 vs. cT3) and lymph node status (cN0 vs. cN1). Primary objective is disease free survival (DFS) at 18?months after randomization. Key secondary objectives are 3-year overall survival (OS) rate and DFS rate, progression during neoadjuvant therapy, R0 and R1 resection rate, quality of life and correlation of DFS, OS and tumor regression with pharmacogenomic markers, tumor biomarkers and molecular analyses (ctDNA, transcriptome, miRNA-arrays). In addition, circulating tumor-DNA will be analyzed in patients with the best and the worst responses to the neoadjuvant treatment. The study was initiated in March 2015 in 26 centers for pancreatic surgery in Germany. DISCUSSION:The NEONAX trial is an innovative study on resectable pancreatic cancer and currently one of the largest trials in this field of research. It addresses the question of the role of intensified perioperative treatment with nab-paclitaxel plus gemcitabine in resectable pancreatic cancers to improve disease-free survival and offers a unique potential for translational research. TRIAL REGISTRATION:ClinicalTrials.gov : NCT02047513, 08/13/2014.
Project description:PURPOSE:Gemcitabine plus cisplatin is active in malignant mesothelioma (MM), although single-arm phase II trials have reported variable outcomes. Vascular endothelial growth factor (VEGF) inhibitors have activity against MM in preclinical models. We added the anti-VEGF antibody bevacizumab to gemcitabine/cisplatin in a multicenter, double-blind, placebo-controlled randomized phase II trial in patients with previously untreated, unresectable MM. PATIENTS AND METHODS:Eligible patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 and no thrombosis, bleeding, or major blood vessel invasion. The primary end point was progression-free survival (PFS). Patients were stratified by ECOG performance status (0 v 1) and histologic subtype (epithelial v other). Patients received gemcitabine 1,250 mg/m(2) on days 1 and 8 every 21 days, cisplatin 75 mg/m(2) every 21 days, and bevacizumab 15 mg/kg or placebo every 21 days for six cycles, and then bevacizumab or placebo every 21 days until progression. RESULTS:One hundred fifteen patients were enrolled at 11 sites; 108 patients were evaluable. Median PFS time was 6.9 months for the bevacizumab arm and 6.0 months for the placebo arm (P = .88). Median overall survival (OS) times were 15.6 and 14.7 months in the bevacizumab and placebo arms, respectively (P = .91). Partial response rates were similar (24.5% for bevacizumab v 21.8% for placebo; P = .74). A higher pretreatment plasma VEGF concentration (n = 56) was associated with shorter PFS (P = .02) and OS (P = .0066), independent of treatment arm. There were no statistically significant differences in toxicity of grade 3 or greater. CONCLUSION:The addition of bevacizumab to gemcitabine/cisplatin in this trial did not significantly improve PFS or OS in patients with advanced MM.