Greater Adverse Events Research Articles

Degarelix/bicalutamide combination versus degarelix alone as initial androgen-deprivation therapy

183 Background: Antiandrogens have been used to prevent symptoms due to testosterone surge in the early phase of treatment with gonadotropin-releasing hormone (GnRH) agonist as well as to add antitumor efficacy. Degarelix, an antagonist of GnRH does not introduce testosterone surge, however, the combination of degarelix and antiandrogen can exert a stronger antitumor effect than degarelix alone. We conducted a phase II study to investigate the early-phase efficacy and safety of combination of degarelix and bicalutamide compared with degarelix alone in patients with prostate cancer (PCa). Methods: Patients with histologically proven adenocarcinoma in the prostate indicated for androgen-deprivation therapy (ADT) were randomly assigned to a treatment group with either combination of degarelix and bicalutamide or degarelix alone. Degarelix was administered subcutaneously with an initial dose of 240 mg followed by 80 mg thereafter every four weeks. Bicalutamide was taken 80 mg every day. The primary endpoint was the percentage of patients whose serum prostate-specific antigen (PSA) declined with greater than 90% of the baseline at Day 28. Secondary endpoints were the transition of serum PSA and testosterone during treatment of 12 weeks, safety, and quality of life. Results: A total of 93 patients were evaluable in this final analysis. Median age was 75 years. Median baseline serum PSA was 10.2ng/ml. Baseline patient characteristics were well-balanced in both arms. The percentage of patients with serum PSA declines greater than 90% from baseline was 34% and 27% in the combination group and the degarelix monotherapy group, respectively (P= 0.503). The transition of serum PSA and testosterone levels were similar in both groups. No grade 3 or greater adverse event was observed in both groups. Conclusions: Adding bicalutamide on degarelix as initial ADT does not produce a greater impact on serum PSA decline in the early-treatment phase compared to degarelix alone. Clinical trial information: UMIN000011506.

Efficacy of EGFR Tyrosine Kinase Inhibitorsin the Adjuvant Treatment forOperable Non-small Cell Lung Cancer by a Meta-Analysis.

The role of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in the adjuvant treatment of non-small cell lung cancer (NSCLC) has not been well-established. Our meta-analysis aimed to determine whether the administration of EGFR-TKIs could improve the outcomes of patients with NSCLC undergoing complete resection. We comprehensively searched databases and extracted data from eligible studies. Disease-free survival (DFS) and overall survival (OS) with hazard ratios (HRs) as well as disease relapse with odds ratios (OR) were calculated using random and/or fixed-effects models. Meta-regression analysis and test for interaction between subgroups were also carried out. A total of 1,960 patients in five studies were included. Adjuvant EGFR-TKI treatment was associated with a significant benefit on DFS (HR, 0.63; 95%CI, 0.41-0.99), corresponding to an absolute benefit of 3.1%at 3 years, yet with significant heterogeneity (I(2)= 83.4%, P<.001). The survival benefit was superior (Pinteraction= .03) in studies with more than an 18-month median treatment duration. EGFR mutation rate was also identified as a source of heterogeneity (P= .017). In the population with EGFR mutations, HR for DFS was 0.48(95%CI, 0.36-0.65), corresponding to an absolute benefit of 9.5%at 3 years, with a reduced risk of distant metastasis (OR, 0.71; 95%CI, 0.56-0.92). Adjuvant EGFR-TKI treatment resulted in a marginally statistically significant benefit on OS (HR, 0.72; 95%CI, 0.49-1.06). Therate of overall grade 3 or greater adverse events was 42.3%(95%CI, 39.1-45.6). Adjuvant EGFR-TKI treatment may enhance disease-free survival and reduce the risk of distant metastasis in patients with EGFR-mutant NSCLC undergoing complete resection.

Chlorambucil plus ofatumumab versus chlorambucil alone in previously untreated patients with chronic lymphocytic leukaemia (COMPLEMENT 1): a randomised, multicentre, open-label phase 3 trial

Treatment for patients with chronic lymphocytic leukaemia who are elderly or who have comorbidities is challenging because fludarabine-based chemoimmunotherapies are mostly not suitable. Chlorambucil remains the standard of care in many countries. We aimed to investigate whether the addition of ofatumumab to chlorambucil could lead to better clinical outcomes than does treatment with chlorambucil alone, while also being tolerable for patients who have few treatment options. We carried out a randomised, open-label, phase 3 trial for treatment-naive patients with chronic lymphocytic leukaemia in 109 centres in 16 countries. We included patients who had active disease needing treatment, but in whom fludarabine-based treatment was not possible. We randomly assigned patients (1:1) to receive oral chlorambucil (10 mg/m(2)) on days 1-7 of a 28 day treatment course or to receive chlorambucil by this schedule plus intravenous ofatumumab (cycle 1: 300 mg on day 1 and 1000 mg on day 8; subsequent cycles: 1000 mg on day 1) for three to 12 cycles. Assignment was done with a randomisation list that was computer generated at GlaxoSmithKline, and was stratified, in a block size of two, by age, disease stage, and performance status. The primary endpoint was progression-free survival in the intention-to-treat population and assessment was done by an independent review committee that was masked to group assignment. The study is registered with ClinicalTrials.gov, number NCT00748189. We enrolled 447 patients, median age 69 years (range 35-92). Between Dec 22, 2008, and May 26, 2011, we randomly assigned 221 patients to chlorambucil plus ofatumumab and 226 patients to chlorambucil alone. Median progression-free survival was 22·4 months (95% CI 19·0-25·2) in the group assigned to chlorambucil plus ofatumumab compared with 13·1 months (10·6-13·8) in the group assigned to chlorambucil only (hazard ratio 0·57, 95% CI 0·45-0·72; p<0·0001). Grade 3 or greater adverse events were more common in the chlorambucil plus ofatumumab group (109 [50%] patients; vs 98 [43%] given chlorambucil alone), with neutropenia being the most common event (56 [26%] vs 32 [14%]). Grade 3 or greater infections had similar frequency in both groups. Grade 3 or greater infusion-related adverse events were reported in 22 (10%) patients given chlorambucil plus ofatumumab. Five (2%) patients died during treatment in each group. Addition of ofatumumab to chlorambucil led to clinically important improvements with a manageable side-effect profile in treatment-naive patients with chronic lymphocytic leukaemia who were elderly or had comorbidities. Chlorambucil plus ofatumumab is therefore an important treatment option for these patients who cannot tolerate more intensive therapy. GlaxoSmithKline, Genmab A/S.

Does prostate size impact upon perioperative outcomes associated with photoselective vaporization of the prostate using the 180W lithium triborate laser?

Introduction:Photoselective vaporization of the prostate (PVP) has been widely adopted as a surgical treatment for lower urinary tract symptoms due to benign prostatic hyperplasia (BPH). Recently, a high-powered 180 W lithium triborate (LBO) laser has become commercially available and there is relatively little information on the impact of this very high-powered laser on perioperative outcomes. Even more so is the impact of the laser on outcomes according to prostate size.Objectives:The objective of this study was to evaluate perioperative outcomes after PVP with the 180W laser, relative to prostate size.Patients and Methods:A prospectively maintained institutional ethics approved database was retrospectively reviewed. Subjects were analyzed according to transrectal ultrasound and categorized into groups namely 0-39 mL, 40-79 mL, 80-120 mL and >120 mL. Perioperative measures included energy utilized, length of operation, duration catheterization, post operative length of stay (POLOS), Clavien-Dindo adverse events and number discharged home within 24 hours catheter free.Results:With increasing prostate size, there was a statistically significant increase in energy utilization and operation time (P < 0.01 between groups). Duration of catheterization, POLOS, incidence of Grade 3 and above Clavien-Dindo adverse events and discharge home catheter free within 24 hours was not statistically significant across groups.Conclusions:Prostate volume impacts upon energy utilized with PVP surgery. Prostate volume does not influence duration of catheterization or POLOS. Clavien-Dindo Grade 3 or greater adverse events were low and do not appear to be influenced by prostate size. The ability to be discharged home catheter free within 24 hours likewise does not appear to be influenced by prostate size.

Presurgical treatment with axitinib in renal cell carcinoma patients with venous extension

In renal cell carcinoma patients with inferior vena cava (IVC) extension, the difficulty of resection increases with the degree of venous extension, which in turn increases the risk of perioperative morbidity and mortality. In addition, the degree of IVC occlusion and associated bland thrombus are reported to be important factors in the choice of operative procedure and in the risk of perioperative complications. Therefore, presurgical treatment to decrease the extent of tumor thrombus would be of significant benefit. Three renal cell carcinoma patients with IVC extension were treated presurgically with axitinib at our institution between September 2012 and November 2013. All patients received axitinib at an initial dose of 5 mg twice daily for 12 weeks. Objective response to treatment was assessed with enhanced computed tomography at 4 and 12 weeks, and therapeutic value was evaluated. Level of inferior vena cava thrombus, according to the classification of Neves et al., and degree of occlusion, according to the classification of Blute et al., were evaluated. Drug-related adverse events and perioperative complications were also investigated. Reduction in primary tumor size was observed in all cases. Two patients showed shortening of tumor thrombus, and a patient with complete occlusion of the IVC by tumor thrombus showed substantial improvement. No grade 3 or greater adverse events and no perioperative complications were observed during treatment. Axitinib may have benefits as a presurgical treatment for renal cell carcinoma patients with IVC extension.

O1-21-2 - Randomized Pii of Concurrent Vs Sequential Alternating Gefitinib and Chemotherapy in Egfr-Mutant Nsclc: Nej005/Tcog0902

Background: The first-line combination of an EGFR-TKI plus platinum-based doublet chemotherapy has yet to be sufficiently evaluated for patients with EGFR-mutant NSCLC. This randomized phase II trial was designed to identify an effective combined regimen of gefitinib (G) plus carboplatin/pemetrexed (CP) for subsequent use in phase III study.Methods: Chemotherapy-naïve patients with advanced non-squamous EGFR-mutated NSCLC were randomly assigned to receive either a concurrent regimen (C group) or a sequential alternating regimen (S group). Patients in the C group received concurrent G (250 mg daily) and CP (AUC = 6 and 500 mg/m2, day 1) of a 3-week cycle for 6 cycles, followed by concurrent G and P maintenance. Patients in the S group initially received G (days 1 to 28) and then CP (day 29 and 51); the cycle was repeated for 3 cycles, followed by alternating G and P maintenance. The primary endpoint was progression-free survival (PFS).Results: All 80 patients enrolled were evaluable for efficacy. Median PFS was 17.2 months in the C group and 15.1 months in the S group (p = 0.41). Although overall survival data are immature (with a median follow-up time of 24.6 months, 10 and 19 death events), median survival times were not reached in the C group, and were 30.0 months in the S group (p = 0.049). Response rates were similar in both groups (87.8% in the C group and 82.1% in the S group). The most common grade 3 or greater adverse events were neutropenia (48.8% and 46.2%), thrombocytopenia (41.5% and 28.2%), and anemia (34.1% and.12.8%). G-related skin rash or diarrhea was not severe, and interstitial lung disease was not frequent (5% of all patients). No treatment-related deaths occurred.Conclusion: This is the first randomized study to investigate the efficacy of a combination of EGFR-TKI and chemotherapy in the EGFR-mutated setting. Both regimens had promising efficacy with predictable toxicities, although concurrent regimens might provide better overall survival.

O3-11-6 - A Phase II Study of Pmab + Iri for Mcrc Pts with Wildkras, Resistant to Fluoropyrimidine, Oxaliplatin and Iri(Ogsg1001)

Background: Anti-Epidermal growth factor receptor (EGFR) antibody therapy showed to be effective in treatment for metastatic colorectal cancer (mCRC) with wild KRAS. Especially in BOND-1 trial, combination chemotherapy with anti-EGFR antibody plus irinotecan(IRI) was expected more effective than anti-EGFR antibody alone, resistant to IRI.There were no report of randomized trial to clarify the difference of efficacy between panitumumab(Pmab) plus IRI and Pmab alone, and no report for Pmab plus IRI in Japanese. We conducted a phase II study to evaluate the efficacy and safetyfor Pmab plus IRI.Methods: Subjects were mCRC patients with wild KRAS, who showed resistance to fluoropyrimidine, oxaliplatin(L-OHP) and IRI, and had measurable disease, ECOG PS 0-2. Pmab(6 mg/kg) plus IRI was administered every two weeks. The primary endpoint was response rate(RR). Secondary endpoints were disease control rate (DCR), progression free survival (PFS), overall survival (OS), response duration, and adverse event (AE).Results: A total of 31 subjects were enrolled between July 2010 and July 2012. Median age was 64 years old (range 42-74). Nineteen patients had liver metastasis, 11 had lungmetastasis and 3 had lymph nodemetastasis. An independent review committee evaluated for efficacy in eligible 31 subjects in accordance with the RECIST ver. 1.1. The RR was29.0% (95%CI,14.2-48.0 %). DCR was 74.2% (95%CI,55.4-88.1%), median PFS was 5.6 months(95%CI: 3.4-8.1) and median OS was 10.6 months(95%CI: 6.9-15.8). In 31 subjects, the incidence of any Grade 3 or greater adverse events was 58.1%. Major adverse events of Grade 3 were diarrhea (19.4%), rash acneiform (12.9%), fatigue (9.7%), anorexia (9.7%). A sudden death and an infusion related reaction were occurred.Conclusion: Combination chemotherapy with Pmab plus IRI was demonstaratedto be safe and more effective than Japanese single arm phase II of Pmab alone. This resultis equal to efficacy and safety of other reports for Pmab plus IRI.

Efficacy and safety of everolimus in korean patients with metastatic renal cell carcinoma following treatment failure with a vascular endothelial growth factor receptor-tyrosine kinase inhibitor.

PurposeThe purpose of this study is to assess the efficacy and safety of everolimus in Korean patients with metastatic renal cell carcinoma (mRCC) for whom initial treatment with a vascular endothelial growth factor receptor-tyrosine kinase inhibitor (VEGFr-TKI) has failed.Materials and MethodsEligible patients with mRCC (any histology) who had progressed on or were intolerant of VEGFr-TKI therapy received oral everolimus (10 mg dose once daily). Tumor response was reassessed according to Response Evaluation Criteria in Solid Tumors (RECIST).ResultsThis study included 100 patientswith a median follow-up duration of 10.2 months, a median progression-free survival (PFS) of 4.2 months (95% confidence interval [CI], 3.4 to 5.0 months), and an overall survival of 10.1 months (95% CI, 6.9 to 13.3 months). The most common grade 3 or greater adverse events (AEs) overall were anemia (13%), pneumonitis (9%), hyperglycemia (8%), and stomatitis (6%). While the incidence of pneumonitis was similar (26 cases, 26%) to the reported incidence in Western patients, the Korean presentations were more severe: 10 patients permanently discontinued everolimus due to pneumonitis, including two deaths on treatment. Statistically significant relationships were established between biologic toxicities, hyperglycemia and anemia, and PFS (hyperglycemia vs. non-hyperglycemia: hazard ratio [HR], 0.61; p=0.055 and anemia vs. non-anemia: HR, 0.51; p=0.021).ConclusionEverolimus was effective in Korean patients with mRCC who had failed initial VEGFr-TKI therapy. While everolimus was well tolerated in general and the AE incidence of this study was similar to those of previous reports, severe pneumonitis was common. Hyperglycemia and anemia showed significant correlation with PFS and thus may be potentially useful as prognostic indicators.

Trastuzumab emtansine in human epidermal growth factor receptor 2-positive metastatic breast cancer: an integrated safety analysis.

The antibody-drug conjugate trastuzumab emtansine (T-DM1) combines the cytotoxic activity of DM1 with the human epidermal growth factor receptor 2 (HER2) -targeted, antitumor properties of trastuzumab. T-DM1 has shown activity in phase I and II single-arm studies in patients with pretreated HER2-positive metastatic breast cancer (MBC) and has demonstrated superior efficacy and improved tolerability versus standard MBC treatments in randomized phase II and III studies. This analysis, combining available data from all single-agent T-DM1 studies to date, was conducted to better define the T-DM1 safety profile. Six studies in patients with HER2-positive MBC who received T-DM1 3.6 mg/kg every 3 weeks and follow-up data from patients in an extension study were analyzed. Analyses included adverse events (AEs) by grade; AEs leading to death, drug discontinuation, or dose reduction; and select AEs. Among 884 T-DM1-exposed patients, the most commonly reported all-grade AEs were fatigue (46.4%), nausea (43.0%), thrombocytopenia (32.2%), headache (29.4%), and constipation (26.5%). The most common grade 3 to 4 AEs were the laboratory abnormalities of thrombocytopenia (11.9%) and increased AST serum concentration (4.3%). These were manageable and not generally associated with clinical symptoms. There were 12 AE-related deaths. AEs resulted in dose reductions in 17.2% of patients and drug discontinuations in 7.0%. In this analysis of 884 T-DM1-exposed patients, grade 3 or greater AEs were infrequent and typically asymptomatic and manageable. This favorable safety profile makes T-DM1 treatment suitable for exploration in other breast cancer settings.

Phase II study of first-line chemotherapy with uracil-tegafur plus oral leucovorin in elderly (≥75 years) Japanese patients with metastatic colorectal cancer: SGOSG-CR0501 study

Oral uracil-tegafur and leucovorin (UFT/LV) therapy for elderly patients with metastatic colorectal cancer (mCRC) requires careful handling in Western countries because of a high incidence (≥20 %) of grade 3 diarrhea. However, its efficacy and safety for elderly Asian patients have not been investigated. In this multicenter cooperative phase II study, the eligibility criteria were: age of 75 years or older, no prior chemotherapy, and histologically confirmed colorectal cancer with one or more measurable lesions. UFT 300 mg/m(2)/day and LV 75 mg/day were administered orally for 28 days followed by a 7-day rest period. Twenty-one patients were enrolled in this study (prior to study termination after approval of bevacizumab), and all patients were eligible for efficacy and safety analysis. The median age was 79 years (range, 75-83 years). The majority of patients (95 %) had ECOG Performance Status 0 or 1. The overall response rate was 33 % (95 % confidence interval [CI], 18-53 %). The median progression-free and overall survivals were 5.3 months (95 % CI 4.0-7.9 months) and 18 months (95 % CI 13-21 months), respectively. Grade 3 or greater adverse events included anorexia (10 %), diarrhea (10 %), and leukopenia (5 %). These results were compatible with those seen in Japanese patients in a previous bridging study between Japan and the US, in which patients under 75 years old were evaluated. UFT/LV therapy was safe and feasible in elderly Japanese patients with mCRC, and further study of UFT/LV therapy in combination with bevacizumab is warranted.

The significance of protocol biopsy after intravesical BCG treatment in patients with non-muscle–invasive bladder cancer.

356 Background: Currently, there are few well-validated data of the optimal schedule of follow-up after BCG intravesical instillation. The objective of the study were to elucidate the ability of conventional exams (cystoscopy, urine cytology) to diagnose presence of carcinoma and the significance of protocol biopsy after BCG intravesical treatment in patients with high-risk non-muscle-invasive bladder cancer (NMIBC). Methods: The study included patients treated with BCG intravesical treatment. From January 2002 to October 2012, we retrospectively reviewed a total of 72 patients (61 men and 11 women). The median age was 72 years (range 47-84). The pathological stages were Tis in 4 patients (6%), Ta in 29 (40%) and T1 in 39 (54%) (T1 with CIS in 30 [42%]). Tumors were multifocal in 56 (78%) and second TUR had been performed in 53 (74%) patients. We investigated the prognosis and accuracy of tumor existence by conventional exams referring with the protocol biopsy. A protocol biopsy was performed within 5 to 9 months after the final TUR. CTCAE v4.0 was used to grade adverse events. Results: Of 72 patients, we performed protocol biopsy in 62 patients and 9 (15%) had cancer. The conventional methods had a sensitivity of 78%, specificity of 81%, positive predictive value of 41% and negative predictive value of 96% in diagnosing cancer. Although three (5%) had grade2 adverse events, there were no grade 3 or greater adverse events. Of 53 patients with no cancer in protocol biopsy, 8 (8%) patients experienced a recurrence but 51patients (96%) were alive with no evidence of disease. Of 9 patients pointed out cancer in protocol biopsy, 7patients (78%) had no evidence of disease recurrence at last follow-up. The 5-year recurrence-free survival rate and overall survival rate were 77% and 95%, respectively. Conclusions: To the best of our knowledge, this is the first report of the ability of conventional exams for follow-up after BCG treatment. Our findings revealed that conventional exams were limited for meticulous follow-up, so that the protocol biopsy will be recommended to obtain the better survival in high-risk NMIBC patients.

A phase II study of panitumumab plus irinotecan for metastatic colorectal cancer with wild KRAS, resistant to fluoropyrimidine, oxaliplatin, and irinotecan in Japanese (OGSG1001).

607 Background: Anti-epidermal growth factor receptor (EGFR) antibody therapy showed to be effective in treatment for metastatic colorectal cancer (mCRC) with wild KRAS. Especially, combination chemotherapy with anti-EGFR antibody plus irinotecan is expected more effective than anti-EGFR antibody alone, resistant to irinotecan. We conducted a phase II trial of panitumumab plus irinotecan for mCRC with wild KRAS resistant to fluoropyrimidine, oxaliplatin, and irinotecan in Japanese. Methods: Subjects were mCRC patients with wild KRAS, who showed resistance to fluoropyrimidine, oxaliplatin, and irinotecan and had measurable disease, ECOG PS 0-2. Panitumumab (6 mg/kg) plus irinotecan (same dose as prior irinotecan) was administered every two weeks. This treatment was provided until progression. The primary endpoint was response rate (RR). Secondary endpoints were disease control rate (DCR), progression-free survival (PFS), overall survival (OS), response duration, and adverse event (AE). Results: A total of 31 subjects were enrolled between July 2010 and July 2012. Median age was 64 years old (range 42-74). Nineteen patients had liver metastasis, 11 had lung metastasis, and 3 had lymph node metastasis. An independent review committee evaluated for efficacy in eligible 31 subjects in accordance with the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. The RR of primary endpoint was 29.0% (95% confidence interval (CI), 14.2-48.0 %). DCR was 74.2% (95%CI, 55.4-88.1%) and median PFS was 5.6 months.(95%CI: 3.4-8.7) In 31 subjects for safety evaluation, the incidence of any Grade 3 or greater adverse events was 58.1%. Major adverse events of grade 3 were diarrhea (19.4%), rash acneiform (12.9%), fatigue (9.7%), anorexia (9.7%). A sudden death and an infusion related reaction were occurred. Conclusions: Combination chemotherapy with panitumumab plus irinotecan was demonstarated to be safe and more effective than Japanese single arm phase II of panitumumab alone for mCRC, resistant to fluoropyrimidine, oxaliplatin and irinotecan. This result in Japanese is equal to other reports of panitumumab plus irinotecan. Clinical trial information: UMIN000003819.

The efficacy and safety outcomes of bevacizumab and systemic therapy in metastatic colorectal cancer patients with peritoneal disease in the AGITG MAX clinical trial and in nontrial patients in two cancer centers.

595 Background: Metastatic colorectal cancer with peritoneal disease (PmCRC) represents a phenotype that may derive a greater clinical benefit from bevacizumab (BEV) due to the effect of VEGF on peritoneal spread and ascites production. However, there is concern of greater adverse events, in particular GI perforations. We investigated the clinical benefit and safety of adding BEV to chemotherapy in PmCRC in clinical trial and nontrial populations. Methods: We compared PFS and OS in PmCRC patients receiving first-line chemotherapy with and without BEV in: (1) the AGITG MAX trial (capecitabine [CAP] vs CAP/BEV +/- mitomycin C) and (2) two cancer centers in New South Wales between Jan 2005 and Dec 2012 (any regimen +/- BEV). Secondary endpoints included chemotherapy duration and GI adverse events. Time to event outcomes were estimated using the method of Kaplan-Meier and comparisons made using the logrank test. Proportional hazards models were used to obtain hazard ratios for regression analysis. Results: See Table. 84 MAX and 69 nontrial pts had PmCRC and there was a 37% reduction in the risk of progression in those receiving BEV, which is similar when compared to the nonperitoneal disease pts (HR= 0.63 95% CI 0.52-0.79 p value &lt; 0.001). OS in the PmCRC group was significantly worse than the nonperitoneal group (14.3 months vs 18.8 months p value = 0.02). Chemotherapy duration was similar across the groups. The rate of notable GI adverse events, including GI perforation was not increased in the PmCRC group receiving BEV in either cohort. One pt had a GI perforation after receiving CAP+BEV. Conclusions: Pts with mCRC and peritoneal disease receiving first-line therapy in trial and nontrial populations appear to derive a similar proportional benefit when BEV is added to systemic therapy without an increase in GI adverse events. However, this subgroup of patients continues to have a worse prognosis. [Table: see text]

Intercalated combination of chemotherapy and erlotinib for patients with advanced stage non-small-cell lung cancer (FASTACT-2): a randomised, double-blind trial

The results of FASTACT, a randomised, placebo-controlled, phase 2 study, showed that intercalated chemotherapy and erlotinib significantly prolonged progression-free survival (PFS) in patients with advanced non-small-cell lung cancer. We undertook FASTACT-2, a phase 3 study in a similar patient population. In this phase 3 trial, patients with untreated stage IIIB/IV non-small-cell lung cancer were randomly assigned in a 1:1 ratio by use of an interactive internet response system with minimisation algorithm (stratified by disease stage, tumour histology, smoking status, and chemotherapy regimen) to receive six cycles of gemcitabine (1250 mg/m(2) on days 1 and 8, intravenously) plus platinum (carboplatin 5 × area under the curve or cisplatin 75 mg/m(2) on day 1, intravenously) with intercalated erlotinib (150 mg/day on days 15-28, orally; chemotherapy plus erlotinib) or placebo orally (chemotherapy plus placebo) every 4 weeks. With the exception of an independent group responsible for monitoring data and safety monitoring board, everyone outside the interactive internet response system company was masked to treatment allocation. Patients continued to receive erlotinib or placebo until progression or unacceptable toxicity or death, and all patients in the placebo group were offered second-line erlotinib at the time of progression. The primary endpoint was PFS in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT00883779. From April 29, 2009, to Sept 9, 2010, 451 patients were randomly assigned to chemotherapy plus erlotinib (n=226) or chemotherapy plus placebo (n=225). PFS was significantly prolonged with chemotherapy plus erlotinib versus chemotherapy plus placebo (median PFS 7·6 months [95% CI 7·2-8·3], vs 6·0 months [5·6-7·1], hazard ratio [HR] 0·57 [0·47-0·69]; p<0·0001). Median overall survival for patients in the chemotherapy plus erlotinib and chemotherapy plus placebo groups was 18·3 months (16·3-20·8) and 15·2 months (12·7-17·5), respectively (HR 0·79 [0·64-0·99]; p=0·0420). Treatment benefit was noted only in patients with an activating EGFR gene mutation (median PFS 16·8 months [12·9-20·4] vs 6·9 months [5·3-7·6], HR 0·25 [0·16-0·39]; p<0·0001; median overall survival 31·4 months [22·2-undefined], vs 20·6 months [14·2-26·9], HR 0·48 [0·27-0·84]; p=0·0092). Serious adverse events were reported by 76 (34%) of 222 patients in the chemotherapy plus placebo group and 69 (31%) of 226 in the chemotherapy plus erlotinib group. The most common grade 3 or greater adverse events were neutropenia (65 [29%] patients and 55 [25%], respectively), thrombocytopenia (32 [14%] and 31 [14%], respectively), and anaemia (26 [12%] and 21 [9%], respectively). Intercalated chemotherapy and erlotinib is a viable first-line option for patients with non-small-cell lung cancer with EGFR mutation-positive disease or selected patients with unknown EGFR mutation status. F Hoffmann-La Roche.

Efatutazone, an Oral PPAR-γ Agonist, in Combination With Paclitaxel in Anaplastic Thyroid Cancer: Results of a Multicenter Phase 1 Trial

A phase 1 study was initiated to determine the safety, potential effectiveness, and maximal tolerated dose and recommended phase 2 dose of efatutazone and paclitaxel in anaplastic thyroid cancer. Patients received efatutazone (0.15, 0.3, or 0.5 mg) orally twice daily and then paclitaxel every 3 weeks. Patient tolerance and outcomes were assessed, as were serum efatutazone pharmacokinetics. Ten of 15 patients were women. Median age was 59 years. Seven patients received 0.15 mg of efatutazone, 6 patients received 0.3 mg, and 2 patients received 0.5 mg. One patient receiving 0.3 mg of efatutazone had a partial response from day 69 to day 175; 7 patients attained stable disease. Median times to progression were 48 and 68 days in patients receiving 0.15 mg of efatutazone and 0.3 mg of efatutazone, respectively; corresponding median survival was 98 vs 138 days. The median peak efatutazone blood level was 8.6 ng/mL for 0.15-mg dosing vs 22.0 ng/mL for 0.3-mg twice daily dosing. Ten patients had grade 3 or greater adverse events (Common Terminology Criteria for Adverse Events), with 2 of these (anemia and edema) related to efatutazone. Thirteen events of edema were reported in 8 patients, with 2 of grade 3 or greater. Eight patients had ≥1 serious adverse event, with 1 of these (anemia) attributed to efatutazone and 1 (anaphylactic reaction) related to paclitaxel. The maximal tolerated dose was not achieved. Angiopoietin-like 4 was induced by efatutazone in tissue biopsy samples of 2 patients. Efatutazone and paclitaxel in combination were safe and tolerated and had biologic activity.

A phase II study on third-line chemotherapy combined bevacizumab with S-1 for metastatic colorectal cancer with mutated KRAS: SAVIOR study.

552 Background: Anti-Epidermal growth factor receptor (EGFR) antibody therapy is expected to be effective in treatment for metastatic colorectal cancer (mCRC) with wild-type KRAS, but for mCRC with mutated KRAS, no salvage treatment has been established. We performed a phase II clinical study on 3rd-line chemotherapy combined bevacizumab with S-1, an oral fluorinated pyrimidine preparation containing a dihydropyrimidine dehydrogenase inhibitor, and bevacizumab for mCRC resistant to oxaliplatin and irinotecan. Methods: Subjects were mCRC patients with mutated KRAS, who showed aggravation even after 2 regimens with oxaliplatin and irinotecan. S-1 (80-120 mg/body) was administered for 4 weeks and withdrawn for 2 weeks. The dose of S-1 was decided according to the subjects’ body surface area. Bevacizumab (5 mg/kg) was administered on Days 1, 15, and 29. This treatment was provided until progression. The primary endpoint was disease control rate (DCR), and secondary endpoints were response rate (RR), median progression free survival (mPFS), overall survival (OS), and adverse event (AE). Results: A total of 31 subjects mutated KRAS were enrolled between August 2009 and July 2011. An independent review committee evaluated antitumor effects in eligible 29 of the 31 subjects in accordance with the Response Evaluation Criteria in Solid Tumors (RECIST). Two subjects in whom antitumor effects could not be evaluated were excluded. The DCR was 69% (95% confidence interval [CI], 49.2-84.7%), RR 0% (95% CI, 0-12.3%), mPFS 3.7 months (95% CI, 2.7-6.5 months), OS 9.0 months (95% CI, 7.5-12.0 months), and the median observation period 9.0 months. In 30 subjects for safety evaluation, the incidence of Grade 3 or greater adverse events was 50%. There was no treatment-related death. Major adverse events were anorexia (Grade 3 or greater, 20%), diarrhea (Grade 3, 10%), and decreased hemoglobin (Grade 3 or greater, 16.7%). Conclusions: The results suggest that 3rd-line chemotherapy combined bevacizumab with S-1 is safe and may delay the progression of mCRC resistant to oxaliplatin and irinotecan with mutated KRAS. Clinical trial information: NCT00974389.

Autologous CIK Cell Immunotherapy in Patients with Renal Cell Carcinoma after Radical Nephrectomy

Objective. To evaluate the efficacy of autologous cytokine-induced killer (CIK) cells in patients with renal cell carcinoma (RCC). Methods. 20 patients diagnosed with TNM stage I or II RCC were randomly divided into two groups, a CIK cell treatment group and a control group. The endpoint was progression-free survival (PFS) evaluated by Kaplan-Meier analyses. Results. CD3+, CD3+/CD8+, CD3+/CD4+, and CD3+/CD56+ levels increased after CIK cell culture (P < 0.01). The median PFS in CIK cell treatment group was significantly longer than that in control group (PFS, 32.2 months versus 21.6 months; log-rank, P = 0.032), all patients were alive during the course of followup, and there are no statistically significant differences between two groups in OS (log-rank, P = 0.214). Grade III or greater adverse events were not observed. Conclusions. CIK cells treatment could prolong survival in patients with RCC after radical nephrectomy and showed acceptable curative effect with potential enhancement of cellular immune function. This trial is registered with Clinicaltrials.gov NCT01799083.

Phase I Study of Bortezomib and Romidepsin in Patients with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, Indolent B-Cell Lymphoma, or Peripheral T-Cell Lymphoma

Abstract 1794Preclinical studies have demonstrated synergistic interactions between proteasome and histone deacetylase (HDAC) inhibitors in diverse hematologic malignancies, including those of B-cell origin. We have previously shown that the combination of the proteasome inhibitor bortezomib and the HDAC inhibitor romidepsin, administered at extremely low concentrations (∼3–5 nM), results in a striking increase in apoptosis in primary CLL cells, including cells from patients with CLL refractory to standard treatments (Dai Y et al. Clin Cancer Res. 2008). These findings prompted initiation of a phase I trial, using a 3+3 design, with the primary objective of determining the maximum tolerated dose (MTD) for the combination of bortezomib and romidepsin in patients with relapsed or refractory chronic lymphocyte leukemia/small lymphocytic lymphoma (CLL/SLL), indolent B-cell lymphoma, or peripheral T-cell lymphoma (PTCL).To date, 11 patients have been enrolled and treated. All of the patients treated have been diagnosed with CLL/SLL (n=11). The male:female ratio was n = 10 (91%):1 (9%); the median age was 56 (range 46–66) years; ECOG performance scores ranged from 0 to 1; and the median number of prior therapies was 4 (range 2–6). The schedule of administration was intravenous bolus bortezomib followed by a 4-hour intravenous infusion of romidepsin on days 1, 8, and 15; on a 28-day cycle. Dose level 1 = bortezomib 1.3 mg/m2, romidepsin 8 mg/m2 (n=3); level 2A = bortezomib 1.3 mg/m2, romidepsin 10 mg/m2 (n=5); and level 2B = bortezomib 1.6 mg/m2, romidepsin 8 mg/m2(n=3). The study is currently enrolling to dose levels 2A and 2B.Adverse events were determined using CTCAE version 4. Dose limiting toxicities (DLTs) were determined per protocol and occur in cycle 1 only. Two DLTs have been observed: 1 at dose level 2A (grade 3 fatigue) and 1 at dose level 2B (grade 3 chills, associated with cytokine release syndrome). Both dose levels will be expanded to 6 DLT-evaluable patients. Non-DLT grade 3 or greater adverse events have included anemia (grade 3, 9%), fatigue (grade 3, 9%), leukopenia (grade 3, 9%), nausea (grade 3, 9%), neutropenia (grade 4, 18%), soft tissue infection (grade 3, 9%), and vomiting (grade 3, 9%). Serious adverse events that were deemed at least possibly related to treatment were grade 3 soft tissue infection with grade 4 neutropenia (1 patient); grade 2 fever/nausea/vomiting which precipitated hospitalization (1 patient); and grade 2 cytokine release syndrome with associated grade 3 shaking chills, and grade 2 nausea/vomiting/diarrhea/oral dysethesia/sweats/photophobia/macular rash (1 patient).All 11 patients treated were evaluable for response. One partial response has been observed to date; the patient (positive for ZAP70; 4 lines of prior chemotherapy) proceeded, after 4 cycles of romidepsin and bortezomib, to allogeneic stem cell transplant. Five patients had a best response of stable disease and 5 had progressive disease. Correlative studies examining pre- and post-treatment expression of NF-κB (nuclear RelA and p52 as a marker of p100 processing), the NF-κB-dependent proteins XIAP and Bcl-xL, and Bim are currently underway.Collectively, these findings indicate that the safety profile is consistent with those reported for bortezomib and romidepsin, with reversible grade 2 to 4 adverse events, in heavily pretreated patients with relapsed/refractory CLL/SLL. The MTD has not yet been reached. Pending identification of the MTD, phase II evaluation of this therapeutic strategy, if warranted, should determine its activity more definitively in this population. Disclosures:Shea:Millennium Pharmaceuticals: Research Funding.

Phase II study of Gleevec plus hydroxyurea in adults with progressive or recurrent low‐grade glioma

We evaluated the efficacy of imatinib plus hydroxyurea in patients with progressive/recurrent low-grade glioma. A total of 64 patients with recurrent/progressive low-grade glioma were enrolled in this single-center study that stratified patients into astrocytoma and oligodendroglioma cohorts. All patients received 500 mg of hydroxyurea twice a day. Imatinib was administered at 400 mg per day for patients not on enzyme-inducing antiepileptic drugs (EIAEDs) and at 500 mg twice a day if on EIAEDs. The primary endpoint was progression-free survival at 12 months (PFS-12) and secondary endpoints were safety, median progression-free survival, and radiographic response rate. Thirty-two patients were enrolled into each cohort. Eleven patients (17%) had before radiotherapy and 24 (38%) had received before chemotherapy. The median PFS and PFS-12 were 11 months and 39%, respectively. Outcome did not differ between the histologic cohorts. No patient achieved a radiographic response. The most common grade 3 or greater adverse events were neutropenia (11%), thrombocytopenia (3%), and diarrhea (3%). Imatinib plus hydroxyurea was well tolerated among recurrent/progressive LGG patients but this regimen demonstrated negligible antitumor activity.

A phase I/II study of biweekly XELIRI plus bevacizumab for patients with metastatic colorectal cancer as second-line chemotherapy (BIXER study): Reports of phase I part and interim analysis of phase II part.

643 Background: Capecitabine is an oral fluoropyrimidine prodrug, which is converted to fluorouracil (5-FU) predominantly in the tumor cells. In Japan, capecitabine is mainly used in combination with oxaliplatin (XELOX) in treatment for metastatic colorectal cancer (mCRC) since its approval in 2009. The results of capecitabine plus Irinotecan (CPT) (XELIRI) with or without bevacizumab (BV) in EU or US patients were previously reported, but not in Japanese. Thus, we conducted this study to assess the safety and efficacy of XELIRI plus BV in Japanese patients with mCRC. Methods: Patients with prior chemotherapy including oxaliplatin and BV for mCRC, wild or hetero type of UGT1A1 *6*28 were eligible for this study. This was a phase I study composed of two steps, and dose limiting toxicity (DLT) was assessed during the first treatment cycle. Treatment comprised capecitabine 1,000 mg/m2 twice daily from the evening of day 1 to the morning of day 8, intravenous CPT 180 mg/m2 on day 1, and BV 5mg/kg on day 1 every two weeks. To evaluate the initial safety, 3-6 patients received XELIRI+BV (CPT 150mg/m2) in step 1, and 6 patients received XELIRI+BV (CPT 180mg/m2) in step 2. If DLT occurred in 1 patient in step1, 3 patients would be newly added to step 1, and if in none of 3 or 1-2 of 6 patients, the step 2 would be started. If DLT occurred in less than or equal to 2 of 6 patients in step 2, phase II study would be proceeded, and if In more than 2 of 6 patients, phase II would be conducted at the recommended dose of step 1. Results: In step 1 and 2 of phase I, initial safety of 9 patients was confirmed without occurrence of DLT. Adverse events observed in step 1 and 2 were: neutropenia in 2 and 1; anorexia in 1 and 1; diarrhea in 1 and 1; stomatitis in 1 and 1; alanine or aspartate aminotransferase increased in 1 and 3, respectively. There was no grade 3 or greater adverse events. Conclusions: In mCRC patients with wild or hetero of UGT1A1*6*28 genotype, safety of biweekly XELIRI+BV was confirmed and recommended dose of CPT-11 was determined as 180mg/m2. Interim analysis of safety of phase II part will be reported at the meeting.