Assessment Of Clinical Benefit Research Articles

Growth modulation index as metric of clinical benefit assessment among advanced soft tissue sarcoma patients receiving trabectedin as a salvage therapy

The growth modulation index (GMI) is the ratio of time to progression with the nth line (TTP(n)) of therapy to the TTP(n)(-1) with the n-1th line. GMI >1.33 is considered as a sign of activity in phase II trials. This retrospective analysis evaluated the concordance between the GMI and the efficacy outcomes in 279 patients with advanced soft tissue sarcoma (ASTS) treated with trabectedin 1.5 mg/m² (24-h infusion every 3 weeks) in four phase II trials. One hundred and forty-two (51%) patients received one prior line and 137 ≥ 2 lines. The median TTP(n) was 2.8 months (range 0.2-26.8), whereas the median TTP(n)(-1) was 4.0 months (0.3-79.5). The median GMI was 0.6 (0.0-14.4). Overall, 177 patients (63%) had a GMI <1; 21 (8%) a GMI equal to 1-1.33 and 81 (29%) a GMI >1.33, which correlated with the median overall survival in those patients (9.1, 13.9 and 23.8 months, respectively, P = 0.0005). A high concordance rate between the GMI and response rate (P < 0.0001) and progression-free survival (PFS, P < 0.0001) was observed. Good performance status (PS) was the only factor associated with GMI >1.33 (PS = 0; P < 0.04). A high GMI was associated with favorable efficacy outcomes in patients treated with trabectedin. Further research is needed to assess GMI as an indicator in this setting.

Assessment of clinical benefit and quality of life in patients undergoing cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for management of peritoneal carcinomatosis.

Peritoneal carcinomatosis (PC) is a challenging problem with poor prognosis. Survival even with the current standard chemotherapy is dismal. Cytoreductive surgery (CRS) and Hyperthermic intraperitoneal chemotherapy (HIPEC) in appropriately selected patients may offer significant survival benefit. In the review article entitled “Assessment of Clinical benefit and quality of life in patients undergoing cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for management of peritoneal carcinomatosis” authors provide a comprehensive review of the available data related to the morbidity, mortality, survival and quality of life with CRS and HIPEC for the management of peritoneal carcinomatosis (1). Several retrospective studies have shown the feasibility and benefit of CRS and HIPEC in the management of various peritoneal surface malignancies (2,3). Although clinical utility of CRS and HIPEC in the management of mesothelioma and peritoneal dissemination of appendiceal malignancies is widely accepted, its role in colorectal cancer peritoneal carcinomatosis has been heavily debated. Randomized controlled trial by Veerwal et al. demonstrated a survival benefit of 9 months for patients with colorectal peritoneal carcinomatosis treated with CRS and HIPEC followed by 5-FU chemotherapy compared to palliative surgery and 5-FU chemotherapy (4). Furthermore, patients who underwent complete cytoreduction had a 5-year survival rate of 45%, which favorably compares to the reported survival for colorectal hepatic metastasectomy. Despite these promising results skepticism still exists, as the patients in the control arm of the trial did not receive current standard chemotherapy. However, recent studies utilizing current standard chemotherapy with or without biologic agents have reported a median overall survival of 10-15 months in patients with colorectal peritoneal carcinomatosis (5,6). These results underscore the decreased efficacy of systemic treatment in the setting of PC, when feasible CRS and HIPEC should be considered as the standard treatment for patients with colorectal cancer peritoneal carcinomatosis. As described in the review article cytoreductive surgery is a major surgical procedure with significant morbidity. However, in appropriately selected patients the risk-benefit ratio favors an aggressive treatment approach. Extent of peritoneal dissemination, measured as peritoneal cancer index (PCI) and the completeness of cytoreduction have been indisputably shown to be major predictors of outcome (7). Patient selection is a challenging task, as the risk-benefit ratio is influenced by multiple factors. In addition, the ability to accurately estimate the extent of peritoneal dissemination and predicting the chances of complete cytoreduction is far from perfect. Esquivel and Pelz have proposed a peritoneal surface disease severity (PSDS) scoring system based on symptoms, extent of disease and histology to stratify patients with colon cancer peritoneal carcinomatosis into different prognostic groups that may aid in patient selection for different treatment (8). The risk-benefit ratio for CRS and HIPEC not only depends on the ability to achieve complete cytoreduction but on the biologic aggressiveness of the tumor, which is heavily weighed into the PSDS score. Multi-institutional prospective validation studies are required to assess the clinical utility of the PSDS scoring system. Finally, the importance of measurement of health related quality of life (HRQoL) cannot be overemphasized in patients undergoing CRS and HIPEC. The authors have provided a comprehensive review of the available scoring systems and the data for QoL. Most studies report a decrease in the quality of life up to six months after CRS and HIPEC, with improvement in majority of patients at one year. This should be taken into consideration while counseling patients about the outcomes of CRS and HIPEC. In summary, management of patients with peritoneal carcinomatosis is complex and requires a multidisciplinary approach. Proper patient selection for CRS and HIPEC based on favorable risk-benefit ratio is of utmost importance. Management should focus on both cancer-specific outcomes and quality of life.

Assessment of clinical benefit and quality of life in patients undergoing cytoreduction and Hyperthermic Intraperitoneal Chemotherapy (HIPEC) for management of peritoneal metastases.

Peritoneal metastasis is a significant clinical challenge; life expectancy following diagnosis is usually very short. Surgical cytoreduction with HIPEC is being used with increasing frequency in selected patients; most outcome data have shown that prolonged median survivals can be observed in selected patients. This review summarizes the published data related to outcome and quality of life after cytoreduction and HIPEC to provide insights into its use in patients with peritoneal carcinomatosis.

Percutaneous left atrial appendage closure for stroke prevention in patients with atrial fibrillation: an assessment of net clinical benefit

The PROTECT-AF (WATCHMAN Left Atrial Appendage System for Embolic Protection in Patients with Atrial Fibrillation) trial found left atrial appendage (LAA) closure an alternative to anticoagulation in selected patients with non-valvular atrial fibrillation (AF). We aim to estimate the net clinical benefit (NCB) of percutaneous LAA closure. Post hoc analysis of outcomes among 707 adults with AF in the PROTECT-AF trial and 566 in the Continued Access (CAP) registry undergoing LAA closure with the Watchman device compared with sustained anticoagulation. Outcomes were ischaemic stroke, intracranial haemorrhage, major bleeding, pericardial effusion, and death, weighted to reflect the relative impact in terms of death and disability. Net clinical benefit was calculated as the sum of annualized rates of these outcomes after intervention minus rates on warfarin. The NCB of LAA closure during 1623 person-years follow-up in the trial was 1.73%/year (95% CI: -0.54 to 4.39%/year) and during 741 patient-years in the registry was 4.97%/year (95% CI: 3.07-7.15%/year). Among patients with a history of ischaemic stroke, the NCB was greater in the registry (8.68%/year, CI: 2.82-14.92%/year) than the trial (4.30%/year, CI -2.07 to 11.25%/year). In the registry, the NCB of LAA closure increased from 2.22%/year (CI: 0.27-6.01%/year) in patients with CHADS(2) scores = 1 to 6.12%/year (CI: 3.19-8.92%/year) in those with scores ≥2. Combining rates of thrombo-embolism, intracranial haemorrhage, major adverse events, and death allows objective comparison of the benefit and risk of device therapy vs. anticoagulation in patients with AF. The NCB of LAA closure is greatest for patients at a higher risk of stroke.

Growth modulation index (GMI) as a metric of clinical benefit assessment among advanced soft tissue sarcoma (ASTS) patients receiving trabectedin as salvage therapy.

10013 Background: Von Hoff has proposed GMI &gt;1.33 in cancer clinical trials as a sign of drug activity. GMI is the ratio between time to progression (TTP) with the nth line (TTPn) of therapy divided by the TTPn-1 with the n-1th line of therapy. With this endpoint, each patient is his/her own control. Methods: We have carried out a retrospective analysis of 279 pretreated ASTS patients treated in four consecutive phase II trials with trabectedin 1.5 mg/m², given as a 24-hour infusion every 3 weeks. Results: The study population consisted of 170 women and 109 men with a median age of 52. The two most common histologies were leiomyosarcoma (145 patients, 52%) and liposarcoma (59, 21%). 142 (51%) patients received one prior line and 137 (49%) ≥2 lines. The median TTPn was 2.8 months (range: 0.2-26.8), whereas the median TTPn-1 was 4.0 months (range: 0.3-79.5). The Spearman correlation coefficient between TTPn-1 and TTPn was 0.07 (p=0.23). The median GMI was 0.6 (range: 0.0-14.4). 177 patients (63%) had a GMI &lt;1, 21 (8%) a GMI = 1-1.33 and 81 (29%) a GMI &gt;1.33. The median overall survival (OS) strongly correlated with GMI groups: OS was 9.1, 13.9 and 23.8 months, respectively (p=0.0005, log-rank test). There were also a strong correlations between response rate and GMI (p&lt;0.0001, Fisher exact test), and between GMI and progression-free survival (&lt;0.0001, log-rank test). The logistic regression analysis retained only performance status (PS) [OR=1.76 if PS=0; p&lt;0.04] associated with GMI&gt;1.33. Sarcoma grade (p=0.21), histological subtype (p=0.16), and number of prior chemotherapy lines (p=0.95) were not associated with GMI&gt;1.33. Conclusions: Overall,≈30% of patients experienced GMI&gt;1.33 regardless of histological subtype or grade, and number of prior lines of chemotherapy. Patients with PS=0 benefit more from trabectedin. GMI&gt;1.33 is associated with longer OS (median ≈24 months). GMI is better defined than previously described parameter such as "Tumor Growth Rate" (Lopez-Martin, Abstract 3293, ASCO 2003). GMI as an indicator of drug activity merits further exploration in this setting.

Pneumonia immunization in older adults: review of vaccine effectiveness and strategies.

Vaccination remains the primary preventive strategy in the elderly against Streptococcus pneumoniae and influenza infections. The effectiveness of this strategy in preventing pneumonia has been in doubt despite the increase in vaccination coverage among older adults. Randomized controlled trials (RCTs) and observational studies aimed at determining clinical outcomes and immune response following pneumococcal vaccination have yielded conflicting results. The protective efficacy of pneumococcal vaccination against pneumonia in older adults has not been firmly established due to a lack of RCTs specifically examining patients ≥ 65 years of age. Similarly, the reported benefits of influenza vaccination have been derived from observational data. The assessment of clinical benefit from influenza vaccination in the elderly population is complicated by varying cohorts, virulence of the influenza strain, and matching of vaccine and circulating viral strains. The presence of selection bias and use of nonspecific end points in these studies make the current evidence inconclusive in terms of overall benefit. The development of more immunogenic vaccines through new formulations or addition of adjuvants holds the promise of revolutionizing delivery and improving efficacy. Dismantling existing barriers through education, providing technology assistance predominantly to developing countries, and establishing clear regulatory guidance on pathways for approval are necessary to ensure timely production and equitable distribution.

Analysis of allergen immunotherapy studies shows increased clinical efficacy in highly symptomatic patients

The assessment of allergen immunotherapy (AIT) efficacy in the treatment for seasonal allergic rhinoconjunctivitis (SAR) symptoms is challenging. Allergen immunotherapy differs from symptomatic therapy in that while symptomatic therapy treats patients after symptoms appear and aims to reduce symptoms, AIT is administered before symptoms are present and aims to prevent them. Thus, clinical studies of AIT can neither establish baseline symptom levels nor limit the enrolment of patients to those with the most severe symptoms. Allergen immunotherapy treatment effects are therefore diluted by patients with low symptoms for a particular pollen season. The objective of this analysis was to assess the effect possible to achieve with AIT in the groups of patients presenting the most severe allergic symptoms. Study centres were grouped into tertiles categorized according to symptom severity scores observed in the placebo patients in each centre (low, middle and high tertiles). The difference observed in the average score in each tertile in active vs placebo-treated patients was assessed. This allowed an estimation of the efficacy that could be achieved in patients from sites where symptoms were high during the pollen season. An increased treatment effect was observed in the most severe patients and was independent of the study analysed and symptom score used. The use of a tertile approach to analyse efficacy in AIT in SAR clinical studies can give a more accurate assessment of potential clinical benefit.

The trouble with translational medicine

Increasingly more reports in the literature are reflecting on the hurdles of effective translation from promising results of biomedical research into useful therapeutics. A recurrent theme is that good intentions are frustrated by extrinsic factors upon which 'translationalists' have little control. It is possible that the problem resides, at least in part, within the translational community itself, which has failed to prioritize the steps required to approach the problem systematically. Most importantly, there is disproportionate emphasis on bench-to-bedside efforts, rather than confronting a priori the need to increase the understanding of human pathophysiology. Thus, therapeutic concepts based on experimental conditions that may not and indeed often do not represent the nature of human genetics lead to drug development that is not sufficiently applicable to the human condition. The damage is then amplified when these ill-fated concepts are tested in clinical trials at great cost. The use of surrogate biomarkers that could allow early assessment of efficacy currently requires long-term assessment of clinical benefit. This can delay by years or decades essential feedback about clinical efficacy. Moreover, scant effort is applied to learning whether a drug has achieved its biological endpoint, or why it failed its clinical endpoint. Thus, the feedback loop is not only delayed, but is often uninformative. As a consequence, researchers continue to produce novel therapeutic candidates based on experimental models without the essential benefit of lessons learned from previous failures. Biomedical research will succeed when drug development is guided by experience gained through informative clinical trials with the purpose of not only testing the effectiveness of treatment but also providing mechanistic insights into the differences between expected and observed results. This can only be achieved through the courageous effort of the research community to change the way biomedical research is funded, published and rewarded.

Accuracy of Oral Mucosal Thickness Measurements Using Spiral Computed Tomography

Assessment of oral mucosal thickness is important in implant surgery; however, examining the soft tissue three dimensionally is difficult. A reamer method is invasive, and a non-invasive ultrasonic method produces only low-resolution images depending on anatomic variations. The emerging technology of spiral computed tomography (CT) is an alternative to the conventional methods. Spiral CT has been a useful diagnostic tool in implant surgery. Although it delivers high radiation doses, spiral CT provides three-dimensional imaging of low-contrast structures. The purpose of the present study is to assess the accuracy of oral mucosal measurements using spiral CT. Thickness of maxillary oral mucosa was measured in five cadavers. The measurement sites were set up in buccal, palatal, and middle of the crest in the missing tooth area in the incisor, canine, premolar, and molar regions. Each cadaver was exposed to spiral CT after installing the measurement guide. After that, each site was physically measured by reamer. Linear regression and correlation analysis were performed to describe the association between radiographic and physical measurements. A total of 114 measurements were performed with statistical analyses. Mean values and standard deviations of physical and radiographic measurements were 3.12 ± 1.43 and 2.83 ± 1.70 mm, respectively. The radiographic and physical measurements demonstrate strong correlation (r = 0.90; P <0.01). Measurement error was 0.52 ± 0.36 mm. According to the regions, the measurements in buccal, palatal, and missing tooth region depicted a significant correlation (r = 0.92, r = 0.85, and r = 0.91, respectively). The boundary of the bone and mucosa was indistinguishable at 23 buccal sites. Twenty-three measurements that could not be distinguished with CT had a mean of 0.69 and standard deviation ± 0.13 mm. The correlation between spiral CT and physical measurement was high except in sites of very thin mucosa. Spiral CT can be considered an alternative method for the measurement of oral mucosal thickness. Because of the higher radiation exposure, caution should be exercised and radiation dosage versus clinical benefit assessment is required.

Consistently Estimating Absolute Risk Difference when Translating Evidence to Jurisdictions of Interest

Economic analysis and assessment of net clinical benefit often requires estimation of absolute risk difference (ARD) for binary outcomes (e.g. survival, response, disease progression) given baseline epidemiological risk in a jurisdiction of interest and trial evidence of treatment effects. Typically, the assumption is made that relative treatment effects are constant across baseline risk, in which case relative risk (RR) or odds ratios (OR) could be applied to estimate ARD. The objective of this article is to establish whether such use of RR or OR allows consistent estimates of ARD. ARD is calculated from alternative framing of effects (e.g. mortality vs survival) applying standard methods for translating evidence with RR and OR. For RR, the RR is applied to baseline risk in the jurisdiction to estimate treatment risk; for OR, the baseline risk is converted to odds, the OR applied and the resulting treatment odds converted back to risk. ARD is shown to be consistently estimated with OR but changes with framing of effects using RR wherever there is a treatment effect and epidemiological risk differs from trial risk. Additionally, in indirect comparisons, ARD is shown to be consistently estimated with OR, while calculation with RR allows inconsistency, with alternative framing of effects in the direction, let alone the extent, of ARD. OR ensures consistent calculation of ARD in translating evidence from trial settings and across trials in direct and indirect comparisons, avoiding inconsistencies from RR with alternative outcome framing and associated biases. These findings are critical for consistently translating evidence to inform economic analysis and assessment of net clinical benefit, as translation of evidence is proposed precisely where the advantages of OR over RR arise.

Weekly combination of non-pegylated liposomal doxorubicin and taxane in first-line breast cancer: wALT trial (phase I–II)

BackgroundThrough different pharmacodynamic–kinetic interactions, weekly administration of proved efficacy agents can overcome resistance with lower toxicity and greater benefit. Based on this assumption, we designed a phase I–II trial with weekly non-pegylated liposomal anthracycline and taxane in first-line breast cancer patients. Patients and methodsWe enrolled 56 previously untreated metastatic breast cancer patients; they were randomly assigned to receive paclitaxel (Taxol) (50 mg/mq) or docetaxel (Taxotere) (30 mg/mq) combined with non-pegylated liposomal anthracycline (25 mg/mq) on days 1, 8 and 15 every 4 weeks. The primary end points were the clinical benefit and treatment-related toxic effects assessment. Secondary end points were time-to-disease progression (TTP) and overall survival (OS). ResultsThe overall clinical benefit was 87.04%. World Health Organization G3–4 toxic effects included neutropenia (45%), anemia (44%), complete alopecia (83%), severe onycholysis and neuropathy. The 24% of patients developed left ventricular ejection fraction reduction but none >10% with recover after treatment completion. The median absolute decrease from baseline was 1%. Median TTP was 11 months and median OS was 23 months. ConclusionsCombined weekly administration of taxane and non-pegylated liposomal anthracycline is well tolerated and clinical benefit data encourage phase III study design.

Fondaparinux with UnfracTionated heparin dUring Revascularization in Acute coronary syndromes (FUTURA/OASIS 8): A randomized trial of intravenous unfractionated heparin during percutaneous coronary intervention in patients with non–ST-segment elevation acute coronary syndromes initially treated with fondaparinux

There is uncertainty regarding the optimal adjunctive unfractionated heparin (UFH) regimen for percutaneous coronary intervention (PCI) in patients with non-ST-segment elevation acute coronary syndrome (NSTE-ACS) treated with fondaparinux. The aim of this study is to evaluate the safety of 2 dose regimens of adjunctive intravenous UFH during PCI in high-risk patients with NSTE-ACS initially treated with fondaparinux and referred for early coronary angiography. This is an international prospective cohort study of approximately 4,000 high-risk patients presenting to hospital with unstable angina or non-ST-segment elevation myocardial infarction, treated with fondaparinux as initial medical therapy, and referred for early coronary angiography with a view to revascularization. Within this cohort, 2,000 patients undergoing PCI will be eligible for enrollment into a double-blind international randomized parallel-group trial evaluating standard activated clotting time (ACT)-guided doses of intravenous UFH versus a non-ACT-guided weight-adjusted low dose. The standard regimen uses an 85-U/kg bolus of UFH if there is no platelet glycoprotein IIb/IIIa (GpIIb-IIIa) inhibitor or 60 U/kg if GpIIb-IIIa inhibitor use is planned, with additional bolus guided by blinded ACT measurements. The low-dose regimen uses a 50 U/kg UFH bolus, irrespective of planned GpIIb-IIIa use. The primary outcome is the composite of peri-PCI major bleeding, minor bleeding, or major vascular access site complications. The assessment of net clinical benefit is a key secondary outcome: it addresses the composite of peri-PCI major bleeding with death, myocardial infarction, or target vessel revascularization at day 30. FUTURA/OASIS 8 will help define the optimal UFH regimen as adjunct to PCI in high-risk NSTE-ACS patients treated with fondaparinux.

A renewed, ethical defense of placebo-controlled trials of new treatments for major depression and anxiety disorders

The use of placebo as a control condition in clinical trials of major depressive disorder and anxiety disorders continues to be an area of ethical concern. Typically, opponents of placebo...

Choosing the best endpoint

Design and endpoints of clinical trials in hepatocellular carcinoma. Llovet JM, Di Bisceglie AM, Bruix J, Kramer BS, Lencioni R, Zhu AX, Sherman M, Schwartz M, Lotze M, Talwalkar J, Gores GJ; for the Panel of Experts in HCC-Design Clinical Trials.The design of clinical trials in hepatocellular carcinoma (HCC) is complex because many patients have concurrent liver disease, which can confound the assessment of clinical benefit. There is an urgent need for high-quality trials in this disease. An expert panel was convened by the American Association for the Study of Liver Diseases to develop guidelines that provide a common framework for designing trials to facilitate comparability of results. According to these guidelines, randomized phase 2 trials with a time-to-event primary endpoint, such as time to progression, are pivotal in clinical research on HCC. Survival remains the main endpoint to measure effectiveness in phase 3 studies, whereas time to recurrence is proposed as an appropriate endpoint in the adjuvant setting. Because progression-free survival and disease-free survival are composite endpoints, they are more vulnerable than others in HCC clinical studies and may not be able to capture clinical benefits. Selection of the target population should be based on the Barcelona Clinic Liver Cancer staging system. New drugs should be tested in patients with well-preserved liver function (Child-Pugh A class). Patients assigned to the control arm should receive standard-of-care therapy, that is, chemoembolization for patients with intermediate-stage disease and sorafenib for patients with advanced-stage disease. Further research is needed to incorporate biomarkers and molecular imaging into clinical research in HCC. These surrogate markers may help to enrich study populations and maximize the cost-benefit ratio of trial execution. Design and conduct of phase 3 trials should be coordinated by centers with appropriate expertise in HCC.[Abstract reproduced by permission of J Natl Cancer Inst 2008;100:698–711.]Link to free abstract at: http://jnci.oxfordjournals.org/cgi/content/abstract/100/10/698

Design and Endpoints of Clinical Trials in Hepatocellular Carcinoma

The design of clinical trials in hepatocellular carcinoma (HCC) is complex because many patients have concurrent liver disease, which can confound the assessment of clinical benefit. There is an urgent need for high-quality trials in this disease. An expert panel was convened by the American Association for the Study of Liver Diseases to develop guidelines that provide a common framework for designing trials to facilitate comparability of results. According to these guidelines, randomized phase 2 trials with a time-to-event primary endpoint, such as time to progression, are pivotal in clinical research on HCC. Survival remains the main endpoint to measure effectiveness in phase 3 studies, whereas time to recurrence is proposed as an appropriate endpoint in the adjuvant setting. Because progression-free survival and disease-free survival are composite endpoints, they are more vulnerable than others in HCC clinical studies and may not be able to capture clinical benefits. Selection of the target population should be based on the Barcelona Clinic Liver Cancer staging system. New drugs should be tested in patients with well-preserved liver function (Child-Pugh A class). Patients assigned to the control arm should receive standard-of-care therapy, that is, chemoembolization for patients with intermediate-stage disease and sorafenib for patients with advanced-stage disease. Further research is needed to incorporate biomarkers and molecular imaging into clinical research in HCC. These surrogate markers may help to enrich study populations and maximize the cost-benefit ratio of trial execution. Design and conduct of phase 3 trials should be coordinated by centers with appropriate expertise in HCC.

A phase II trial of tremelimumab (CP-675,206) in patients with advanced refractory or relapsed melanoma

9023 Background: A phase II, open-label, single-arm study was conducted to assess antitumor activity of tremelimumab (CP- 675,206), a fully human, anticytotoxic T lymphocyte-associated antigen 4 monoclonal antibody, in patients with advanced melanoma. Methods: Patients with measurable surgically incurable stage III or IV melanoma who had progressed, relapsed, or could not tolerate previous treatment received 15 mg/kg tremelimumab administered IV every 12 weeks for up to 4 cycles or until progression of disease or intolerable toxicity. Patients with clinical benefit were eligible for ≤ 4 additional doses. The primary study endpoint was proportion of confirmed objective RECIST responses per independent review, and secondary endpoints included safety, duration of response, and overall survival (OS). Results: Of 251 patients enrolled, 246 patients (241 response-evaluable) received a median of 1 dose (range, 1 to 7). Preliminary RECIST objective response rate was 8.3% (20 PRs, of which 5 are pending independent confirmation). In addition, 13/15 (86.7%) confirmed PRs are ongoing (4.0+ to 11.1+ months). The majority of PRs involved target lesions in lung, lymph nodes, and/or liver. Clinical benefit rate was 22.8% (PRs + SDs ≥ 70 days since first dose). In addition, 7 patients (2.9%) with mixed responses (ie, best overall response of PD but PR in target lesion) remain alive on study with censored OS (9.7+ to 13.5+ months). Median OS was 10.0 months. The majority of drug-related adverse events (AEs) were mild to moderate, and grade 3/4 AEs were primarily diarrhea (n=28, 11.4%), fatigue (n=6, 2.4%), and colitis (n=5, 2.0%). There were 2 (0.8%) treatment-related deaths (1 sudden death and 1 diverticular perforation). Conclusions: This study does not demonstrate a second-line response rate exceeding 10% but the duration of response of this regimen suggests a role for tremelimumab in this population. A full assessment of clinical benefit will await survival data from this study and the ongoing, randomized phase III first-line study. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Pfizer Pfizer Pfizer Pfizer Pfizer Pfizer

Long-term survival after pancreatic cancer treatment

Pancreatic cancer is a nearly lethal disease. Patients have such a poor prognosis because there are no early symptoms. Upon presentation, most patients already have regional and systemic spread of the disease. With cure rates below 3%, long-term survival is difficult to measure. Thus, the assessment of clinical benefit has been based not only on observed 5-year survival but more frequently on actuarial, median, and disease-free survival. Surgery remains the only hope for cure, but median survival remains low despite improvements in peri- and postoperative treatment of complications and sharp decreases in perioperative morbidity and mortality. The addition of adjuvant chemo- and radiotherapy has provided a survival advantage of 6 to 10 months (increasing median survival to 20 months). However, the long-term benefit, if any, is still to be determined. Neoadjuvant therapies are also undergoing evaluation, but their role has not yet been established. True long-term survival may ultimately depend on the development of screening tools that will allow early detection (before regional and systemic spread) of this lethal disease.

Prospective early response imaging biomarker for neoadjuvant breast cancer chemotherapy.

The American Cancer Society estimates that in 2006, 212,920 women will be diagnosed with breast cancer and that 40,970 women will die from the disease. The development of more efficacious chemotherapies has improved outcomes, but the rapid assessment of clinical benefit from these agents remains challenging. In breast cancer patients receiving neoadjuvant chemotherapy, treatment response is traditionally assessed by physical examination and volumetric-based measurements, which are subjective and require macroscopic changes in tumor morphology. In this study, we evaluate the feasibility of using diffusion magnetic resonance imaging (MRI) as a reliable and quantitative measure for the early assessment of response in a breast cancer model. Mice implanted with human breast cancer (MX-1) were treated with cyclophosphamide and evaluated using diffusion MRI and growth kinetics. Histologic analyses using terminal nucleotidyl transferase-mediated nick end labeling and H&E were done on tumor samples for correlation with imaging results. Cyclophosphamide treatment resulted in a significant reduction in tumor volumes compared with controls. The mean apparent diffusion change for treated tumors at days 4 and 7 posttreatment was 44 +/- 5% and 94 +/- 7%, respectively, which was statistically greater (P < 0.05) than the control tumors at the same time intervals. The median time-to-progression for control and treated groups was 11 and 32 days, respectively (P < 0.05). Diffusion MRI was shown to detect early changes in the tumor microenvironment, which correlated with standard measures of tumor response as well as overall outcome. Moreover, these findings show the feasibility of using diffusion MRI for assessing treatment response of a breast tumor model in a neoadjuvant setting.

CNTO 328, an Anti-Interleukin (IL)-6 Monoclonal Antibody (mAb) - Preliminary Results of Subjects with Castleman's Disease from a Phase 1 Study in Selected Hematological Malignancies.

Background: IL-6 is a pleiotropic cytokine, the dysregulation of which plays an etiological role in many diseases. Multicentric Castleman's disease (CD) is a polyclonal lymphoproliferative disorder in which IL-6, overproduced by enlarged lymph nodes, is responsible for B-cell proliferation, auto-immune phenomena, systemic inflammatory manifestations (eg, fever, fatigue, and weight loss) and abnormal laboratory findings, including anemia, hyper-γ-globulinemia, hypoalbuminemia, thrombocytosis and increases in acute-phase proteins (eg, CRP, ESR and fibrinogen). The inflammatory syndrome can be severe and refractory to steroids, chemotherapy and even autologous stem cell transplantation. CNTO 328 is a chimeric mAb that specifically binds and neutralizes human IL-6 with high affinity. A phase I trial is being conducted to assess the safety and PK of CNTO 328 in subjects with CD and other hematological diseases.Methods: This trial enrolls subjects with non Hodgkin's B-cell lymphoma, multiple myeloma, or CD in cohorts exploring doses ranging from 3 to 12mg/kg given intravenously repeated either weekly, or every 2, or 3 weeks. Dose limiting toxicity (DLT) is defined as a ≥Grade 3 event (excluding hematologic toxicity), or ≥Grade 2 allergic reaction/hypersensitivity by NCI CTCAE attributed to CNTO 328 after the first administration. Clinical benefit assessment is based on improvements in Hb, fatigue, anorexia, fever/night sweats, weight, and size of target lymph node.Results: Results from the first 7 CD subjects enrolled in Cohorts 1 (n=1, CNTO 328 3mg/kg q 2 weeks), 2 (n=2, CNTO 328 6mg/kg q 2 weeks) and 3 (n=4, CNTO 328 12mg/kg q 3 weeks) are currently available. At present time, subjects have received a median number of 4 (range 3 to 21) doses. CNTO 328 alone was well tolerated and no DLTs were observed. Non-related to CNTO 328 Grade 3 AEs such as anemia, thrombocytosis, fatigue and one possibly-related AE (ie, vomiting, grade 3) were observed. In addition, 3 subjects experienced Grade 3 SAEs that were deemed either unrelated or unlikely related to CNTO 328. Six evaluable subjects with CD showed a response by clinical benefit assessment including improvement in Hb and in severe thrombocytosis, and fatigue, reduction of fever, resolution of rash, improvement in skin tumors, or decrease in lymphadenopathy. PK and PD analysis from these subjects is currently ongoing and data from these analyses will be presented.Conclusions: Treatment with CNTO 328 has been well tolerated in CD subjects at doses up to 12mg/kg q 3 weeks, and no allergic reactions have been observed after repeated dosing. Preliminary results suggest that CNTO 328 can abrogate the effects of IL-6 and induce both clinical and biochemical responses in CD.

Treatment of the primary hyperoxalurias: A new chapter

Despite advances in the enzymology, molecular genetics, and clinical knowledge of the primary hyperoxalurias, few treatments are available. Oxalobacter formigenes is a promising new therapy with potential to induce secretion of oxalate into the intestinal lumen, where it can be degraded by the bacteria.