Previously Treated Research Articles

Creation of a neovascular age-related macular degeneration national database using a web-based platform: Fight Retinal Blindness Spain. Report 1: Visual outcomes.

To study the visual outcomes of neovascular AMD (nAMD) treated with anti-vascular endothelial growth factor (VEGF) drugs at national level. Multicenter national database of nAMD eyes treated with anti-VEGF intravitreal injections (ranibizumab, aflibercept, bevacizumab) in fixed bimonthly (FB) or treat-and-extend (TAE) regimens. Demographics, visual acuity (VA) in logarithm of the minimum angle of resolution (logMAR) ETDRS letters at baseline and subsequent visits, number of injections and visits data were collected using a validated web-based tool (Fight Retinal Blindness!). 1273 eyes (1014 patients) were included, 971 treatment naïve (TN) and 302 previously treated (PT). Baseline VA (mean ± SD) was 57.5 (±19.5) and 62.2 (±17) (p > 0.001), and 24 months final VA was 60.4 (±21.2) and 58.8 (±21.1) (p=0.326), respectively. Mean VA change at 12/24 months was +4.2/+2.9 letters in TN eyes and +0.1/-3.4 letters in PT eyes (p < 0.001/p < 0.001). The percentage of ≥15 letters gainers/losers at 24 months was 24.8%/14.5% in TN, and 10.3%/15.7% in PT eyes. The median number of injections/visits at 12 months was 7/9 in TN and 6/8 in PT (p=0.002/p < 0.001) and at 24 months was 11/16 in TN and 11/14 in PT (p=0.329/p < 0.001). Study drugs included ranibizumab (39.5%), aflibercept (41.2%) and bevacizumab (19.3%). Independent, large-scale national audits are feasible if committed health care professionals are provided with efficient information technology systems to do them. The results described here represent an adequate measurement of the quality of care delivered nationwide and benchmark the clinical management of nAMD at a country level compared to other real-world international cohorts.

Efficacy and Safety of Ublituximab in Combination with Umbralisib (U2) in Patients with Chronic Lymphocytic Leukemia (CLL) By Treatment Status: A Sub-Analysis of the Phase 3 Unity-CLL Study

Efficacy and Safety of Ublituximab in Combination with Umbralisib (U2) in Patients with Chronic Lymphocytic Leukemia (CLL) By Treatment Status: A Sub-Analysis of the Phase 3 Unity-CLL Study

Favorable Outcomes for Patients Treated with U2 with Co-Morbidities or Concomitant Medications: A Retrospective Analysis of Unity-CLL Phase 3 Trial

Favorable Outcomes for Patients Treated with U2 with Co-Morbidities or Concomitant Medications: A Retrospective Analysis of Unity-CLL Phase 3 Trial

Enhanced Safety and Tolerability of Dose Intensive Pentostatin and Rituximab in Patients with CLL or Low-Grade B-Cell NHL.

BackgroundRecent studies have suggested that combination chemotherapy with a purine analog and a monoclonal antibody may have additive as well as synergistic activity in the treatment of NHL and CLL. The first immunochemotherapeutic regimen combined fludarabine (F) and rituximab (R). Although it was efficacious, it was also myelotoxic and immunosuppressive. This multicenter Phase II trial investigated the efficacy and safety of another purine analog, pentostatin (P), in combination with R in the treatment of NHL and CLL patients. (Some of this data has been presented at the 2005 Pan-Pacific Lymphoma Conference).MethodsOne hundred forty-seven patients were enrolled in this study. Eligibility criteria allowed previously treated (PT) and treatment naïve (UT) patients diagnosed with low-grade NHL (REAL classification) or stage II, III, or IV CLL (mod. Rai staging). Treatment consisted of intravenous infusions of R (375 mg/m2) on day 1 and R (375 mg/m2) plus dose intensive P (4 mg/m2) on days 8, 15, 22, 36, 43, and 50, completing 1 cycle. Clinical evaluation was performed after 60 days. If complete response or progressive disease was documented, the treatment was stopped. All other patients were eligible to then receive cycle 2. Patients were stratified by disease and by prior treatment status.ResultsOne hundred thirty three patients were eligible for evaluation. One hundred sixty six cycles were administered. Response rate (RR) for NHL-PT was 51% and for NHL-UT was 78%. RR for CLL-PT was 34% and for CLL-UT 42%. There were 30 NHL patients eligible for cycle 2 and 22 went on to receive the additional cycle. Ten patients (45%) achieved an improved objective response. Seventeen CLL patients were eligible for cycle 2 and 8 completed cycle 2. There were 2 (25%) patients that achieved an improved objective response. Median duration of response (DoR) was 11.7, 21.5, 11.9, and 23.7 months, respectively. Median progression-free survival (PFS) was 14.8, 23.5, 13.9, and 25.6 months, respectively. There was a single case of grade 4 neutropenia in each of the PT and UT groups. Overall, neutropenia was the most common adverse event (AE) (6%) in the PT group and was the most common hematological AE (7%) in the UT group. Four patients died within 30 days of receiving chemotherapy (age range 64–88). Causes of death were respiratory insufficiency (2), MI/CAD, and sepsis/CLL.ConclusionsThis immunochemotherapeutic regimen of P+R is active in previously untreated and treated patients with indolent NHL or stage II–IV CLL. The objective response can be improved with prolonged therapy. With only 2/133 evaluable patients experiencing Gr 4 neutropenia, we have demonstrated that this dose intensive regimen was very safe and well tolerated. Future trials comparing the tolerability and efficacy of P+R in combination with cyclophosphamide and/or mitoxantrone to other standard regimens are warranted. The use of combination therapy in elderly patients should be used with caution due to associated co-morbidities.

Screening: a unique study of otorhinolaryngeal manifestations in 400 patients of pulmonary tuberculosis being diagnosed and treated under revised national tuberculosis control programme

&lt;p class="abstract"&gt;&lt;strong&gt;Background:&lt;/strong&gt; Tuberculosis (TB) is primarily a disease of lungs but can affect any part of the body. Among extrapulmonary TB, tuberculosis of otorhinolaryngeal region is uncommon but not rare. Despite the best efforts of the RNTCP, tuberculosis is still a major health problem in India. In our study screening of the pulmonary tuberculosis patients was done to know the incidence and pattern of otorhinoloryngeal manifestations and also to know the treatment outcome after follow up of patient till completion of DOTS therapy under RNTCP.&lt;/p&gt;&lt;p class="abstract"&gt;&lt;strong&gt;Methods:&lt;/strong&gt; This study included 400 pulmonary tuberculosis patients, both sputum positive and sputum negative (200 patients in each group) of newly treated (ND) and previously treated (PT) categories. After complete history, physical and local examination, suspected patients were evaluated for otorhinolaryngeal manifestations of tuberculosis. The diagnosis was confirmed after culture swabs, fine needle aspiration cytology (FNAC) and biopsy for histopathological examination (HPE).&lt;/p&gt;&lt;p class="abstract"&gt;&lt;strong&gt;Results:&lt;/strong&gt; Out of total 400 patients majority of patients belong to 21-30 years age group. Out of total 400 patients, 5 (1.25%) patients were having laryngeal tuberculosis, 1 (0.25%) patient of tubercular otitis media and 2 (0.5%) patients were having nasal TB. Results of our study are consistent with previously done studies despite RNTCP treatment. The treatment outcome was good after completion of ATT.&lt;/p&gt;&lt;p class="abstract"&gt;&lt;strong&gt;Conclusions:&lt;/strong&gt; Every patient of pulmonary TB with complaint related to otorhinolaryngeal region should be examined and followed up with high suspicion of ENT related tuberculosis.&lt;/p&gt;

Differential response to intravitreal dexamethasone implant in na\xefve and previously treated diabetic macular edema eyes

BackgroundTo identify different response patterns to intravitreal dexamethasone implants (IDI) in naïve and previously treated (PT) diabetic macular edema (DME) eyes in a real-life setting.Methods342 IDI injections (203 DME eyes) were included. Number of IDI injections, percentage (%) of eyes with 1, 2, 3 and ≥ 4 injections, time to reinjections, visual acuity (VA), intraocular pressure (IOP) and central retinal thickness (CRT) were evaluated for naïve and PT DME eyes over 24 months.ResultsMean number of injections was significantly lower in naïve vs PT DME eyes (1.40 ± 0.9 vs 1.82 ± 0.9, p < 0.001). The percentage of eyes receiving 1 injection was significantly higher in naïve vs PT DME eyes (76.1 vs 47.7), (p < 0.001). However, it was significantly lower for 2 (16.4 vs 29.4), or 3 injections (1.4 vs 17.6) (both p < 0.001), with no differences in eyes receiving ≥4 injections (5.9 vs 5.1 respectively, p = 0.80). Mean time to reinjection was not significantly different between both groups for the second, third and fourth injection (9.6 ± 4.0 vs 10.0 ± 5.5, p = 0.75, 13.2 ± 4.0 vs 16.0 ± 3.5, p = 0.21 and 21.7 ± 3.8 vs 19.7 ± 5.8, p = 0.55). VA scores were consistently better in naïve vs PT DME eyes at all studied timepoints, with no significant differences in CRT reduction or adverse effect rates.ConclusionNaïve DME eyes received lower number of IDI injections and showed better VA levels than PT DME eyes for 24 months in a real-world setting. This data supports the IDI use in early DME stages and provide further evidence of better IDI response when used as first-line therapy.

Treatment patterns, persistence and adherence rates in patients with type 2 diabetes mellitus in Japan: a claims-based cohort study

ObjectiveTo determine real-world trends in antidiabetic drug use, and persistence and adherence, in Japanese patients with type 2 diabetes mellitus (T2DM).DesignRetrospective evaluation of administrative claims data (2011–2015) using the Japan...

Sunitinib in patients with pancreatic neuroendocrine tumors (panNETs): Exploratory pharmacogenomic analyses.

255 Background: In a phase IV trial (NCT01525550), median progression-free survival (PFS) was 13.2 mo in sunitinib-treated patients (pts) with well-differentiated panNETs. Objective response rate (ORR) was 24.5% and median overall survival (OS) was 37.8 mo. Exploratory analyses evaluated potential associations between single nucleotide polymorphisms (SNP) in genes involved in angiogenesis, protein transport or inflammatory response and clinical outcomes. Methods: Blood samples were genotyped using TaqMan assays for 12 SNPs previously associated with panNET risk, prognosis or drug effect. Associations between SNP and PFS or OS were assessed by comparing genotypes within treatment-naïve (TN), previously treated (PT) and combined groups, and within a genotype between treatment groups, using Kaplan-Meier analysis and Cox proportional hazards models. Fisher’s exact test was used for association between ORR and genotype. PFS and ORR were investigator-assessed. P values displayed are unadjusted and Bonferroni method was used for multiplicity adjustment. Results: 56 pts were genotyped: 25 TN and 31 PT. There were no significant associations between genotype and PFS or OS but there was a trend toward shorter PFS in pts with VEGFR1 rs9554320 C/A versus C/C (hazard ratio [HR] 1.78; 95% confidence interval [CI] 0.83–3.82; p = 0.117) and VEGFR1 rs9582036 A/C versus A/A (HR 1.88; 95% CI 0.9–3.93; p = 0.102). The genotypes G/G of VEGFA rs2010963 (p = 0.041) , G/G of VEGFA rs833068 (p = 0.041) and A/C of VEGFR1 rs9582036 (p = 0.046) showed a trend toward a higher ORR in the PT versus TN group. Genotype T/T of VEGFR2 rs7692791 (p = 0.103) showed a trend toward to a lower ORR in the TN versus PT group. Higher ORR was associated with IL1B rs16944 G/A versus G/G (46.4% vs 4.5%; p = 0.001) in the combined group. Conclusions: Potential associations between ORR and VEGFA rs2010963 and rs833068, VEGFR1 rs9582036 and VEGFR2 rs7692791 were observed. IL1B rs16944 was significantly associated with ORR, consistent with the role of IL1B in panNET etiology and development. Most correlations were not significant after adjustment for multiplicity. Clinical trial information: NCT01525550.

Tolerability and discontinuation rates in teriflunomide-treated patients. A real-world clinical experience.

Objectives:To assess the real-world tolerability of teriflunomide in multiple sclerosis (MS) patients from a large Canadian MS Centre of Care to determine whether previously treated (PT) patients have different tolerability thresholds than treatment-naive (TN) patients, leading to differing discontinuation rates.Methods:This non-interventional, single-center, retrospective chart review examined all patients who were prescribed commercial teriflunomide between July 2014 and May 2015 at the MS Clinic in the Ottawa General Hospital and Research Institute, Ottawa, Canada.Results:A total of 119 patient charts were reviewed (29 TN and 90 PT). Overall, 19 (15.9%) patients discontinued teriflunomide after a mean treatment duration of 35 weeks. The most common reason for discontinuation was side effects in 8 patients (42%).Discontinuation due to intolerability alone occurred in 13 patients. The number of discontinuations was not sufficient to demonstrate a statistically significant difference between TN and PT patients (p=0.1).Conclusions:This retrospective chart review provides some evidence about the real-world tolerability of teriflunomide. Discontinuations were low overall and consistent with previously reported clinical trial data. There was no significant difference in discontinuation rates between patients in the TN and PT groups. We believe that teriflunomide is a safe and well-tolerated oral alternative to injectable therapies.

Treatment patterns in hyperlipidaemia patients based on administrative claim databases in Japan

Background and aimsReal-world evidence on treatment of hyperlipidaemia (HLD) in Japan is limited. We aimed to describe treatment patterns, persistence with, and adherence to treatment in Japanese patients with HLD. MethodsRetrospective analyses of adult HLD patients receiving drug therapy in 2014–2015 were conducted using the Japan Medical Data Center (JMDC) and Medical Data Vision (MDV) databases. Depending on their HLD treatment history, individuals were categorised as untreated (UT) or previously treated (PT), and were followed for at least 12 months. Outcomes of interest included prescribing patterns of HLD drug classes, persistence with treatment at 12 months, and adherence to treatment. ResultsData for 49,582 and 53,865 patients from the JMDC and MDV databases, respectively, were analysed. First-line HLD prescriptions for UT patients were predominantly for moderate statins (JMDC: 75.9%, MDV: 77.0%). PT patients most commonly received combination therapy (JMDC: 43.9%, MDV: 52.6%). Approximately half of the UT patients discontinued treatment during observation. Within each cohort, persistence rates were lower in UT patients than in PT patients (JMDC: 45.0% vs. 77.5%; MDV: 51.9% vs. 85.3%). Adherence was ≥80% across almost all HLD drug classes, and was slightly lower in the JMDC cohort than MDV cohort. ConclusionsMost common prescriptions were moderate statins in UT patients and combination therapy in PT patients. The high discontinuation rate of HLD therapy in UT patients warrants further investigation and identification of methods to encourage and support long-term persistence.

Adequacy of examining one sputum specimen in tuberculosis drug resistance surveys

Objective/backgroundCollection of one spot and one morning sputum specimen is recommended for tuberculosis (TB) drug resistance surveys. This was a retrospective analysis of Mycobacterium tuberculosis cultures isolated from two spot sputum specimens collected from smear positive TB patients in a TB drug resistance survey. It was conducted to understand the value of a second specimen. MethodsA TB drug resistance survey was conducted in the state of Tamil Nadu, India, to estimate the prevalence of drug resistance among new sputum smear-positive (NSP) and previously treated (PT) patients diagnosed in Revised National Tuberculosis Control Program microscopy centers. A total of 2425 patients (1524 NSP and 901 PT cases) were enrolled in the study. From these patients, two spot sputum specimens (C and D) were collected within a period of 2h. No preservative was added to sputum. The samples were transported at ambient conditions without cold storage to the central laboratory for culture of M. tuberculosis. Culture yield from each sample was computed and analyzed. ResultsThe proportion of cultures retrieved from C and D specimens among NSP cases (89.3% and 89.7%) and PT cases (90.8% and 90.3%) were similar. The culture grades of C and D samples were comparable (chi-square test, 3560.135; p<.001) and the agreement was moderate (kappa test, 0.454). ConclusionThe findings of the study reveal the adequacy of single spot sputum specimen from smear positive pulmonary TB patients for bacteriological examination in a quality-assured TB laboratory to determine precisely the level of drug resistance in a province of India.

Abstract 5448: In vitro drug response (IVDR), biomarkers (BM) and clinical outcome (CO) in malignant glioma (GM) patients

Abstract Assessment of the tumor-associated (TA) response factors may serve to guide targeted salvage therapy. This is a retrospective correlative analysis of in vitro test results with clinical outcome of anonymized patients with MG. In a centralized testing facility, IVDR to at least ten chemotherapeutic drugs (Chemo) and immunohistochemistry (IHC)-derived TA BMs (including Ki67, p53, EGFR, MGMT, GSTpi, and MDR-1) were assessed in viable tumor resections from 65 previously treated (PT) and untreated (UT) patients with progressive and recurrent MGs (10 astrocytomas [A], 36 glioblastoma multiforme [GBM], and 19 gliomas of various histology), and correlated results with CO (response [RES] and time to progression [TTP]). IVDR results were generated by exposing aliquots of tumor cell suspensions to single agent Chemo at physiologic doses for 5-days, and determining the percentage of cell growth inhibition (PCI) via tritium uptake. Chemo included Camptothecin (SN-38 is active species), Carmustine (BCNU), platinum analogs Carboplatin (CARBO) and cisplatin (CP), Temozolomide (TEMO) and Dacarbazine (DTIC). For each drug tested, tumor responses were categorized into either extreme drug resistance (EDR) or Intermediate plus Low Drug Resistance [IDR/LDR]. Standard IHC tests on paraffin-embedded tumor tissue sections yielded BM expression from which frequency rates were determined. Patients’ resections and treatments were performed at a single medical center between 1994 and 1998; and included surgery alone or combined with irradiation (XRT) and single-agent or combination Chemo. Biopsies were obtained from recurrent patients prior to second-line therapy. The median time between treatment and TTP or recurrence was 10 months. For each drug, IVDR profiles were comparatively similar, with the exception of tumors from PT patients which were significantly more resistant to CARBO (N = 20; 2-tailed t test, p = 0.0433) and CPLAT (N = 22; p = 0.0076). Frequencies of BM expression between PT (N = 29) and UT patients (N = 54) were similar among tumor types, except for GBMs from patients who progressed following treatment. Their tumors generally overexpressed EGFR (1.8-fold) and MGMT (2.4-fold). Patients’ overall RES rate was 24%, while rates for A (33%), GBMs (6%) and other gliomas (58%) differed significantly (Fisher exact test, p = 0.0104). Most patients (81%) exhibited PD following therapy, and had relatively similar EDR vs. IDR/LDR response profiles for median TTP (10 months vs. 10 months), and median survival. For TEMO, CPT-11, and BCNU - common drugs used against MGs, there were no significant differences in median TTP, median survival, or overall survival (Log-rank, p&amp;lt;0.05, p = 0.1301 and p = 0.6123, respectively). Results suggest that a detailed assessment of molecular mechanisms related to IVDR and TA BMs may be required to identify (non)response factors that facilitate stratifying patient treatment leading to improved CO. Citation Format: Ricardo J. Parker, Michael Myers, Patric Schiltz. In vitro drug response (IVDR), biomarkers (BM) and clinical outcome (CO) in malignant glioma (GM) patients. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5448. doi:10.1158/1538-7445.AM2015-5448

High rates of ofloxacin resistance in Mycobacterium tuberculosis among both new and previously treated patients in Tamil Nadu, South India.

Periodic drug resistance surveillance provides useful information on trends of drug resistance and effectiveness of tuberculosis (TB) control measures. The present study determines the prevalence of drug resistance among new sputum smear positive (NSP) and previously treated (PT) pulmonary TB patients, diagnosed at public sector designated microscopy centers (DMCs) in the state of Tamil Nadu, India. In this single-stage cluster-sampling prevalence survey, 70 of 700 DMCs were randomly selected using a probability-proportional to size method. A cluster size of 24 for NSP and a varying size of 0 to 99 for PT cases were fixed for each selected DMC. Culture and drug susceptibility testing was done on Lowenstein-Jensen medium using the economic variant of proportion sensitivity test for isoniazid (INH), rifampicin (RMP), ofloxacin (OFX) and kanamycin (KAN). Human Immunodeficiency Virus (HIV) status was collected from patient records. From June 2011 to August 2012, 1524 NSP and 901 PT patients were enrolled. Any RMP resistance and any INH resistance were observed in 2.6% and 15.1%, and in 10.4% and 30% respectively in NSP and PT cases. Among PT patients, multi drug resistant TB (MDR-TB) was highest in the treatment failure (35%) group, followed by relapse (13%) and treatment after default (10%) groups. Extensively drug resistant TB (XDRTB) was seen in 4.3% of MDR-TB cases. Any OFX resistance was seen in 10.4% of NSP, 13.9% of PT and 29% of PT MDR-TB patients. The HIV status of the patient had no impact on drug resistance levels. RMP resistance was present in 2.6% of new and 15.1% of previously treated patients in Tamil Nadu. Rates of OFX resistance were high among NSP and PT patients, especially among those with MDR-TB, a matter of concern for development of new treatment regimens for TB.

Long-term survival in patients with metastatic melanoma who received ipilimumab in four phase II trials.

9053 Background: Ipilimumab (Ipi) has shown improved overall survival (OS) in two phase III trials of patients (pts) with metastatic melanoma (MM), with survival follow-up of &gt;4 years in one trial. The present analyses provide survival follow-up of &gt;5 years in four phase II trials of Ipi in MM. Methods: Pts with MM were enrolled in one of four phase II trials: (1) CA184-004, a biomarker study with Ipi at 3 or 10 mg/kg in treatment-naive (TN) and previously treated (PT) pts; (2) CA184-007, with Ipi at 10 mg/kg +/- prophylactic budesonide in TN and PT pts; (3) CA184-008, a single-arm study with Ipi at 10 mg/kg in PT pts; and (4) CA184-022, a dose-ranging study of Ipi at 0.3, 3, or 10 mg/kg in PT pts (crossover from lower dose groups to 10 mg/kg was allowed upon disease progression). Ipi was administered q3 wk x4 (induction), followed by maintenance (q12 wk from week 24) in eligible pts. Some pts were retreated with Ipi at 10 mg/kg upon disease progression. Along with survival data collected through March 2012 for studies 007, 008, and 022, we report updated 5-year OS data for study 004 collected through September 2012. Results: Five-year OS rates for TN and PT pts are reported in studies 007, 008, and 022, with combined analyses for TN and PT pts within each dose group in study 004 (Table). The results show that survival rates reach a plateau beginning at year 3. Conclusions: In pts who received Ipi at 3 or 10 mg/kg in phase II studies, regardless of prior treatment, a proportion (12.3–49.5%) remained alive 5 years after the start of treatment. These results demonstrate long-term survival with Ipi therapy in MM. An ongoing phase III trial will compare OS for Ipi at 3 vs 10 mg/kg in pts with MM. Clinical trial information: NCT00162123. [Table: see text]

Both Hematologic and Renal Response Affect Overall Survival of Myeloma Patients with Acute Kidney Injury,

Abstract 3949Acute kidney injury (AKI) is a common but serious sequela of multiple myeloma. Recently, the International Myeloma Working Group (IMWG) introduced a new renal response criteria with complete (CRenal), partial (PRenal) and minimal (MRenal) responses. This study compares the IMWG criteria with other models to determine their correlation with overall survival (OS).Patients with multiple myeloma and AKI were identified from centers around the world. OS was calculated from the day of AKI. Renal function was assessed by estimated glomerular filtration rate (eGFR) via MDRD method. Hematologic response was the best achieved as assessed by International Uniform Response Criteria for Multiple Myeloma. Only patients with peak serum creatinine (Scr) ≥ 2.0 mg/dl were included. Separate analyses were performed on the newly diagnosed (ND) versus previously treated (PT) patients.A total of 158 patients were collected from centers in United States, United Kingdom, France and Austria. Fourteen patients were excluded for having peak Scr < 2.0 mg/dl and one for repeated episodes of AKI. Median age of the 143 patients was 64 (34 – 87) years, 58.7% were male and 115 were newly diagnosed. Median Scr was 5.1 (2.0 to 18.6) mg/dl and median eGFR was 10.6 (2.8 – 36.5) ml/min/1.72 m2. Dialysis was required in 49.3%, and 72.9% were dialysis independent at the end of the study.By IMWG criteria, median OS ranged between 6.0 months (m) in PT patients with no renal response (NRenal) to 23.7m in patients with CRenal, p = 0.34 (Table 1). In ND patients, OS was 31.4m in NRenal vs 73.8m in CRenal (p = 0.08). However, OS was similar between PRenal and CRenal, p = 0.70 (Figure 1). If only patients with a hematologic PR or better were analyzed, the OS range was 6.0m in NRenal to 23.7m in CRenal in PT patients (p = 0.85) and 36.6m in NRenal to 73.8m in CRenal in ND patients, p = 0.73.Table 1Previously TreatedNMedian SurvivalNMedian Survival (>PR)CRenal323.7 m323.7 mPRenal413.1 m312.8 mMRenal512.0 m119.2 mNRenal166.0 m56.0 mp-value0.340.85Newly DiagnosedCRenal2273.8 m2273.8 mPRenal27Not Reached23Not ReachedMRenal2265.6 m1965.6 mNRenal4331.4 m2136.6 mp-value0.080.73 [Display omitted] The best model tested was one that defined renal response (RR) as regaining or maintaining dialysis independence and no response (NR) as dialysis dependence. RR was associated with a superior survival for both PT patients (13.5 m vs 6.0m (NR), p = 0.03) and ND patients (73.8m vs 20.1m (NR), p < 0.001). RR increased with the depth of hematologic response, p = 0.04. RR occurred in 75% of the PT patients with hematologic PR or better and 66.7% in those with less than PR, p = 0.64. In ND patients, RR occurred in 85.7% of those with PR or better and 54.6% of those with PR or less, p = 0.003. This may explain the differences in OS when hematologic response was considered. In PT patients with hematologic PR or better, renal response did not improve OS (21m vs 6m, p = 0.28) but it remained beneficial in the ND patients (73.8m vs 35.1m, p = 0.04, Figure 2). Renal response was not significantly associated with OS for any patient with hematologic response that was VGPR or better. In a multivariate analysis, RR (p = 0.001), ND (p <0.001) and PR or better hematologic response (p = 0.046) were associated with OS. [Display omitted] The results of our study suggest renal response is important to OS but the depth of response was not as important. Renal response was most important when the hematologic response was less than a VGPR. This supports renal response as part of the overall response assessment in multiple myeloma patients. Based on our results, reducing the number of response categories and simplifying the current consensus criteria seems justified.Median survival of the 143 patients evaluated by the IMWG renal response criteria. Overall survival was calculated by Kaplan Meier method. Differences in survival were evaluated by Log-Rank test. Disclosures:Ludwig:Mundipharma, Janssen-Cilag: Research Funding, Speakers Bureau. Hutchison:The Binding Site: Honoraria.

A phase II trial of nab‐paclitaxel (ABI‐007) and carboplatin in patients with unresectable stage IV melanoma

There is increasing evidence that paclitaxel and carboplatin are clinically active in the treatment of metastatic melanoma (MM). ABI-007 is an albumin-bound formulation of paclitaxel that has demonstrated single-agent activity against metastatic melanoma. A parallel phase II trial was conducted in patients with unresectable stage IV melanoma who were either chemotherapy naive (CN) or previously treated (PT). The treatment regimen consisted of ABI-007 (100 mg/m(2) ) and carboplatin area under the curve (AUC2) administered on days 1, 8, and 15 every 28 days. The primary aim of this study was objective response rate (RECIST). Seventy-six patients (41 CN and 35 PT) were enrolled between November 2006 and July 2007. Three patients withdrew consent prior to starting treatment. The median number of treatment cycles was 4. There were 10 (25.6%) responses (1 complete response [CR] and 9 partial responses [PRs]) in the CN cohort (90% CI, 16.7%-42.3%) and 3 (8.8%) responses (3 PRs) in the PT cohort (90% CI, 2.5%-21.3%). Median progression-free survival was 4.5 months in the CN cohort and 4.1 months in the PT cohort. Median overall survival (OS) was 11.1 months in the CN group and 10.9 months in the PT group. Severe toxicities in both groups (Common Terminology Criteria for Adverse Effects v.3.0 ≥grade 3) included neutropenia, thrombocytopenia, neurosensory problems, fatigue, nausea, and vomiting. The weekly combination of ABI-007 and carboplatin appears to be moderately well tolerated, with promising clinical activity as therapy in patients who are chemotherapy naive and with modest antitumor activity in those previously treated.

A phase II trial of carboplatin (C) and nab-paclitaxel (ABI-007-nab-P) in patients with unresectable stage IV melanoma: Final data from N057E

9055 Background: There is increasing evidence that paclitaxel and carboplatin are clinically active in the treatment of metastatic melanoma (MM). Nab-P is an albumin-bound paclitaxel with ability to bind SPARC (secreted protein acid rich in cysteine), that is overexpressed in MM and associated with poor prognosis. This study explores the clinical activity of the combination of nab-P and C in patients (pts) with stage IV melanoma and SPARC correlatives. Methods: A parallel phase II trial was conducted in pts with unresectable stage IV melanoma, who were either chemotherapy naïve (CN) or were previously treated (PT). A treatment regimen consisting of nab-P (100 mg/m2) and C (AUC 2) was administered on days 1, 8, and 15 of a 28 day cycle. The primary aim of this study was to assess whether tumor response rate (CR + PR by RECIST) was ≤15% vs ≥35% in the CN group and ≤5% vs ≥ 20% in the PT cohort. Major eligibility criteria: ≥18 years of age, ECOG PS ≤2, adequate organ function, platinum or taxane naive, peripheral neuropathy &lt; grade 2, and no untreated brain metastasis; no pregnant and/or nursing women. Tumor tissue was tested for SPARC and level 3 immunohistochemical staining was considered positive. Results: 76 pts (41-CN and 35 PT) enrolled from 11/2006 - 7/2007, 3 pts (2-CN, 1-PT) cancelled prior to starting treatment. The median number of cycles administered was 4 (range 1–18-CN and 1–10-PT). There were 11 (28.2%) confirmed responses (1 CR and 10 PRs) in the CN cohort (90% CI: 16.7–42.3%) and 3 (8.8%) confirmed responses (3 PRs) in the PT cohort (90% CI: 2.5–21.3%). Median PFS was 4.5 months (CN) and 4.1 months (PT). Median OS was 11.1 months (CN) and 10.9 months (PT).The most common severe toxicities in both groups (CTCAE ≥ grade 3) included neutropenia, thrombocytopenia, neuro-sensory, fatigue, nausea, and vomiting. PFS was not affected by SPARC positivity; however, based on limited data there is some evidence that OS may be longer with tumoral SPARC positivity (10.0 vs 12.8 mo; SPARC negative vs SPARC positive). Conclusions: The weekly combination of nab-P and C appears to be well tolerated with promising clinical activity as front line or salvage therapy in pts with MM. SPARC positivity may be associated with improved OS. No significant financial relationships to disclose.

Efficacy and Safety of the Combination of Genasense™ (Oblimersen Sodium, Bcl-2 Antisense Oligonucleotide), Fludarabine and Rituximab in Previously Treated and Untreated Subjects with Chronic Lymphocytic Leukemia.

Bcl-2 is an anti-apoptotic protein closely linked to chemotherapy resistance and inferior survival in patients (pts) with CLL. Genasense (G) enhances apoptosis induced by fludarabine (F), dexamethasone, and rituximab (R) in vitro. Despite limited single-agent activity in heavily pre-treated CLL pts, G significantly increased the rate of durable complete responses (CR) in combination with fludarabine (F) and cyclophosphamide in relapsed or refractory CLL (Rai, ASH 2004). Down-regulation of Bcl-2 sensitizes CLL cells to apoptosis induced by F and R. In order to examine the impact of G on the FR combination, we initiated a phase II study of the combination of FRG in pts with either previously untreated (UT) or relapsed, previously treated (PT) CLL who require systemic treatment. Eligibility includes: plts ≥ 50,000/mm3; serum Cr ≤ 1.5 mg/dL; adequate organ function; negative Coombs; no history of autoimmune hemolytic anemia. In cycle 1, G is given by continuous intravenous infusion at 1.5 mg/kg/d days 1 to 7. R is given in a dose-escalating schema: 125 mg/m2 on day 4 and 250mg/m2 on day 6, with F (25 mg/m2/d) on days 6 to 8. In subsequent 28-day cycles (up to 6), the dose of G is escalated to 3 mg/kg/d days 1 to 7, with R 375 mg/m2 on day 5 and F days 5 to 7.Results: To date, 24 pts have been enrolled (19 PT and 5 UT). Characteristics included: median age, 56.5 yrs (range 25–82 yrs); Rai stage III, 6 pts (4 PT and 2 UT) and IV, 6 pts (6 PT and 0 UT). Median prior regimens (PT pts), 2; 13/19 (68%) had received F and R previously. Median # cycles administered: 6 (both UT and PT). Four PT pts discontinued treatment before completing 6 cycles, 2 due to disease progression, and 2 with prolonged (> 4 week) Grade 3 thrombocytopenia/neutropenia. One PT pt completed only 3 cycles of R due to an R-related infusion reaction, but completed 6 cycles of G and F. Among the 5 UT pts, there was 1 case of grade 4 neutropenia. Among the 19 PT pts, there were 2 cases each of grade 4 thrombocytopenia and neutropenia. One of 5 UT pts had an SAE of reversible acute renal insufficiency. Seven of 19 PT pts (8 events total) experienced an SAE. These included R-related infusion reactions (2 pts), bacteremia (2 pts) and 1 pt each with fever, lymph node abscess, pneumonia, and thrombocytopenia/neutropenia. Responses have been observed in 5/5 UT pts (1 molecular CR (mCR), 1 nPR and 3 PR) and 10/19 PT pts (1 mCR, 2 nPR and 7 PR).Conclusions: 24 pts have been treated with the combination of FRG. Employing a three-day regimen of F, good tolerability and efficacy have been noted in relapsed/refractory patients. Based on these results, an additional cohort receiving a full 5-day regimen of F is ongoing with measurement of Genasense PK and bcl-2 intracellular levels (mRNA and protein).

Infections in Patients with Chronic Lymphocytic Leukemia Treated with Chemoimmunotherapy.

Chronic lymphocytic leukemia (CLL) is a clonal B cell malignancy characterized by defects in both cellular and humoral immunity. Each immune defect can be linked to common infectious complications affecting these patients. Predisposition to infections can be compounded by immunosuppression from cytotoxic chemotherapy. The purine analog fludarabine has been associated with a spectrum of infections caused by prolonged T lymphocyte depletion. The combination of fludarabine, cyclophosphamide, and rituximab (FCR) was developed based on complementary activity of the combination. FCR has significant activity in both chemotherapy-naïve (ChN) and previously treated (PrT) patients with CLL. We analyzed risk factors for infection and describe the infections experienced by both ChN and PrT patients during FCR treatment.We performed a retrospective review of medical records of 224 ChN and 177 PrT patients with CLL treated with the FCR regimen at MD Anderson Cancer Center from 7/99-8/02. Review was until relapse, death, or end of treatment. We focused on infectious events that occurred during and within 30 days of the last cycle of FCR treatment. Prophylaxis for herpes virus (valacyclovir) was recommended for all patients. Prophylaxis for P carinii (trimethoprim-sulfa) was recommended for all PrT patients and was done at the discretion of the treating physician for ChN patients.Infectious events were experienced by 96/224 (43.2%) ChN and 99/177 (56.2%) PrT patients. Causative agents were identified in 23% of events for ChN and 17% of events for the PrT patients (Table 1). There was a higher incidence of any event (p=0.012) and major infectious (MI) events (p<0.001) in PrT versus ChN patients. Major infections included pneumonia, sepsis and fever of unknown origin.Among ChN patients, univariate analysis identified low serum IgG (<700 mg/dL) (p=0.04), increased WBC count (p=0.049), and >2 chemotherapy courses (p=0.044) as risk factors for MI. Multivariate analysis identified low serum IgG (p=0.03) as the only predictor for MI. Among PrT patients, univariate analysis identified female gender (p=0.015) and baseline hemoglobin level (p=0.031) as risk factors for MI. Multivariate analysis identified increased WBC count (p=0.026) and high (>4.0 mg/dL) beta-2 microglobulin (ß2M) (p=0.027) as risk factors for MI in PrT patients.Among ChN and PrT patients none of the variables were found to be risk factor for minor infections (mI) in univariate analysis; multivariate analysis identified high ß2M (p=0.034) and splenomegaly (p=0.033) as significant predictors for occurrence of mI among PrT patients.For ChN patients, the nadir neutrophil count was not significantly associated with occurrence of mI or MI over the 6 courses of treatment. On the contrary, it was associated with occurrence of minor, major and any infection in the PrT patients. FCR is a higly effective and well-tolerated regimen. IgG <700 mg/dL was the main predictive variable for MI in ChN patients; baseline WBC count and ß2M >4.0 mg/L were the main predictive variables for MI in PrT patients.Table 1Confirmed Infectious agentChN Events/224 PtsPrT Events/177/PtsGram+ bacteria14Gram- bacteria41Candida species10Aspergillus species21Pneumocystis carinii20VZV36HSV64CMV31

Open-label, multicenter, phase II trial of ABI-007 in previously treated and previously untreated patients with metastatic malignant melanoma

7558 Background: ABI-007 (Abraxane TM), is an albumin-bound, nanoparticle form of paclitaxel with an improved therapeutic index that may be related to biological interactions with endogenous albumin receptors (eg, gp60) and binding proteins (eg, SPARC). The albumin-binding protein SPARC (osteonectin) was overexpressed in primary and metastatic malignant melanomas but not in normal melanocytes (Ledda et al, J Invest Derm 108:210, 1997) and was a predictor of clinical outcome in thin melanomas (Massi et al, Human Path 30:339, 1999). Methods: We conducted a Phase II study of ABX administered weekly for 3 weeks q4w without premedication in chemotherapy-naive (CN) (150 mg/m2) and previously treated (PT) (100 mg/m2) patients (pts) with measurable metastatic malignant melanoma (MMM). Results: 13 CN and 36 PT pts have been enrolled; 11 CN and 13 PT pts are currently evaluable for toxicity and response. Median age was 59 (range, 32–79); median number of metastatic sites was 2 (range, 1–8); median ECOG PS was 0 (range, 0–1). 8 CN and 12 PT pts had visceral involvement. The median number of monthly cycles received was 4 (range, 2–6) for CN pts and 4 (range, 1–6) for PT pts. 9 CN and 25 PT pts are continuing treatment. 84% (CN) and 92% (PT) of cycles were given without dose modification. No treatment-related (TR) deaths or TR grade (G) 4 toxicities occurred; no cases of febrile neutropenia were reported. TR G3 toxicities included fatigue (13%); neutropenia (13%); leukopenia (8%); rash (8%); alopecia, anemia, infection, lymphedema, motor neuropathy, and tumor pain (4% each). 3 CN and 9 PT pts have progressive disease. 2 CN pts have achieved a partial response; 1 additional CN and 4 PT pts with stable disease have continued on ABX without progression for >/= 24 weeks. Conclusions: ABX was well tolerated and resulted in long-term disease control in patients with MMM, some of whom had rapidly progressive disease while on previous therapy. Final study results will be presented. However, based on these encouraging early results in pts with aggressive visceral disease, further studies with ABX in MMM are being considered. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration American BioScience American BioScience