Background AT-101 is an oral inhibitor of the anti-apoptotic Bcl proteins (Bcl-2, Bcl-XL, Bcl-W, and Mcl-1) and an inducer of the pro-apoptotic proteins noxa and puma. We studied the efficacy of AT-101 in patients with recurrent chemosensitive extensive stage – small cell lung cancer (ES-SCLC). Methods Patients with recurrent “sensitive” SCLC (defined as no progression during and no disease recurrence < 2 months after completion of first-line platinum-based chemotherapy) were eligible. AT-101 was administered 20 mg orally daily for 21 out of 28 days each cycle for up to 6 cycles. The primary endpoint was the objective response rate. Results At the time of planned interim evaluation, none of the 14 evaluable patients enrolled in the first stage had any response to therapy and the study was closed permanently for further accrual. Three patients (21 %) achieved stable disease after two cycles of therapy. Grade 3 toxicities included anorexia, fatigue, and nausea/vomiting. Conclusions AT-101 is not active in patients with recurrent chemosensitive SCLC. Supported by N01-CM62205.

BACKGROUND:The authors investigated the putative surrogate endpoints of best response, complete response (CR), confirmed response, and progression-free survival (PFS) for associations with overall survival (OS), and as possible surrogate endpoints for OS. METHODS: Individual patient data from 870 untreated extensive stage small-cell lung cancer patients participating in 6 single-arm (274 patients) and 3 randomized trials (596 patients) were pooled. Patient-level associations between putative surrogate endpoints and OS were assessed by Cox models using landmark analyses. Trial-level surrogacy of putative surrogate endpoints were assessed by the association of treatment effects on OS and individual putative surrogate endpoints. Trial-level surrogacy measures included: R 2 from weighted least squares regression model, Spearman correlation coefficient, and R 2 from bivariate survival model (Copula R 2 ). RESULTS: Median OS and PFS were 9.6 (95% confidence interval [CI], 9.1-10.0) and 5.5 (95% CI, 5.2-5.9) months, respectively; best response, CR, and confirmed response rates were 44%, 22%, and 34%, respectively. Patient-level associations showed that PFS status at 4 months was a strong predictor of subsequent survival (hazard ratio [HR], 0.42; 95% CI, 0.35-0.51; concordance index 0.63; P < .01), with 6-month PFS being the strongest (HR, 0.41; 95% CI, 0.35-0.49; concordance index, 0.66, P < .01). At the trial level, PFS showed the highest level of surrogacy for OS (weighted least squares R 2 ¼ 0.79; Copula R 2 ¼ 0.80), explaining 79% of the variance in OS. Tumor response endpoints showed lower surrogacy levels (weighted least squares R 2 0.48). CONCLUSIONS: PFS was strongly associated with OS at both the patient and trial levels. PFS also shows promise as a potential surrogate for OS, but further validation is needed using data from a larger number of randomized phase 3 trials.

Background Continued cigarette smoking after small cell lung cancer (SCLC) diagnosis has been shown to shorten patients’ survival, but little is known about the impact of smoking and cessation on quality of life (QOL) profile (e.g., overall QOL, pain, fatigue, cough, dyspnea, appetite change, and performance status) in SCLC survivors (who survived at least 6 months post initial diagnosis). In this study, we sought to evaluate the relationship between cigarette smoking and QOL profiles in SCLC patients. Methods A total of 223 survivors were classified into five groups: never smokers, former smokers (quit more than 1 year prior to diagnosis), recent quitters (quit within 1 year surrounding diagnosis), late quitters (quit after 1 year post diagnosis) and never quitters. One hundred and sixty-eight of these survivors were matched with 334 lung-cancer-free controls on age, gender, and smoking status for comparative analysis. QOL scales were scored from 0 (worse) to 100 (best). Conditional logistic regression, linear mixed-effect models, and Wilcoxon signed rank tests were used. Results SCLC survivors consistently showed a significant deficit in QOL profile; e.g., mean overall QOL in patients was 17.5 points worse than the controls (p < 0.0001). Among all smokers, former smokers reported the best QOL profile, while late or never quitters reported the worst. The recent quitters showed an improving trend in QOL profile and lower percent of reduced appetite (an average of 43%) compared to the late or never quitters (58%). Conclusions Our study confirmed the negative impact of smoking on SCLC survivors’ QOL and found that smoking cessation surrounding the time of diagnosis could improve overall QOL and symptoms. The findings of this study provide evidence for oncologists to recommend smoking cessation to their SCLC patients.

III.

Hypothesis We conducted this pooled analysis to assess the prognostic value of pretreatment Quality of Life (QOL) assessments on overall survival (OS) in advanced non-small cell lung cancer (NSCLC). Methods Four hundred twenty patients with advanced NSCLC (stages IIIB with pleural effusion and IV) from six North Central Cancer Treatment Group trials were included in this study. QOL assessments included the single-item Uniscale (355 patients), Lung Cancer Symptom Scale (217 patients), and Functional Assessment of Cancer Therapy-Lung (197 patients). QOL scores were transformed to a 0 to 100 scale with higher scores representing better status and categorized using the sample median or clinically deficient score (CDS, ≤50 versus >50). Cox proportional hazards models stratified by study were used to evaluate the prognostic importance of QOL on OS alone and in the presence of other prognostic factors such as performance status, age, gender, body mass index, and laboratory parameters. Results Pretreatment QOL accessed by Uniscale was significantly associated with OS univariately (p < 0.0001). Uniscale (p < 0.0001; hazard ratio = 1.6 for the sample median and 2.0 for the CDS categorization) and body mass index were the only significant predictors of OS multivariately. The median survival of patients who had a Uniscale score less than or equal to the CDS (≤50) was 5.7 versus 11.1 months for the >50 group; and 7.8 versus 13 months for the less than or equal to sample median (≤83) group and >83 group, respectively. The Lung Cancer Symptom Scale and the Functional Assessment of Cancer Therapy-Lung total scores were not significant predictors of OS. Conclusions Pretreatment QOL measured by Uniscale is a significant and an independent prognostic factor for OS, and QOL should be routinely integrated as a stratification factor in advanced NSCLC trials.

This Phase I clinical trial has demonstrated that these 2-drug and 3-drug combinations are generally well tolerated and safely administered. The main DLTs in both regimens were hematologic, specifically thrombocytopenia. The 3-drug combination can be considered as a platform for future studies in specific tumor types.

Objective Protein kinase C iota (PKCι) is overexpressed in non-small cell lung (NSCLC), ovarian and pancreatic cancers where it plays a critical role in oncogenesis. The gold compound aurothiomalate (ATM) has been shown to inhibit PKCι signaling and exhibits potent anti-tumor activity in preclinical models. We sought to determine the maximum tolerated dose (MTD) of ATM. Methods We conducted a phase I dose escalation trial of ATM in patients with NSCLC, ovarian or pancreatic cancer. Patients received ATM IM weekly for three cycles (cycle duration 4 weeks) at 25 mg, 50 mg or 75 mg in a 3+3 design. The dose was not escalated for individual patients. Blood samples were analyzed for elemental gold levels. Patients were evaluated every four weeks for toxicity and every eight weeks for response. Results Fifteen patients were enrolled in this study. Six patients were treated at 25 mg, 7 patients at 50 mg, and 2 at 75 mg. There was 1 dose limiting toxicity at 25 mg (hypokalemia), one at 50 mg (urinary tract infection), and none at 75 mg. There were 3 grade 3 hematologic toxicities. The recommended MTD of ATM is 50 mg. Patients received treatment for a median of 2 cycles (range 1-3). There appeared to be a dose-related accumulation of steady-state plasma concentrations of gold consistent with linear pharmacokinetics. Conclusions In summary, this phase I study was successful in identifying ATM 50 mg IM weekly as the MTD. Future clinical investigations targeting PKCι are currently in progress.

Introduction We investigated the relationships between progression-free survival (PFS), response, confirmed response, and failure-free survival (FFS) with overall survival (OS) to assess their suitability as primary endpoints in phase II (P2) trials for advanced NSCLC. Methods Individual data of 284 patients from 4 P2 trials were pooled. Progression status and response were modeled as time dependent variables in a multivariable (adjusted for baseline age, gender, stage, and performance status) Cox proportional hazards (PH) model for OS, stratified by trial. Subsequently, Cox PH models were used to assess the impact of PFS, response, confirmed response and FFS on subsequent survival, using landmark analysis at 8, 12, 16, 20, and 24 weeks. Model discrimination was evaluated using the concordance (c) index. Results The overall median OS, PFS and FFS were 9.6, 3.7 and 2.8 months, and the response and confirmed response rates were 21% and 15% respectively. Both progression status and response as time dependent covariates were significantly associated with OS (p<0.0001; p=0.009). PFS and FFS at 12 weeks significantly predicted for subsequent survival with the strongest c-index and hazard ratio (HR) combination in landmark analyses (HR, c-index: PFS - 0.39, 0.67; FFS - 0.37, 0.67). The c-indices for response and confirmed response were low (0.59-0.60), indicating their inability to sufficiently discriminate subsequent patient survival outcomes. Conclusions Failure-free survival or progression-free survival at 12 weeks is a stronger predictor of subsequent patient survival compared to tumor response, and should be routinely used as endpoints in phase II trials for advanced NSCLC.