A Randomized Phase IIb Trial of myo-Inositol in Smokers with Bronchial Dysplasia.

Previous preclinical studies and a phase I clinical trial suggested that myo-inositol may be a safe and effective lung cancer chemopreventive agent. We conducted a randomized, double blind, placebo-controlled phase IIb study to determine the chemopreventive effects of myo-inositol in smokers with bronchial dysplasia. Smokers with ≥1 site of dysplasia identified by autofluorescence bronchoscopy-directed biopsy were randomly assigned to receive oral placebo or myo-inositol, 9 g once a day for 2 weeks, and then twice a day for 6 months. The primary endpoint was change in dysplasia rate after 6 months of intervention on a per-participant basis. Other trial endpoints reported herein include Ki-67 labeling index, blood and bronchoalveolar lavage fluid (BAL) levels of proinflammatory, oxidant/antioxidant biomarkers, and an airway epithelial gene expression signature for PI3K activity. Seventy-four (n = 38 myo-inositol and n = 36 placebo) participants with a baseline and 6-month bronchoscopy were included in all efficacy analyses. The complete response and the progressive disease rates were 26.3% versus 13.9% and 47.4% versus 33.3%, respectively, in the myo-inositol and placebo arms (P = 0.76). Compared with placebo, myo-inositol intervention significantly reduced IL6 levels in BAL over 6 months (P = 0.03). Among those with a complete response in the myo-inositol arm, there was a significant decrease in a gene expression signature reflective of PI3K activation within the cytologically normal bronchial airway epithelium (P = 0.002). The heterogeneous response to myo-inositol suggests a targeted therapy approach based on molecular alterations is needed in future clinical trials to determine the efficacy of myo-inositol as a chemopreventive agent. Cancer Prev Res; 9(12); 906-14. ©2016 AACR.

Impact of disease progression date determination on progression-free survival estimates in advanced lung cancer.

BACKGROUND: In patients with advanced lung cancer, overall survival is largely influenced by progression status. Because progression-free survival (PFS)-based endpoints are controversial, the authors evaluated the impact of the progression date (PD) determination approach on PFS estimates. METHODS: Individual patient data from 21 trials (14 North Central Cancer Treatment Group trials and 7 Southwest Oncology Group trials) were used. The reported PD (RPD) was defined as either the radiographic scan date or the clinical deterioration date. PD was determined using Method 1 (M1), the RPD; M2, 1 day after the last progression-free scan; M3, midpoint between the last progression-free scan and the RPD; and M4, an interval-censoring approach. PFS was estimated using Kaplan-Meier (M1-M3), and maximum-likelihood (M4) methods. Simulation studies were performed to understand the impact of the length of time elapsed between the last progression-free scan and the PD on time-to-progression estimates. RESULTS: PFS estimates using the RPD were the highest, and M2 was the most conservative. M3 and M4 were similar because the majority of progressions occurred during treatment (ie, frequent disease assessments). M3 was influenced less by the length of the assessment schedules (percentage difference from the true time-to-progression, <1.5%) compared with M1 (11% to 30%) and M2 (-8% to -29%). The overall study conclusion was unaffected by the method used for randomized trials. CONCLUSIONS: The magnitude of difference in the PFS estimates was large enough to alter trial conclusions in patients with advanced lung cancer. The results indicate that standards for PD determination, the use of sensitivity analyses, and randomized trials are critical when designing trials and reporting efficacy using PFS-based endpoints.

Endpoints in phase II trials for advanced non-small cell lung cancer.

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 trials for advanced non-small cell lung cancer. METHODS: Individual data of 284 patients from four phase II 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 model for OS, stratified by trial. Subsequently, Cox proportional hazards 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 index (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 combination in landmark analyses (hazard ratio, 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: FFS or PFS at 12 weeks is a stronger predictor of subsequent patient survival compared with tumor response and should be routinely used as endpoints in phase II trials for advanced non-small cell lung cancer.

Evaluation of glutathione metabolic genes on outcomes in advanced non-small cell lung cancer patients after initial treatment with platinum-based chemotherapy: an NCCTG-97-24-51 based study.

INTRODUCTION: We evaluated the role of glutathione-related genotypes on overall survival, time to progression, adverse events, and quality of life (QOL) in stage IIIB/IV non-small cell lung cancer patients who were stable or responding from initial treatment with platinum-based chemotherapy and subsequently randomized to receive daily oral carboxyaminoimidazole or a placebo. METHODS: Of the 186 total patients, 113 had initial treatment with platinum therapy and DNA samples of whom 46 also had QOL data. These samples were analyzed using six polymorphic DNA markers that encode five important enzymes in the glutathione metabolic pathway. Patient QOL was assessed using the Functional Assessment of Cancer Therapy-Lung and the UNISCALE QOL questionnaires. A clinically significant decline in QOL was defined as a 10% decrease from baseline to week-8. Multivariate analyses were used to evaluate the association of the genotypes on the four endpoints. RESULTS: Patients carrying a GCLC 77 genotype had a worse overall survival (hazard ratio (HR) = 1.5, p = 0.05). Patients carrying the GPX1-CC genotype had a clinically significant decline in the UNISCALE (odds ratio (OR): 7.5; p = 0.04), total Functional Assessment of Cancer Therapy-Lung score (OR: 11.0; p = 0.04), physical (OR: 7.1; p = 0.03), functional (OR: 5.2; p = 0.04), and emotional well-being constructs (OR: 23.8; p = 0.01). CONCLUSIONS: Genotypes of glutathione-related enzymes, especially GCLC, may be used as host factors in predicting patients' survival after platinum-based chemotherapy. GPX1 may be an inherited factor in predicting patients' QOL. Further investigation to define and measure the effects of these genes in chemotherapeutic regimens, drug toxicities, disease progression, and QOL are critical.