Predictors of Success of Phase II Pediatric Oncology Clinical Trials.

BACKGROUND: There are limited data to predict which novel childhood cancer therapies are likely to be successful. To help rectify this, we sought to identify the factors that impact the success of phase II clinical trials for pediatric malignancies. MATERIALS AND METHODS: We examined the impact of 24 preclinical and trial design variables for their influence on 132 phase II pediatric oncology clinical trials. Success was determined by an objective assessment of patient response, with data analyzed using Fisher's exact test, Pearson's chi-square test, and logistic regression models. RESULTS: Trials that evaluated patients with a single histological cancer type were more successful than those that assessed multiple different cancer types (68% vs. 47%, 27%, and 17% for 1, 2-3, 4-7, and 8+; p < .005). Trials on liquid or extracranial solid tumors were more successful than central nervous system or combined trials (70%, 60%, 38%, and 24%; p < .005), and trials of combination therapies were more successful than single agents (71% vs. 28%; p < .005). Trials that added therapies to standard treatment backbones were more successful than trials testing novel therapies alone or those that incorporated novel agents (p < .005), and trials initiated based on the results of adult studies were less likely to succeed (p < .05). For 61% of trials (80/132), we were unable to locate any relevant preclinical findings to support the trial. When preclinical studies were carried out (52/132), there was no evidence that the conduct of any preclinical experiments made the trial more likely to succeed (p < .005). CONCLUSION: Phase II pediatric oncology clinical trials that examine a single cancer type and use combination therapies have the highest possibility of clinical success. Trials building upon a standard treatment regimen were also more successful. The conduct of preclinical experiments did not improve clinical success, emphasizing the need for a better understanding of the translational relevance of current preclinical testing paradigms. IMPLICATIONS FOR PRACTICE: To improve the clinical outcomes of phase II childhood cancer trials, this study identified factors impacting clinical success. These results have the potential to impact not only the design of future clinical trials but also the assessment of preclinical studies moving forward. This work found that trials on one histological cancer type and trials testing combination therapies had the highest possibility of success. Incorporation of novel therapies into standard treatment backbones led to higher success rates than testing novel therapies alone. This study found that most trials had no preclinical evidence to support initiation, and even when preclinical studies were available, they did not result in improved success.

Increased Survival for Children With Acute Myeloid Leukemia Results From Improved Postrelapse Treatment.

BACKGROUND: The treatment for pediatric acute myeloid leukemia (AML) has not changed significantly over the past 3 decades, yet outcomes have improved with cure rates increasing from 30% to over 60% of all newly diagnosed children over this period. This improvement in survival has been attributed to both treatment intensification and improved supportive care over the decades, although the precise impact of each remains unknown. PATIENTS AND METHODS: We retrospectively analyzed a unique cohort of 276 patients with de novo AML diagnosed in childhood, all treated with the same chemotherapy protocol over a 25-year period from 1986 to 2012. RESULTS: The contemporary cohort (2000-2012), compared with the historical cohort (1986-1999) had significantly improved overall survival (75% vs. 50%; hazard ratio, 2.17; 95% confidence interval, 1.15-2.93), lower disease-related mortality (38% vs. 19%, P=0.02) and were significantly more likely to receive an allogeneic transplant after relapse (stem cell transplantation [SCT], 73% vs. 12%; P<0.0001). Allogeneic transplant postrelapse was associated with a significantly improved survival across the entire cohort (overall survival 50% for allogeneic SCT vs. 12% for autologous or none, P<0.0001). There was no significant difference between the contemporary and historical cohorts in treatment-related mortality (13% vs. 7%, P=0.42) or relapse rates after induction (50% in older cohort vs. 40% in recent era, P=0.25), suggesting consistency of induction treatment efficacy and toxicity across the 2 periods. CONCLUSIONS: This data suggests improved survival in pediatric AML in the modern era has predominantly resulted from changes in treatment after relapse, including increased use of allogeneic SCT.

Clinical Importance of Myc Family Oncogene Aberrations in Epithelial Ovarian Cancer.

BACKGROUND: The Myc oncogene family has been implicated in many human malignancies and is often associated with particularly aggressive disease, suggesting Myc as an attractive prognostic marker and therapeutic target. However, for epithelial ovarian cancer (EOC), there is little consensus on the incidence and clinical relevance of Myc aberrations. Here we comprehensively investigated alterations in gene copy number, expression, and activity for Myc and evaluated their clinical significance in EOC. METHODS: To address inconsistencies in the literature regarding the definition of copy number variations, we developed a novel approach using quantitative polymerase chain reaction (qPCR) coupled with a statistical algorithm to estimate objective thresholds for detecting Myc gain/amplification in large cohorts of serous (n = 150) and endometrioid (n = 80) EOC. MYC, MYCN, and MYCL1 mRNA expression and Myc activity score for each case were examined by qPCR. Kaplan-Meier and Cox-regression analyses were conducted to assess clinical significance of Myc aberrations. RESULTS: Using a large panel of cancer cell lines (n = 34), we validated the statistical algorithm for determining clear thresholds for Myc gain/amplification. MYC was the most predominantly amplified of the Myc oncogene family members, and high MYC mRNA expression levels were associated with amplification in EOC. However, there was no association between prognosis and increased copy number or gene expression of MYC/MYCN/MYCL1 or with a pan-Myc transcriptional activity score, in EOC, although MYC amplification was associated with late stage and high grade in endometrioid EOC. CONCLUSION: A systematic and comprehensive analysis of Myc genes, transcripts, and activity levels using qPCR revealed that although such aberrations commonly occur in EOC, overall they have limited impact on outcome, suggesting that the biological relevance of Myc oncogene family members is limited to certain subsets of this disease.

A brief measure of vocational activity and community participation: development and reliability of the Activity and Participation Questionnaire.

OBJECTIVES: Social and economic marginalization are significant problems for many people living with mental illness. Clinicians and policy-makers have increased their focus on these aspects of recovery. Current outcome measures, however, do not support this focus, and detailed functional measures are not suitable for routine clinical use. This report describes the development and test-retest reliability of the Activity and Participation Questionnaire (APQ6); a self-report measure of vocational activity and social participation for routine use in community mental health services. METHOD: The APQ6 was developed from concepts of the Australian Bureau of Statistics Labour Force Surveys and Census. Field testing and consumer consultation were undertaken in New South Wales (NSW) mental health rehabilitation services. Test-retest reliability trials were conducted simultaneously by research teams in NSW and Queensland. RESULTS: Pairs of short-cycle test-retest reliability interviews were obtained from 129 mental health service consumers. Consumer feedback and test-retest reliability results at question and item levels indicate good construct validity. The measure has utility as both a telephone and a personal interview in community mental health settings. CONCLUSIONS: The reported psychometric properties support the proposed use of the APQ6 as a recovery-orientated measure focusing on vocational activity and community participation. The APQ6 is being introduced for routine use by NSW mental health services.