C17 Council

Innovative therapeutic approaches are needed to alleviate the burden of life-limiting, rare, and chronic conditions affecting children, adolescents, and young adults (CAYA). This includes a need for improved access to both clinical research and to non-approved or off-label therapies, together with, ultimately, more therapies achieving regulatory approval in Canada. The single patient study (SPS), also known as an open label individual patient (OLIP) study, was introduced by Health Canada to open access to non-marketed drugs where a clinical trial is not readily available, but the drug is considered too investigational to be managed on a standard Special Access Program. SPS is designed for patients who have a serious or life-threatening condition and have exhausted available treatment options. Our report summarizes this relatively new development in the Canadian regulatory environment and highlights the opportunities and challenges as identified by regulators, pharmaceutical representatives, academic researchers, and patient/parent advocates.

Simple SummaryLow-dose continuous oral chemotherapy may work together with targeted tyrosine kinase inhibitors to target a cancer’s ability to promote new blood supply (angiogenesis). We undertook a phase I study of the combination of oral topotecan and pazopanib in children with relapsed or refractory solid tumors to determine the optimal safe dose. Overall, the treatment combination was well tolerated with few severe side effects. Although there were no objective responses, stable disease was achieved in 40% of treated patients, suggesting that this combination may have a role in the maintenance setting following treatment with alternative chemotherapy regimens.Oral metronomic topotecan represents a novel approach to chemotherapy delivery which, in preclinical models, may work synergistically with pazopanib in targeting angiogenesis. A phase I and pharmacokinetic (PK) study of this combination was performed in children with relapsed/refractory solid tumors. Oral topotecan and pazopanib were each administered daily without interruption in 28-day cycles at five dose levels (0.12 to 0.3 mg/m2 topotecan and 125 to 160 mg/m2 pazopanib powder for oral suspension (PfOS)), with dose escalation in accordance with the rolling-six design. PK studies were performed on day 1 and at steady state. Thirty patients were enrolled, with 26 evaluable for dose-limiting toxicity (DLT), with median age 12 years (3–20). Toxicities were generally mild; the most common grade 3/4 adverse events related to protocol therapy were neutropenia (18%), thrombocytopenia (11%), lymphopenia (11%), AST elevation (11%), and lipase elevation (11%). Only two cycle 1 DLTs were observed on study, both at the 0.3/160 mg/m2 dose level comprising persistent grade 3 thrombocytopenia and grade 3 ALT elevation. No AEs experienced beyond cycle 1 required treatment discontinuation. The best response was stable disease in 10/25 patients (40%) for a median duration of 6.4 (1.7–45.1) months. The combination of oral metronomic topotecan and pazopanib is safe and tolerable in pediatric patients with solid tumors, with a recommended phase 2 dose of 0.22 mg/m2 topotecan and 160 mg/m2 pazopanib. No objective responses were observed in this heavily pre-treated patient population, although 40% did achieve stable disease for a median of 6 months. While this combination is likely of limited benefit for relapsed disease, it may play a role in the maintenance setting.

Background:The objectives of this study were to describe the impact of trial enrollment at diagnosis on event-free and overall survival in paediatric acute lymphoblastic leukaemic (ALL) using a population-based approach.Methods:We conducted a retrospective cohort study that included children newly diagnosed with ALL between 1 and 14 years of age. The data source was the Cancer in Young People in Canada (CYP-C) national paediatric cancer population-based database. We conducted univariate and multiple Cox proportional hazards models.Results:There were 2569 children with ALL; 1408 (54.8%) were enrolled on a clinical trial at initial diagnosis. Event-free survival at 5 years was 89.8%±0.9 vs 84.1%±1.2. (P<0.0001) for those enrolled and not enrolled on a clinical trial, respectively. Overall survival at 5 years was higher for those enrolled (94.1%±0.7) vs not enrolled (90.5%±1.0; P=0.001). In a model that adjusted for demographic, leukaemic and socioeconomic factors, enrollment on trials was significantly associated with better event-free survival (hazard ratio (HR) 0.67, 95% confidence interval (CI) 0.47–0.95; P=0.023), but not overall survival (HR 0.69, 95% CI 0.44–1.08; P=0.102).Conclusions:Event-free survival was significantly better in children with ALL enrolled on a clinical trial. Future research should identify barriers to clinical trial enrollment for children with ALL.

BackgroundPrimary objective was to describe the proportion of children newly diagnosed with cancer enrolled on a therapeutic clinical trial. Secondary objectives were to describe reasons for non-enrollment and factors associated with enrollment on trials.MethodsIn this retrospective cohort study, we included children newly diagnosed with cancer between 0 and 14 years of age and diagnosed from 2001 to 2012. We used data from the Cancer in Young People in Canada (CYP-C) national pediatric cancer population-based database. CYP-C captures all cases of pediatric cancer (0–14 years) diagnosed and treated at one of the 17 tertiary pediatric oncology centers in Canada. Non-enrollment was evaluated using univariate and multiple logistic regression analysis.ResultsThere were 9204 children with cancer included, of whom 2533 (27.5%) were enrolled on a clinical trial. The most common reasons cited for non-enrollment were lack of an available trial (52.2%) and physician choice (11.2%). In multiple regression, Asian and Arab/west Asian race were associated with lower enrollment (P = 0.006 and P = 0.032 respectively). All cancer diagnoses were more likely to be enrolled compared to astrocytoma and children with acute lymphoblastic leukemia had an almost 18-fold increased odds of enrollment compared to astrocytoma (P < 0.0001). Greater distance from the tertiary care center was independently associated with non-enrollment (P < 0.0001).ConclusionsIn Canada, 27.5% of children with cancer are enrolled onto therapeutic clinical trials and lack of an available trial is the most common reason contributing to non-enrollment. Future research should better understand reasons for lack of trial availability and physician preferences to not offer trials.

Tantalum powder is now being used as a bronchographic agent. Like most metal powders, tantalum powder carries an exposion hazard when nebulized. Therefore, we have tested non-explosive tantalum oxide (Ta2O5) as a substitute for metallic tantalum powder. No precautionary measures need be taken when tantalum oxide is used for bronchography. Although the radiodensity of tantalum oxide is less than that of tantalum by a factor of 0.5 per volume and 0.8 per mass, some technical advantages make it superior to metallic tantalum. The chemical inertness and the biological properties of tantalum and tantalum oxide are similar. No fibrogenic reactions due to non-cleared deposits have been found for up to one year in either man or experimental animals.

SUMMARYOptimum growth and maximum aflatoxin production by Aspergillus flavus were obtained on a basal medium containing 0.8 mg of zinc per liter. The effect of several other trace metals on the toxin production was evaluated. Aflatoxin production was inhibited by the presence of barium ions in the medium. Cadmium ions, in contrast, stimulated aflatoxin production.