Access to innovative therapies in pediatric oncology: Report of the nationwide experience in Canada.

BACKGROUND: The need for new therapies to improve survival and outcomes in pediatric oncology along with the lack of approval and accessible clinical trials has led to "out-of-trial" use of innovative therapies. We conducted a retrospective analysis of requests for innovative anticancer therapy in Canadian pediatric oncology tertiary centers for patients less than 30 years old between 2013 and 2020. METHODS: Innovative therapies were defined as cancer-directed drugs used (a) off-label, (b) unlicensed drugs being used outside the context of a clinical trial, or (c) approved drugs with limited evidence in pediatrics. We excluded cytotoxic chemotherapy, cellular products, and cytokines. RESULTS: We retrieved data on 352 innovative therapy drug requests. Underlying diagnosis was primary CNS tumor 31%; extracranial solid tumor 37%, leukemia/lymphoma 22%, LCH 2%, and plexiform neurofibroma 6%. RAS/MAP kinase pathway inhibitors were the most frequently requested innovative therapies in 28% of all requests followed by multi-targeted tyrosine kinase inhibitors (17%), inhibitors of the PIK3CA-mTOR-AKT pathway (8%), immune checkpoints inhibitors (8%), and antibody drug conjugates (8%). In 112 out of 352 requests, innovative therapies were used in combination with another anticancer agent. 48% of requests were motivated by the presence of an actionable molecular target. Compassionate access accounted for 52% of all requests while public insurance was used in 27%. Mechanisms of funding varied between provinces. CONCLUSION: This real-world data collection illustrates an increasing use of "out-of-trial" innovative therapies in pediatric oncology. This new field of practice warrants further studies to understand the impact on patient trajectory and equity in access to innovative therapies.

IKZF3/Aiolos H195Y mutation identified in a mouse model of B cell leukemia results in altered DNA binding and altered STAT5-dependent gene expression.

Precursor B cell acute lymphoblastic leukemia (Pre-B-ALL) arises from developing B cells and frequently involves mutations in genes encoding transcription factors. In this study, we investigated the function of mutations in the transcription factor IKZF3 (Aiolos), R137* and H195Y, discovered in a mouse model of pre-B-ALL. R137* IKZF3 mutation resulted in a truncated protein, while electrophoretic mobility shift assay showed that H195Y IKZF3 mutation resulted in a protein with altered DNA binding. 38B9 pre-B cell lines were generated expressing WT and H195Y IKZF3 proteins. Anti-IKZF3 ChIP-seq showed that H195Y IKZF3 interacted with a larger number of sites that were different than WT IKZF3. Treatment with interleukin-7 induced changes in gene expression in 38B9 cells expressing WT IKZF3, but did not induce any changes in gene expression in cells expressing H195Y IKZF3. Anti-STAT5 ChIP-seq showed that expression of H195Y IKZF3 resulted in redistribution of STAT5 binding sites in the genome. H195Y IKZF3 binding sites overlapped with a subset of STAT5 binding sites, including in the promoter of the Cish gene. These findings suggest that H195Y mutation of IKZF3 results in altered DNA binding specificity and altered binding of STAT5 to target genes.

Thiopurine Methyltransferase Intermediate Metabolizer Status and Thiopurine-Associated Toxicity During Maintenance Therapy in Childhood Acute Lymphoblastic Leukemia.

Mercaptopurine is a cornerstone of maintenance chemotherapy in childhood acute lymphoblastic leukemia (ALL). Its cytotoxic effects are mediated by 6-thioguanine nucleotides (TGNs) incorporation into lymphocyte DNA. Thiopurine methyltransferase (TPMT) inactivates mercaptopurine, and deficiency resulting from genetic variants increases TGN exposure and hematopoietic toxicity. Although mercaptopurine-dose reduction reduces toxicity risk without compromising relapse rate in patients with TPMT deficiency, dosing recommendations for those with moderately reduced activity (intermediate metabolizer (IM)) are less clear and their clinical impacts have yet to be established. This cohort study assessed the effect of TPMT IM status on mercaptopurine-associated toxicity and TGN blood exposure in pediatric patients with ALL initiated on standard dose mercaptopurine. Of 88 patients studied (mean age 4.8 years), 10 (11.4%) were TPMT IM, and all had undergone ≥ 3 cycles of maintenance therapy (80% completed). A larger proportion of TPMT IM than normal metabolizers (NM) had febrile neutropenia (FN) during the first two cycles of maintenance, reaching significance in the second cycle (57% vs. 15%, respectively; odds ratio = 7.33, P < 0.05). Compared to NM, FN events occurred more frequently and with prolonged duration in IM in cycles 1 and 2 (adjusted P < 0.05). IM had a 2.46-fold increased hazard ratio for FN, and about twofold higher TGN level than NM (P < 0.05). Myelotoxicity was more common in IM than NM (86% vs. 42%, respectively) during cycle 2 (odds ratio = 8.2, P < 0.05). TPMT IM initiated at a standard mercaptopurine dose are at greater risk for FN during early cycles of maintenance therapy, thus our findings support genotype-guided dose adjustment to reduce toxicity.

Osteosarcoma emboli presenting as chronic thromboembolic pulmonary hypertension in a child.

A 13-year-old girl presented with hypoxemia during adjuvant chemotherapy for an osteosarcoma of the left distal femur. She underwent an amputation complicated by a post-operative pulmonary embolism (PE). Three months post-operatively, she was admitted to hospital with severe hypoxemia and diagnosed with pulmonary hypertension on echocardiogram in the context of extensive bilateral PE on computed tomography. She was planned for elective pulmonary thromboendarterectomy, but rapidly deteriorated requiring emergent surgery. At the time of surgery, she was found to have extensive tumor emboli throughout both pulmonary arteries. She recovered well post-operatively but died 2 months later from progressive disease.

Association of Virtual Care Expansion With Environmental Sustainability and Reduced Patient Costs During the COVID-19 Pandemic in Ontario, Canada.

Importance: There is a growing focus on environmental sustainability in health care. Objective: To estimate the environmental and patient-level financial benefits associated with the widespread adoption of virtual care during the COVID-19 pandemic. Design, Setting, and Participants: This population-based cross-sectional study obtained data from linked administrative databases in the universal health care system of Ontario, Canada, from March 2020 to December 2021. Participants included all people with a physician claim for at least 1 episode of virtual care. Exposures: Patients were stratified by age, socioeconomic status quintiles, Charlson Comorbidity Index, and area of residence (rural or urban). Main Outcomes and Measures: The primary outcomes were total travel distance and estimated travel-related carbon dioxide emissions avoided owing to virtual care visits. Different model assumptions were used to account for electric and hybrid vehicles and public transit use. The secondary outcomes were estimated patient costs (gasoline, parking, or public transit expenses) avoided. Results: During the 22-month study period, 10 146 843 patients (mean [SD] age, 44.1 [23.1] years; 5 536 611 women [54.6%]) had 63 758 914 physician virtual care visits. These visits were associated with avoidance of 3.2 billion km of travel distance and between 545 and 658 million kg of carbon dioxide emissions. Patients avoided an estimated total of $569 to $733 million (Canadian [US $465-$599 million]) in parking, public transit, and gasoline costs. Carbon dioxide emission avoidance and patient cost savings were more apparent in patients living in rural areas, those with higher comorbidity, and those who were older than 65 years. Conclusions and Relevance: Results of this study suggest that virtual care was associated with a large amount of carbon dioxide emissions avoided owing to reduced patient travel and with millions of dollars saved in parking, gasoline, or public transit costs. These benefits are likely to continue as virtual care is maintained as part of the health care system.

Low-Dose Metronomic Topotecan and Pazopanib (TOPAZ) in Children with Relapsed or Refractory Solid Tumors: A C17 Canadian Phase I Clinical Trial.

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.

Avelumab in paediatric patients with refractory or relapsed solid tumours: dose-escalation results from an open-label, single-arm, phase 1/2 trial.

BACKGROUND: We report dose-escalation results from an open-label, phase 1/2 trial evaluating avelumab (anti-PD-L1) in paediatric patients with refractory/relapsed solid tumours. METHODS: In phase 1, patients aged < 18 years with solid (including central nervous system [CNS]) tumours for which standard therapy did not exist or had failed were enrolled in sequential cohorts of 3-6 patients. Patients received avelumab 10 or 20 mg/kg intravenously every 2 weeks. Primary endpoints were dose-limiting toxicities (DLTs) and grade ≥ 3 treatment-emergent adverse events (AEs). RESULTS: At data cut-off (27 July 2021), 21 patients aged 3-17 years had received avelumab 10 mg/kg (n = 6) or 20 mg/kg (n = 15). One patient had three events that were classified as a DLT (fatigue with hemiparesis and muscular weakness associated with pseudoprogression; 20 mg/kg cohort). Grade ≥ 3 AEs occurred in five (83%) and 11 (73%) patients in the 10 and 20 mg/kg cohorts, respectively, and were treatment-related in one patient (7%; grade 3 [DLT]) in the 20 mg/kg cohort. Avelumab exposure in paediatric patients receiving 20 mg/kg dosing, but not 10 mg/kg, was comparable or higher compared with approved adult dosing (10 mg/kg or 800 mg flat dose). No objective responses were observed. Four patients with CNS tumours (20 mg/kg cohort) achieved stable disease, which was ongoing in two patients with astrocytoma at cut-off (for 24.7 and 30.3 months). CONCLUSION: In paediatric patients with refractory/relapsed solid tumours, avelumab monotherapy showed a safety profile consistent with previous adult studies, but clinical benefits were limited.

A Canadian Study of Cisplatin Metabolomics and Nephrotoxicity (ACCENT): A Clinical Research Protocol.

BACKGROUND: Cisplatin, a chemotherapy used to treat solid tumors, causes acute kidney injury (AKI), a known risk factor for chronic kidney disease and mortality. AKI diagnosis relies on biomarkers which are only measurable after kidney damage has occurred and functional impairment is apparent; this prevents timely AKI diagnosis and treatment. Metabolomics seeks to identify metabolite patterns involved in cell tissue metabolism related to disease or patient factors. The A Canadian study of Cisplatin mEtabolomics and NephroToxicity (ACCENT) team was established to harness the power of metabolomics to identify novel biomarkers that predict risk and discriminate for presence of cisplatin nephrotoxicity, so that early intervention strategies to mitigate onset and severity of AKI can be implemented. OBJECTIVE: Describe the design and methods of the ACCENT study which aims to identify and validate metabolomic profiles in urine and serum associated with risk for cisplatin-mediated nephrotoxicity in children and adults. DESIGN: Observational prospective cohort study. SETTING: Six Canadian oncology centers (3 pediatric, 1 adult and 2 both). PATIENTS: Three hundred adults and 300 children planned to receive cisplatin therapy. MEASUREMENTS: During two cisplatin infusion cycles, serum and urine will be measured for creatinine and electrolytes to ascertain AKI. Many patient and disease variables will be collected prospectively at baseline and throughout therapy. Metabolomic analyses of serum and urine will be done using mass spectrometry. An untargeted metabolomics approach will be used to analyze serum and urine samples before and after cisplatin infusions to identify candidate biomarkers of cisplatin AKI. Candidate metabolites will be validated using an independent cohort. METHODS: Patients will be recruited before their first cycle of cisplatin. Blood and urine will be collected at specified time points before and after cisplatin during the first infusion and an infusion later during cancer treatment. The primary outcome is AKI, defined using a traditional serum creatinine-based definition and an electrolyte abnormality-based definition. Chart review 3 months after cisplatin therapy end will be conducted to document kidney health and survival. LIMITATIONS: It may not be possible to adjust for all measured and unmeasured confounders when evaluating prediction of AKI using metabolite profiles. Collection of data across multiple sites will be a challenge. CONCLUSIONS: ACCENT is the largest study of children and adults treated with cisplatin and aims to reimagine the current model for AKI diagnoses using metabolomics. The identification of biomarkers predicting and detecting AKI in children and adults treated with cisplatin can greatly inform future clinical investigations and practices.

CONTEXTE: Le cisplatine, un agent utilisé en chimiothérapie pour traiter les tumeurs solides, entraîne de l'insuffisance rénale aiguë (IRA); un facteur de risque connu de néphropathie chronique et de mortalité. Le diagnostic de l'IRA repose sur des biomarqueurs qui ne sont mesurables qu'après l'apparition d'une lésion rénale et d'une déficience fonctionnelle; ce qui empêche le diagnostic et le traitement précoce de la maladie. La métabolomique s'efforce d'établir le profil des métabolites impliqués dans le métabolisme des tissus cellulaires en relation avec des facteurs liés à la maladie ou au patient. Une étude canadienne portant sur la métabolomique et la néphrotoxicité du cisplatine (ACCENT) s'est amorcée, elle explore la puissance de la métabolomique dans l'identification de nouveaux biomarqueurs permettant de prédire le risque de néphrotoxicité du cisplatine et d'en distinguer la présence. L'objectif étant de mettre en œuvre des stratégies d'intervention précoce, dès l'apparition de l'IRA, et de limiter la gravité de la maladie. OBJECTIFS: Décrire la conception et la méthodologie de l'étude ACCENT. Cette étude vise à établir et à valider des profils métabolomiques, dans l'urine et le sérum, associés au risque de néphrotoxicité médiée par le cisplatine chez les enfants et les adultes. TYPE D'ÉTUDE: Étude de cohorte prospective. CADRE: Six centres canadiens d'oncologie (trois centres pédiatriques, un centre pour adultes et deux centres mixtes). SUJETS: L'étude porte sur 300 adultes et 300 enfants pour qui un traitement par cisplatine est prévu. MESURES: L'IRA sera confirmée par mesure de la créatinine et des électrolytes dans le sérum et l'urine au cours de deux cycles de perfusion de cisplatine. De nombreuses variables relatives au patient et à la maladie seront recueillies prospectivement avant et pendant le traitement. Les analyses métabolomiques des échantillons de sérum et d'urine seront effectuées par spectrométrie de masse. Une approche métabolomique non ciblée sera utilisée pour analyser les échantillons avant et après les perfusions de cisplatine pour identifier les biomarqueurs candidats d'une IRA découlant du traitement par cisplatine. Les métabolites candidats seront validés dans une cohorte indépendante. MÉTHODOLOGIE: Les patients seront recrutés avant le premier cycle de cisplatine. Le sang et l'urine seront recueillis à des moments précis, soit avant et pendant le traitement; plus précisément lors de la première perfusion, puis d'une perfusion subséquente au cours du traitement contre le cancer. Le principal critère d'évaluation est la présence d'IRA, laquelle sera établie selon la définition classique fondée sur la mesure de la créatinine sérique et d'une autre définition fondée sur les anomalies électrolytiques. Un examen des dossiers trois mois après la fin du traitement par cisplatine sera effectué afin de documenter la santé rénale et la survie des patients. LIMITES: Il pourrait être impossible de corriger tous les facteurs confusionnels mesurés et non mesurés lors de l'évaluation de la prédiction de l'IRA à l'aide de profils de métabolites. La collecte de données sur plusieurs sites sera un défi. CONCLUSION: ACCENT est la plus vaste étude portant sur des enfants et des adultes traités avec le cisplatine; cette étude tente de revoir le modèle actuel en utilisant la métabolomique pour diagnostiquer l'IRA. L'identification de biomarqueurs permettant de prédire et de détecter l'IRA chez les enfants et les adultes traités par cisplatine pourrait grandement éclairer les futures études et pratiques cliniques. RENSEIGNEMENTS SUR L'ENREGISTREMENT DE L'ESSAI CLINIQUE: ClinicalTrials.gov, insuffisance rénale induite par le cisplatine, NCT04442516.

Bleomycin-associated Lung Toxicity in Childhood Cancer Survivors.

Pulmonary disease is a significant morbidity among childhood cancer survivors. The aim of this study was to characterize the pulmonary dysfunction experienced by childhood cancer survivors treated with bleomycin. A cross-sectional analysis of pulmonary function testing (PFT) in survivors treated with bleomycin was preformed. The most recent posttherapy PFT was assessed. Spirometry and lung volumes were categorized as normal, restrictive, obstructive, or mixed. Diffusing capacity of carbon monoxide (DLCO) was categorized as normal or abnormal. PFT data of 143 survivors was analyzed. PFTs were performed a median of 2.3 years (interquartile range, 1.4 to 4.9) from completion of therapy. Spirometry was abnormal in 58 (41%), only 5 (9%) had respiratory symptoms. Forty-two (70%) had obstructive, 11 (18%) restrictive, and 5 (9%) mixed ventilatory defects. The majority of abnormalities were mild (91%). DLCO was abnormal in 27. Reductions were mild in 96%. Patients with a history of relapse were more likely to develop abnormalities in spirometry and/or DLCO (odds ratio=5.02, 95% confidence interval: 1.3-19.4, P=0.01; odds ratio=3.47, 95% confidence interval: 1.01-11.9, P=0.03). Asymptomatic abnormalities of PFT are common among childhood cancer survivors treated with bleomycin and associated with a history of relapse. Research studying the risk for clinical progression of this dysfunction is warranted.

A phase I study of histone deacetylase inhibitor, pracinostat (SB939), in pediatric patients with refractory solid tumors: IND203 a trial of the NCIC IND program/C17 pediatric phase I consortium.

BACKGROUND: Pracinostat (SB939) is a potent oral inhibitor of class 1, 2, and 4 histone deacetylases (HDAC). The adult recommended phase II dose (RP2D) is 60 mg po three times per week (t.i.w.) for 3 weeks every 4 weeks. This study assessed the toxicities and pharmacokinetics of pracinostat and determined the RP2D in children with refractory solid tumors. METHODS: Pediatric patients with refractory solid tumors were treated with oral pracinostat t.i.w. for 3 consecutive weeks, followed by 1 week off dosing. Three dose levels-25, 35, and 45 mg/m(2) were evaluated using a standard 3 + 3 cohort design. Pharmacokinetic (PK) studies were optional. RESULTS: Twelve patients were enrolled. The most common diagnosis was Ewing sarcoma. Most adverse events (AEs) were hematological with five (40%) patients experiencing grade 3 neutropenia. Non-hematological AEs were generally grade 1. No dose limiting toxicities occurred. More hematological and non-hematological AEs occurred at 45 mg/m(2) : Two of five patients experienced Grade 3 neutropenia and one each Grade 3 thrombocytopenia and leucopenia, Grade 1 fatigue and anorexia occurred in three. The RP2D was declared to be 45 mg/m(2) (comparable to an adult dose of 80 mg). One patient had a best response of stable disease (duration of 2.9 months). Three patients on 25 mg/m(2) and one each on 35 and 45 mg/m(2) participated in the PK study. No dose related changes in Cmax or AUC occurred. CONCLUSIONS: Pracinostat is reasonably well tolerated in children with refractory solid tumors. The RP2D is 45 mg/m(2) .

Cranial nerve palsies in childhood parameningeal rhabdomyosarcoma.

BACKGROUND: Children with parameningeal rhabdomyosarcoma (PM RMS) and cranial nerve palsy (CNP) are at risk for permanent neurologic dysfunction. Clinicians often consider the use of emergent therapies such as expedited radiation and/or corticosteroids; however, there is a paucity of information describing the natural history of CNP in PM RMS. We sought to describe the clinical features of patients with PM RMS plus associated CNP and to evaluate the patient, disease, and treatment-related factors that impacted neurologic recovery. METHODS: We conducted a retrospective review of PM RMS cases treated at the Hospital for Sick Children between 1985 and 2010. RESULTS: Thirty-five children were treated for PM RMS, 19 (54%) of whom presented with CNP. Children with CNP were nine times more likely to have other high-risk features (cranial base bony erosion and/or intracranial extension) at the time of presentation than children without CNP (OR 9.6, 95% CI 1.69, 54.79, P = 0.013). In addition to commencing chemotherapy, 13 patients (68%) received expedited RT and corticosteroids, four (21%) corticosteroids alone, and two (11%) received only standard chemotherapy and RT. At last follow up of the 11 survivors, neurologic recovery was complete in five (45%), partial in five (45%), and absent in one (9%). CONCLUSIONS: In our cohort, recovery of PM RMS associated CNP was often incomplete despite multi-modal therapy. A larger cohort of patients is required to determine the utility of emergent initiation of radiation or corticosteroids. This study will facilitate the counseling of future families on the long-term neurologic recovery CNP in PM RMS.