Dose-Finding Trials in Pediatric Oncology
John O’Quigley, Alexia Iasonos, Björn Bornkamp in Handbook of Methods for Designing, Monitoring, and Analyzing Dose-Finding Trials, 2017
Addition of another pill results in a BSA-adjusted dose higher than the target dose but closer than what it would have been if another pill were not added. Then, again, the BSA-adjusted dose falls below this target dose as BSA increases further until the next pill is added to the administered dosage. The relative effect of adding another pill on the BSA-adjusted dosage diminishes as BSA increases, which gives rise to the funnel-shaped appearance of the deliverable dosage as a function of BSA. As is apparent from Figure 4.1, while some variation from the target dose is present for both 130 and 170 mg/m BSA-adjusted actual daily doses, the proposed dose levels are sufficiently far apart (the two “funnels” are clearly separated) to enable the study of this agent in pediatric populations even when some variations from targeted doses are preset. To illustrate this further, we will use a vignette from a recently published PBTC trial [19] of GDC-0449 (PBTC-025, NCT00822458). GDC-0449 (Vismodegib, Genentech, San Francisco, CA) was a first-in-class SHH pathway inhibitor via the inhibition of SMO. SMO is a membrane-associated protein that functions downstream of the PTCH1 gene in the SHH pathway [19]. Initial phase I trial of GDC-0449 was conducted for a population of patients with advanced, metastatic solid tumors [24]. An impressive response rate of 60% was observed in patients with basal cell carcinoma on this trial. There was one additional response that was noted which occurred in a patient with metastatic medulloblastoma [24]. Medulloblastoma is a malignant brain tumor that occurs predominantly in children, though it can also occur in adults. The SHH pathway is known to be aberrant in a subset of these patients. Responses are exceedingly rare in patients with recurrent/progressive medulloblastoma, and thus, a phase I trial was initiated by the PBTC to study the safety and tolerability of this agent in pediatric patients with recurrent medulloblastoma based on an abundance of preclinical data and rationale [26, 27] as well as the response noted above. The trial also aimed to study the PK characteristics of this agent in children and even more importantly, to determine whether developmental toxicities specific to children such as growth defects in bones and teeth in skeletally immature patients were associated with the use of this agent as suggested by preclinical experiments conducted in young mice [28, 29]. GDC-0449 was supplied by Genentech and was distributed by the National Cancer Institute’s (NCI) Cancer Therapy Evaluation Program (CTEP). The pediatric trial was designed to use safety and PK data to select between two dose levels, namely 85 and 170 mg/m, to recommend for the subsequent phase II trial. The adult recommended dose was 150 mg/day, which was equivalent to the 85 mg/m dose level. Enrollment was initiated at 85 mg/m, and barring excessive toxicity, treatment of six patients per dose level was planned where patients were to be enrolled in cohorts of three. The safety observation period was defined as the first 28 days of treatment, and a lower dose, 60 mg/m, was provided in the event that 85 mg/m turned out to be unsafe. Similar to the escalation rules used in the 3 + 3 design, if no more than one patient in a cohort of six patients experienced a dose-limiting toxicity (DLT), then the dose would be escalated to 170 mg/m and a similar approach would be used to study its safety. If both dose levels proved to be safe (i.e., no more than one DLT in six patients), then the PK parameters would be used to choose the dose to be carried forward to the phase II trial.
DTI of Developmental and Pediatric Disorders
Andrei I. Holodny in Functional Neuroimaging, 2019
The treatment of medulloblastoma involves a combination of surgery, radiation, and chemotherapy and is associated with significant morbidity in children. Patients who survive treatment often develop significant cognitive and neuropsychological deficits (100,101). Radiation, in particular, is known to damage white matter in the brain (102). DTI has demonstrated its unique ability to quantitatively assess treatment-induced white matter injury in a study involving posttreatment medulloblastoma survivors (86). FA. values were found to be significantly reduced in multiple regions that appeared normal on conventional MR images, defining a new role for DTI as a marker in treatment-induced white matter injury.
Targeting Subgroup-specific Cancer Epitopes for Effective Treatment of Pediatric Medulloblastoma
Surinder K. Batra, Moorthy P. Ponnusamy in Gene Regulation and Therapeutics for Cancer, 2021
Although the mainstay of therapy for medulloblastoma remains unchanged, current focus has shifted to not only improving five-year event-free survival but also long-term treatment-related sequelae resulting from cytotoxic therapies instituted during critical periods of growth and development. With a more refined understanding of molecular pathways implicated in phenotypic transformation to medulloblastoma, multiple viable pre-clinical models have been generated for the SHH and WNT subgroups, thereby facilitating the development and testing of targeted anti-neoplastic therapies, some of which are now under clinical investigation. Contrarily, the non-SHH/WNT subgroups 3 and 4, which carry the highest incidence and worst prognosis, have few good pre-clinical models. Thus, good conceptual therapeutic tactics have been restricted to in vitro successes and xenograft mouse models. With continued refinement of our understanding of these two subgroups, the generation of the first pre-clinical [non-xenograft] mouse model of non-SHH/WNT subgroup medulloblastoma may be undertaken, allowing the fair assessment of targeted therapies, such as myc-inhibitors, kinase inhibitors, HDAC inhibitors, and immunotherapy, on tumor behavior in the context of non-SHH/WNT medulloblastoma. Hereafter, the largest impact may be instituted on the subgroup with the direst need for such therapies given the poor overall survival and high-risk of the fragile patients afflicted with this malignancy.
Intellectual, educational, and situation-based social outcome in adult survivors of childhood medulloblastoma
Published in Developmental Neurorehabilitation, 2019
Virginie Kieffer, Mathilde P. Chevignard, Georges Dellatolas, Stephanie Puget, Frederic Dhermain, Jacques Grill, Dominique Valteau-Couanet, Christelle Dufour
Purpose: To investigate intellectual and situation-based social outcome and educational achievement in adult survivors of childhood medulloblastoma and analyse factors influencing outcome Methods: We collected demographic, medical and cognitive data, and social and educational outcome at a mean time since the end of treatments of 14.9 years in 58 adults, aged 19–35 years, consecutively treated in a single cancer center between 1989 and 2005. Results: Ten survivors had severe intellectual disability, 12 were still studying, 23 had a regular employment and 13 were unemployed. Full Scale Intellectual Quotient, assessed 6.6 years after the end of treatments, ranged from 46 to 131. It was strongly associated with educational achievement and significantly lower in patients who experienced postoperative cerebellar mutism, and when parental education level was low. Conclusion: These factors should be systematically considered at diagnosis in order to offer adequate and timely assessments and interventions.
Genetics of medulloblastoma: clues for novel therapies
Published in Expert Review of Neurotherapeutics, 2010
Sara Onvani, Arnold B Etame, Christian A Smith, James T Rutka
Medulloblastoma is the most common malignant brain tumor in children. Current medulloblastoma therapy entails surgery, radiation and chemotherapy. The 5-year survival rate for patients ranges from 40 to 70%, with most survivors suffering from serious long-term treatment-related sequelae. Additional research on the molecular biology and genetics of medulloblastoma is needed to identify robust prognostic markers for disease-risk stratification, to improve current treatment regimes and to discover novel and more effective molecular-targeted therapies. Recent advances in molecular biology have led to the development of powerful tools for the study of medulloblastoma tumorigenesis, which have revealed new insights into the molecular underpinnings of this disease. Here we discuss the signaling pathway alterations implicated in medulloblastoma pathogenesis, the techniques used in molecular profiling of these tumors and recent molecular subclassification schemes. Particular emphasis is given to the identification of novel molecular targets for less toxic, patient-tailored therapeutic approaches.
SHH inhibitors for the treatment of medulloblastoma
Published in Expert Review of Neurotherapeutics, 2015
Ayman Samkari, Jason White, Roger Packer
Medulloblastoma is the most common malignant brain tumor of childhood. It is currently stratified into four molecular variants through the advances in transcriptional profiling. They include: wingless, sonic hedgehog (SHH), Group III, and Group IV. The SHH group is characterized by constitutive activation of the SHH signaling pathway, and genetically characterized by mutations in patched homolog 1 (PTCH1) or other downstream pathway mutations. SHH inhibitors have become of great clinical interest in treating SHH-driven medulloblastoma. Many inhibitors are currently in different stages of development, some already approved for other SHH-driven cancers, such as basal cell carcinoma. In vitro and in vivo medulloblastoma studies have shown efficacy and these findings have been translated into Phase I and II clinical trials. In this review, we present an overview of SHH medulloblastoma, as well as a discussion of currently available SHH inhibitors, and the challenges associated with their use.
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