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Clinical trial design
Published in Charles F. Levenback, Ate G.J. van der Zee, Robert L. Coleman, Clinical Lymphatic Mapping in Gynecologic Cancers, 2022
Scott Jordan, Brian M. Slomovitz
GROINSV3/CV2020 is a NCI cancer therapy evaluation program (CTEP)-approved study to investigate prospectively if increasing radiotherapy to 56 Gy and adding chemosensitization can adequately treat patients with greater than 2 mm of lymph node involvement or with extracapsular spread. This is a prospective phase II trial only enrolling patients after SLN biopsy. Similar to the other GROINS studies, early stopping rules are incorporated to prevent an ineffective treatment.
Regulation of Gastrointestinal Neuropeptide Gene Expression and Processing
Published in Edwin E. Daniel, Neuropeptide Function in the Gastrointestinal Tract, 2019
The human and rat prepro GRP consist of 148 and 147 amino acids, respectively, as originally deduced from cloning studies (see Figure 6A)·182,185 The human GRP1—27 and rat GRP1—29 structures are preceded by a signal peptide of presumably 23 amino acid length, and followed by an amide-donating Gly residue, a double base (Lys–Lys) processing site, and CTEP, being 95 (residues 54 to 148) and 92 amino acids, respectively.182,185 However, three other human prepro GRPs have been deduced from two other cloning studies; form I had a substitution at amino acid position 134 (Pro instead of Leu),181,183 whereas the other two types had major nucleotide deletions (see Section IV.A), resulting in the deletion of amino acid residues 128 to 134 (form II) and the deletion of amino acid residues 122 to 148 together with an insertion of 17 new residues (form III), the latter two prepro-GRPs being 141 and 138 residues, respectively.181,183 The rat CTEP in brain seems to be homologous to the human form III prepro GRP.181
Dose-Finding Trials in Pediatric Oncology
Published in John O’Quigley, Alexia Iasonos, Björn Bornkamp, Handbook of Methods for Designing, Monitoring, and Analyzing Dose-Finding Trials, 2017
Arzu Onar-Thomas, Fridtjof Thomas
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).
An evaluation of selumetinib for the treatment of neurofibromatosis type 1-associated symptomatic, inoperable plexiform neurofibromas
Published in Expert Review of Precision Medicine and Drug Development, 2021
Laura K. Metrock, Mina Lobbous, Bruce Korf
Selumetinib showed evidence of clinical efficacy in the phase 1 and 2 trials in children and young adults with inoperable plexiform neurofibromas. The phase 1 study was a multi-center study conducted between September 2011 and February 2014. The trial was developed by investigators at the National Cancer Institute (NCI) in collaboration with the NCI Cancer Therapy Program (CTEP). Twenty-four children of ages 3 to 18 years were enrolled and received selumetinib 20–30 mg/m2 twice daily in a continuous dosing schedule. Partial response, defined as a decrease in tumor volume by 20% from baseline, was observed in 17 of the 24 patients (71%). Response was seen in 9 of 12 patients receiving 20 mg/m2 twice daily, five of six patients receiving 25 mg/m2 twice daily, and 3 of 6 patients receiving 30 mg/m2 twice daily. Disease progression defined as an increase in tumor volume by more than 20% from baseline was not observed at the time of the analysis. Additionally, subjective decreases in tumor-related pain, disfigurement, and functional impairment were reported [14].
Spectrum of PD-1 and PD-L1 inhibitor cutaneous adverse events in skin of color: a retrospective, single-institutional study in an urban community
Published in Acta Oncologica, 2021
Tracy Ngo, Claudia Hossain, Anthony K. Guzman, Balazs Halmos, Yevgeniy Balagula, Beth McLellan
We conducted a retrospective analysis of the electronic medical records of a tertiary academic medical center with a dedicated supportive oncodermatology service and identified patients who received PD-1 or PD-L1 immunotherapy from 2016 to 2019 and referred to dermatology. Patients from that cohort were then evaluated for possible cutaneous adverse events from their immunotherapy. Dermatological findings were separated into 15 categories for comparison. Cases with unusual morphologies that cannot be described with classic nomenclature were listed as ‘other.’ Method of diagnosis, treatment, and outcomes of cutaneous adverse events were recorded. Causality was assessed with WHO-UMC causality categories: certain, probable/likely, possible, unlikely, conditional/unclassified, and unassessable/unclassifiable. Grading of adverse events was assigned per the National Cancer Institute Cancer Therapy Evaluation Program (CTEP) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03, ranging from 1 to 5. Patient demographics, including gender, race, and ethnicity were summarized.
Lessons learned from exceptional responders
Published in Expert Review of Precision Medicine and Drug Development, 2019
Gopa Iyer, Jonathan E. Rosenberg
The above observations motivated the National Cancer Institute (NCI) to begin the Exceptional Responders Initiative (NCT02243592), a national study allowing physicians to submit pre-treatment tumor specimens (and normal tissue when possible) to the NCI from patients who experienced exceptional responses to anti-cancer therapy for detailed genomic analysis. The goal is to define the molecular etiology of these responses. Exceptional responders were defined as patients who had a complete response or durable (lasting ≥6 months) partial response to a therapy that resulted in ≤10% of patients experiencing such responses in the context of a clinical trial or based on historical experience with the agent. Patients were also eligible who experienced sustained complete or partial responses lasting ≥3 times the median response duration as described in the literature. The NCI’s Cancer Therapy Evaluation Program (CTEP) reviewed a decade of phase 2 clinical trials and identified an adequate number of patients who met the above criteria to make this effort feasible [13]. The study has now closed to accrual, and the results of the genomic analysis are pending.