A phase 1 study of prexasertib (LY2606368), a CHK1/2 inhibitor, in pediatric patients with recurrent or refractory solid tumors, including CNS tumors: A report from the Children's Oncology Group Pediatric Early Phase Clinical Trials Network (ADVL1515)

2021 ◽  
Author(s):  
Thomas Cash ◽  
Elizabeth Fox ◽  
Xiaowei Liu ◽  
Charles G. Minard ◽  
Joel M. Reid ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Solid Tumors ◽  
Early Phase ◽  
Pediatric Patients ◽  
Phase 1 ◽  
Cns Tumors ◽  
Oncology Group ◽  
Phase 1 Study ◽  
Early Phase Clinical Trials

scholarly journals Phase 1 Study of Valproic Acid in Pediatric Patients with Refractory Solid or CNS Tumors: A Children's Oncology Group Report

2010 ◽  
Vol 17 (3) ◽  
pp. 589-597 ◽  
Author(s):  
Jack M. Su ◽  
Xiao-Nan Li ◽  
Patrick Thompson ◽  
Ching-Nan Ou ◽  
Ashish M. Ingle ◽  
...  
Keyword(s):  
Valproic Acid ◽  
Pediatric Patients ◽  
Phase 1 ◽  
Cns Tumors ◽  
Oncology Group ◽  
Phase 1 Study ◽  
Group Report

scholarly journals A phase 1 study of cabozantinib in children and adolescents with recurrent or refractory solid tumors, including CNS tumors: Trial ADVL1211, a report from the Children's Oncology Group

2018 ◽  
Vol 65 (8) ◽  
pp. e27077 ◽  
Author(s):  
Meredith K. Chuk ◽  
Brigitte C. Widemann ◽  
Charles G. Minard ◽  
Xiaowei Liu ◽  
AeRang Kim ◽  
...  
Keyword(s):  
Children And Adolescents ◽  
Solid Tumors ◽  
Phase 1 ◽  
Cns Tumors ◽  
Oncology Group ◽  
Phase 1 Study

Understanding patient expectations in early-phase clinical trials

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 6543-6543
Author(s):  
K. P. Weinfurt ◽  
D. M. Seils ◽  
J. P. Tzeng ◽  
K. L. Compton ◽  
D. P. Sulmasy ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Early Phase ◽  
Positive Attitude ◽  
Phase 1 ◽  
Experimental Therapy ◽  
High Expectations ◽  
Early Phase Trials ◽  
Semistructured Interviews ◽  
Two Factors ◽  
Early Phase Clinical Trials

6543 Background: Participants in early-phase clinical trials have reported high expectations of benefit from their participation. There is concern that participants misunderstand the trials to which they have consented. Such concerns are based on assumptions about what patients mean when they respond to questions about likelihood of benefit. In this study, we explored some of these assumptions. Methods: Participants were 27 women and 18 men in phase 1 or 2 oncology trials and randomized to 1 of 3 interview protocols corresponding to 3 target questions about likelihood of benefit: frequency-type (‘Out of 100 patients who participate in this study, how many do you expect will have their cancer controlled as a result of the experimental therapy?‘); belief-type (‘How confident are you that the experimental therapy will control your cancer?‘); and vague (‘What is the chance that the experimental therapy will control cancer?‘). In semistructured interviews, we queried participants about how they understood and answered the target question. Each participant then answered and discussed one of the other target questions. Results: Participants tended to provide higher expectations in response to the belief-type question (median, 80) than in response to the frequency-type or vague questions (medians, 50) (P=.02). Only 7 (16%) participants said their answers were based on what they were told during the consent process. The most common justifications for responses involved positive attitude (n=27 [60%]) and references to physical health (n=23 [51%]). References to positive attitude were most common among participants with high (>70%) expectations of benefit (n=11 [85%]) and least common among those with low (<50%) expectations of benefit (n=3 [27%]) (P=.04). Conclusions: We identified two factors that should be considered when determining whether high expectations of benefit are signs of misunderstanding. First, participants report different expectations of benefit depending on how the question is asked. Second, the justifications participants give for their answers suggest that many participants use their responses to express hope rather than to describe their understanding of the clinical trial. These findings should inform methods for evaluating the quality of informed consent in early-phase trials. No significant financial relationships to disclose.

Phase 1 study of sorafenib and irinotecan in pediatric patients with relapsed or refractory solid tumors.

2014 ◽  
Vol 32 (15_suppl) ◽  
pp. 10052-10052 ◽  
Author(s):  
Holly Jane Meany ◽  
Jeffrey Dome ◽  
Pamela S. Hinds ◽  
Rochelle Bagatell ◽  
Suzanne Shusterman ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Pediatric Patients ◽  
Phase 1 ◽  
Phase 1 Study

A Phase 1 Study of ABT-751, an Orally Bioavailable Tubulin Inhibitor, Administered Daily for 7 Days Every 21 Days in Pediatric Patients with Solid Tumors

2006 ◽  
Vol 12 (16) ◽  
pp. 4882-4887 ◽  
Author(s):  
Elizabeth Fox ◽  
John M. Maris ◽  
Brigitte C. Widemann ◽  
Kysa Meek ◽  
Anne Goodwin ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Pediatric Patients ◽  
Phase 1 ◽  
Phase 1 Study ◽  
Tubulin Inhibitor ◽  
Orally Bioavailable

scholarly journals EPCT-05. A PHASE 1/2 STUDY OF AVAPRITINIB FOR KIT- OR PDGFRA-MUTANT PEDIATRIC RELAPSED/REFRACTORY SOLID TUMORS

2021 ◽  
Vol 23 (Supplement_1) ◽  
pp. i47-i47
Author(s):  
Susan Chi ◽  
Antony Hsieh ◽  
Megan Foley ◽  
Hongliang Shi ◽  
Preethi Swamy ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Primary Endpoint ◽  
Targeted Therapies ◽  
Pediatric Patients ◽  
Overall Response Rate ◽  
Response Rate ◽  
Phase 1 ◽  
Cns Tumors ◽  
Activation Loop ◽  
Overall Response

Abstract Prognosis for pediatric patients with advanced relapsed/refractory (R/R) solid (including central nervous system [CNS]) tumors is poor; targeted therapies achieve response rates of only ~15%. Germ cell tumors and high-grade glioma (HGG) are the most common with KIT mutations; sarcoma and HGG are the most common tumors with platelet-derived growth factor receptor alpha (PDGFRA) mutations. Two-year overall survival is &lt;10% for pediatric patients with diffuse intrinsic pontine glioma, often driven by PDGFRA mutations. No KIT/PDGFRA targeted therapies are currently approved for pediatric patients with R/R solid tumors. The selective KIT and PDGFRA inhibitor, avapritinib, demonstrated potent activity against KIT activation-loop (exon 17), juxtamembrane (exon 11), and extracellular-domain (exon 9) mutants (IC50 &lt;2 nM), and PDGFRA activation-loop (D842V) mutants (IC50=0.24 nM). CNS penetration in preclinical models (brain-to-plasma ratios at steady-state ranging from 0.74–1.00) demonstrated potential for activity against CNS tumors. Avapritinib is approved for the treatment of adults with unresectable/metastatic gastrointestinal stromal tumors (GIST) harboring PDGFRA exon 18 mutations (including D842V) in the USA based on an overall response rate ³84% with 59% response durations &gt;6 months, and in the EU for adults with unresectable/metastatic GIST harboring a PDGFRA D842V mutation. The objectives of this 2-part phase 1/2 multicenter, open-label study, anticipated to enroll 31 patients from Q3 2021, are to assess avapritinib safety, preliminary efficacy, and pharmacokinetics in pediatric patients with KIT/PDGFRA-mutant solid R/R tumors. Eligible patients are aged 2 to &lt;18 years with no alternative treatment options. Part 1 will enroll ≥6 patients; primary endpoint is confirmed age and body surface area physiologically-based pharmacokinetic modeling dose to provide equivalent exposure to the 300 mg adult avapritinib dose. Part 2 will enroll ≥25 patients at the recommended modeled avapritinib dose from Part 1; primary endpoint is overall response rate. Avapritinib once-daily will be administered in continuous 28-day cycles.

Informed consent for early-phase clinical trials: therapeutic misestimation, unrealistic optimism and appreciation

2019 ◽  
Vol 45 (6) ◽  
pp. 384-387 ◽  
Author(s):  
Jodi Halpern ◽  
David Paolo ◽  
Andrew Huang
Keyword(s):  
Clinical Trials ◽  
Informed Consent ◽  
Early Phase ◽  
Phase 1 ◽  
Trial Participation ◽  
Unrealistic Optimism ◽  
Personal Significance ◽  
Decision Making Capacity ◽  
Early Phase Clinical Trials ◽  
Motivation To Participate

Unrealistic therapeutic beliefs are very common—the majority of patient-subjects (up to 94%) enrol in phase 1 trials seeking and expecting significant medical benefit, even though the likelihood of such benefit has historically proven very low. The high prevalence of therapeutic misestimation and unrealistic optimism in particular has stimulated debate about whether unrealistic therapeutic beliefs in early-phase clinical trials preclude adequate informed consent. We seek here to help resolve this controversy by showing that a crucial determination of when such therapeutic beliefs are ethically problematic turns on whether they are causally linked and instrumental to the motivation to participate in the trial. Thus, in practice, it is ethically incumbent on researchers to determine which understanding and beliefs lead to the participant’s primary motivation for enrolling, not to simply assess understanding, beliefs and motivations independently. We further contend that assessing patient-subjects’ appreciation as a component of informed consent—it is already an established component of decision-making capacity assessments—can help elucidate the link between understanding-beliefs and motivation; appreciation refers to an individual’s understanding of the personal significance of both the medical facts and the experience of trial participation. Therefore, we recommend that: (1) in addition to the usual question, ‘Why do you want to participate in this trial?’, all potential participants should be asked the question: ‘What are you giving up by participating in this trial?’ and (2) researchers should consider the settings in which it may be possible and practical to obtain ‘two-point consent’.

Phase 1/2 study of the selective TRK inhibitor larotrectinib in pediatric patients with cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS10577-TPS10577 ◽  
Author(s):  
Noah Federman ◽  
Catherine Michelle Albert ◽  
Brian Turpin ◽  
Leo Mascarenhas ◽  
Ramamoorthy Nagasubramanian ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Pediatric Patients ◽  
Lymphoblastic Leukemia ◽  
Phase 1 ◽  
Objective Response ◽  
Cns Tumors ◽  
Spindle Cell Sarcoma ◽  
Phase 2 ◽  
Infantile Fibrosarcoma ◽  
Molecular Abnormalities

TPS10577 Background: Neurotrophin ligands and their receptors TRKA, TRKB, and TRKC (encoded by NTRK1, NTRK2, and NTRK3) are important for growth regulation, differentiation and survival of neurons. Translocations involving the NTRK1/2/3 kinase domain, mutations involving the TRK ligand-binding site, and amplifications of NTRK, have been described in diverse tumor types and may contribute to tumorigenesis. A broad range of pediatric malignancies have been found to harbor NTRK fusions, including infantile fibrosarcoma (IFS), spindle-cell sarcoma, congenital mesoblastic nephroma, pediatric papillary thyroid cancer, pediatric gliomas and Ph-like acute lymphoblastic leukemia. Larotrectinib is the first small-molecule selective inhibitor of TRKA, -B, and -C in clinical development and preliminary data from the adult phase 1 trial demonstrate prolonged responses in patients with TRK fusions and a favorable safety profile. Methods: We have initiated an open-label, multi-center, international Phase 1/2 study with larotrectinib in pediatric patients with solid tumors and primary CNS tumors (NCT02637687). Patients with advanced cancer between the ages of 1 year and 21 years are eligible, as well as patients as young as 1-month of age with a documented NTRK fusion. Patients with IFS who have not had definitive surgery are also eligible. Larotrectinib is administered orally twice daily on a continuous 28-day schedule. Dosing is based on body surface area. Larotrectinib is available in an oral liquid formulation and capsules. Following identification of the maximum tolerated dose of larotrectinib in the phase 1 portion, the phase 2 portion will commence. The phase 2 portion will enroll patients with NTRK-translocated tumors and measurable disease into three cohorts: 1) infantile fibrosarcoma; 2) extracranial solid tumors; and 3) primary CNS tumors. The primary endpoint for the phase 2 portion is objective response rate, with duration of response and progression free survival as secondary efficacy endpoints. Each phase 2 cohort will enroll in a single stage of up to 10 patients per cohort. Molecular abnormalities will be characterized through the analysis of archival tissue. Enrollment began in December 2015 and is ongoing. Clinical trial information: NCT02637687.

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