BackgroundPediatric low-grade gliomas (PLGG) are the most frequent brain tumors in children. Up to 50% will be refractory to conventional chemotherapy. It is now known that the majority of PLGG have activation of the MAPK/ERK pathway. The same pathway is also activated in plexiform neurofibromas (PNs) which are low-grade tumors involving peripheral nerves in patients with neurofibromatosis type 1 (NF1). These lesions are known to be refractory to chemotherapy. Specific MEK inhibitors such as trametinib are now available and have been approved for other cancers harboring mutations in the MAPK/ERK pathway such as melanoma. We have observed significant responses to trametinib in patients with refractory PLGG in our institutions and results from the phase I study are promising. The treatment appears not only efficacious but is also usually well tolerated. We hypothesize that we will observe responses in the majority of refractory PLGG and PN treated with trametinib in this phase 2 study.MethodsThe primary objective is to determine the objective response rate of trametinib as a single agent for treatment of progressing/refractory tumors with MAPK/ERK pathway activation. The TRAM-01 study is a phase II multicentric open-label basket trial including four groups. Group 1 includes NF1 patients with progressing/refractory glioma. Group 2 includes NF1 patients with plexiform neurofibroma. Group 3 includes patients with progressing/refractory glioma with KIAA1549-BRAF fusion. Group 4 includes other patients with progressing/refractory glioma with activation of the MAPK/ERK pathway. Eligible patients for a given study group will receive daily oral trametinib at full dose for a total of 18 cycles of 28 days. A total of 150 patients will be enrolled in seven Canadian centers. Secondary objectives include the assessment of progression-free survival, overall survival, safety and tolerability of trametinib, serum levels of trametinib and evaluation of quality of life during treatment.DiscussionTrametinib will allow us to target directly and specifically the MAPK/ERK pathway. We expect to observe a significant response in most patients. Following our study, trametinib could be integrated into standard treatment of PLGG and PN.Trial registrationClinicalTrials.gov Identifier: NCT03363217 December 6, 2017.
Our aim was to assess whether infants influence the quantity and quality of their mothers’ speech to them and, in turn, whether this maternal speech influences children's later language. As 189 mothers interacted with each of their twins at age 0;5, we calculated the number of utterances, the proportion of sensitive utterances, and the proportion of self-repeated utterances they produced. We later assessed the twins’ language comprehension and production when they were 1;6, 2;6, and 5;2. Quantity of maternal speech predicted child language at 5;2, whereas sensitivity predicted child language at 2;6 and 5;2 and partial self-repetition predicted child language at 1;6. Conversely, sensitivity and partial self-repetition in maternal speech at 0;5 were associated with genetic factors from the child, indicating that infant characteristics influence the quality of maternal speech. Overall, our findings stress the importance of considering both directions in the association between maternal speech and child characteristics.
BACKGROUND Pediatric low-grade gliomas (PLGG) are the most frequent brain tumors in children. It is known that the majority of PLGG have activation of the MAPK/ERK pathway. METHODS This ongoing multicenter phase II trial includes three progressing/refractory PLGG groups: NF1 patients, KIAA1549-BRAF fusion patients and patients with other activation of the MAPK/ERK pathway (excluding V600E). The primary objective was to evaluate the overall response rate based on RANO criteria after daily oral trametinib administration for 18 cycles, lasting 28 days each. Secondary objectives include the assessment of progression-free survival, tolerability of trametinib, serum levels of trametinib and quality of life evaluation during treatment. RESULTS As of February 12 2021, 50 patients have been enrolled (NF1: n=10; KIAA1549-BRAF fusion: n=31; other: n=9 including 5 patients with FGFR1 alterations). Median age is 8.8 years (range 2.4-25.5). Median follow-up is 17.5 months (range 4.7-28.5). Forty-three patients are evaluable. The overall response includes: 4 partial response (PR) (9%), 18 minor response (MR) (42%), 17 stable disease (40%), 4 progressive disease (9%). Median time to response is 5.5 months (range 2.4-13.8). Median duration of response is 6.1 months (range 0.6-26.5). Progression free survival at 12 months is 79.9% (95% CI 68.5-93.6%) and median progression free survival has not yet been reached. Treatment was discontinued for 30 patients: 16 after completing 18 cycles as planned, 5 for progressive disease, 5 for adverse events, 4 for other reasons. A total of 8 patients progressed after discontinuation of treatment including 6 patients (37.5%) that completed 18 cycles. Five of these patients had achieved minor response prior to discontinuation. CONCLUSION Trametinib is a potentially effective targeted therapy for patients with recurrent/refractory PLGG. Treatment was overall well tolerated. This ongoing trial will continue to gather data on response rate, duration of response and safety of trametinib for PLGG.
2042 Background: Pediatric low-grade gliomas (PLGG) are the most frequent brain tumors in children and the majority of PLGG have activation of the MAPK/ERK pathway. Plexiform neurofibromas (PN) are found in up to 50% of patients with neurofibromatosis type 1 (NF1). Trametinib has been used widely to treat PLGG and PN, but no clinical trial has reported its efficacy. Methods: This multicenter phase II trial includes patients aged ≥ 1 month to ≤ 25 years with progressing/refractory PLGG groups or PN. The primary objective was to evaluate the overall response rate after daily oral trametinib administration for eighteen 28-day cycles. Results: As of January 31st, 2022, 60 patients with PLGG and 45 patients with PN have been enrolled. Median age is 9.5 years (range 1.8-25.4) for PLGG and 11 years (range 0.7-19.8) for PN. Median follow-up is 18 months (range 0.1-38.1). Fifty-three patients with PLGG were evaluable. The overall response includes: 1 complete response (CR) (1.9%), 7 partial response PR (13.2%), 17 minor response MR (32.1%), 23 stable disease (SD) (43.4%) and 5 progressive disease (PD) (9.4%). Twenty-eight patients with a total of 32 PN were available for volumetric analysis. Volumetric assessment demonstrated an overall response rate of 60.7% compared to 24.1% when using RECIST 1.1 and 62.5% of PN showed a decrease of more than 20% in volume. Median volume change was a decrease of 30% (range -93.5 to 14.3). A total of 59 (69.4%) patients discontinued treatment as planned after 18 cycles and 9 (10.6%) patients had to stop trametinib due to adverse events. Conclusions: Response rates observed in our study suggest that trametinib is a potentially effective targeted therapy for patients with recurrent/refractory PLGG and PN. Treatment was overall well tolerated. This trial will continue to gather data on duration of response and long-term outcome for PLGG and PN treated with trametinib. Clinical trial information: NCT03363217.
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