scholarly journals EPCT-01. PHASE I STUDY OF DAY101 (TAK580) IN CHILDREN AND YOUNG ADULTS WITH RADIOGRAPHICALLY RECURRENT OR PROGRESSIVE LOW-GRADE GLIOMA (LGG)

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii304-iii304
Author(s):  
Karen Wright ◽  
Emily Krzykwa ◽  
Lianne Greenspan ◽  
Susan Chi ◽  
Kee Kiat Yeo ◽  
...  
Keyword(s):  
Young Adults ◽  
Phase I ◽  
Phase I Study ◽  
Pediatric Patients ◽  
Mapk Pathway ◽  
Pharmacokinetic Parameters ◽  
Low Grade ◽  
Children And Young Adults ◽  
Dose Levels

Abstract BACKGROUND We report a phase I study examining pharmacokinetics, safety and recommended dosage of the type 2 RAF inhibitor DAY101 in children/young adults with radiographically recurrent/progressive LGGs harboring MAPK pathway alterations. METHODS Applying a 3 + 3 design, patients < 18 years of age with radiographically recurrent/progressive LGG received oral DAY101 weekly for 4-week cycles up to a maximum of 2 years, if deriving clinical benefit. The starting DAY101 dosage was 280 mg/m2. Dose limiting toxicities were determined after one cycle. RESULTS We treated nine eligible patients at 280, 350, and 420 mg/m2. Eight patients had KIAA1549:BRAF fusions. One patient with NF1 did not have a biopsy. There were no DLTs. Weekly administration of DAY101 in children resulted in dose-proportional increases in Cmax and AUC similar to that described in adults. A 2.2-fold mg/kg exposure difference was observed with respect to weight-based dosing and suggested a correlation to best radiographic RANO responses of 2 complete responses, 2 partial responses, 3 stable disease, and 2 progressive disease (independently-reviewed). Median time to response was 10.5 weeks (range: 8–32 weeks). CONCLUSION The phase 1A data provide initial pharmacokinetic parameters to describe oral weekly dosing of DAY101 in pediatric patients with radiographically recurrent/progressive LGG. Plasma exposures of DAY101 achieved in adults can be reached in pediatric patients. Oral weekly DAY101 is well-tolerated and possesses anti-tumor activity. The amended protocol will explore additional dose levels and the potential for differential dosing to achieve similar responses across a variety of BSAs.

416 Results of phase I study of bolus 5-fluorouracil in children and young adults with recurrent ependymoma

2014 ◽  
Vol 50 ◽  
pp. 133
Author(s):  
K.D. Wright ◽  
D.C. Turner ◽  
K.M. Haddock ◽  
M.O. Jacus ◽  
K.E. Harstead ◽  
...  
Keyword(s):  
Young Adults ◽  
Phase I ◽  
Phase I Study ◽  
Recurrent Ependymoma ◽  
Children And Young Adults

scholarly journals Phase I study of 5-fluorouracil in children and young adults with recurrent ependymoma

2015 ◽  
Vol 17 (12) ◽  
pp. 1620-1627 ◽  
Author(s):  
Karen D. Wright ◽  
Vinay M. Daryani ◽  
David C. Turner ◽  
Arzu Onar-Thomas ◽  
Nidal Boulos ◽  
...  
Keyword(s):  
Young Adults ◽  
Phase I ◽  
Phase I Study ◽  
Recurrent Ependymoma ◽  
Children And Young Adults

Phase I study of neoadjuvant 5-fluorouracil (5FU) chemoradiation (CRT) and trametinib in patients with locally advanced rectal cancers (LARC).

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 685-685
Author(s):  
Christina Sing-Ying Wu ◽  
Terence M Williams ◽  
Lai Wei ◽  
Hamida Umar ◽  
Sameh Mikhail ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Study ◽  
Tumor Tissue ◽  
Mapk Pathway ◽  
Locally Advanced ◽  
Complete Response ◽  
Maximum Tolerated Dose ◽  
Braf Mutations ◽  
Expansion Cohort ◽  
Dose Levels

685 Background: RAS/BRAF mutations constitutively activate the MAPK pathway in colorectal cancer, and may promote resistance to CRT. We propose that trametinib, a MEK1/2 inhibitor, in combination with 5FU CRT for patients with LARC will improve outcome. Methods: Phase I study with standard 3+3 design in patients with Stage II/III rectal cancer with 3 dose levels of trametinib: 0.5, 1, and 2mg daily with 5FU 225mg/m2/day and 50.4 Gy. Trametinib was given over a 5-day lead-in and continued through the course of CRT. Patients undergo surgery 6-10 weeks after the completion of CRT. An expansion cohort at the maximum tolerated dose (MTD) with 12 patients is ongoing. Tumor tissue is collected prior to therapy, at day 4/5 of trametinib, and at surgery. The primary endpoint is to determine the MTD of trametinib with CRT. Results: 15 patients (10 males, 5 females) have been enrolled and 14 patients are evaluable for toxicities to date. Median age is 53 years (range 35-74). Patients have completed enrollment to all dose levels, with 1 dose-limiting toxicity of diarrhea attributed to 5FU CRT. No grade 4/5 toxicities, and toxicities are shown in the table. Generalized skin rash led to trametinib discontinuation after 2 weeks of therapy for 1 patient, and was held 3 days for 2 patients. At the trametinib dose level of 2mg, 3 out of 7 (43%) patients had a pathological complete response and the average neoadjuvant rectal (NAR) score is 8.1. Tumor RAS/BRAF mutation status is determined. Analysis of tumor tissue shows dose-dependent decrease in phosphorylated-ERK1/2 with increasing doses of trametinib. Conclusions: Initial evaluation shows that the combination of trametinib with 5FU CRT is tolerable and effective, and warrants further investigation in LARC. Clinical trial information: NCT01740648. [Table: see text]

Phase I study of bevacizumab, sorafenib, and low-dose cyclophosphamide (CYC) in children and young adults with refractory solid tumors.

2011 ◽  
Vol 29 (15_suppl) ◽  
pp. 9500-9500 ◽  
Author(s):  
V. M. Santana ◽  
S. D. Baker ◽  
B. McCarville ◽  
C. F. Stewart ◽  
J. Wu ◽  
...  
Keyword(s):  
Young Adults ◽  
Phase I ◽  
Solid Tumors ◽  
Phase I Study ◽  
Low Dose ◽  
Children And Young Adults

scholarly journals CTNI-19. PHASE I TRIAL OF DAY101 IN PEDIATRIC PATIENTS WITH RADIOGRAPHICALLY RECURRENT OR PROGRESSIVE LOW-GRADE GLIOMA (LGG)

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii46-ii46
Author(s):  
Karen Wright ◽  
Emily Krzykwa ◽  
Lianne Greenspan ◽  
Susan Chi ◽  
Kee Kiat Yeo ◽  
...  
Keyword(s):  
Phase I ◽  
Progressive Disease ◽  
Pediatric Patients ◽  
Phase 1 ◽  
Pharmacokinetic Parameters ◽  
Low Grade ◽  
Weekly Administration ◽  
Surface Areas ◽  
Grade 3 ◽  
Anti Tumor Activity

Abstract BACKGROUND We report phase I data examining pharmacokinetics, safety and preliminary efficacy of the dimeric, pan-RAF inhibitor DAY101 (formerly TAK-580/MLN2480) in pediatric patients with radiographically recurrent/progressive LGGs harboring MEK/ERK pathway alterations. METHODS Oral DAY101 was administered weekly to patients < 18 years of age with radiographically recurrent/progressive LGG for 4-week cycles up to a maximum of 2 years. The starting DAY101 dosage was 280 mg/m2. Dose limiting toxicities were determined after one cycle. RESULTS We treated nine eligible patients at 280, 350, and 420 mg/m2. Seven patients had KIAA1549:BRAF fusions, one a novel SRGAP3-RAF1 gene fusion and one with NF1 mutation. PK parameters following weekly administration of DAY101 in children mirrored the adult data, with dose-proportional increases in Cmax and AUC observed. There were no DLTs. The most common toxicity was skin rash followed by achromotrichia and nevi formation. There was only one grade 3 elevation is CPK and no grade 4 adverse events. A 2.2-fold mg/kg exposure difference was observed with respect to weight-based dosing and suggested a correlation to independent, centrally reviewed best radiographic RANO responses of 2 complete responses, 2 partial responses, 3 stable disease, and 2 progressive disease. Median time to response was 10.5 weeks (range: 8–32 weeks). CONCLUSIONS These phase 1 data provide initial pharmacokinetic parameters outlining oral weekly dosing of DAY101 in pediatric patients with radiographically recurrent and progressive LGG. Plasma exposures of DAY101 are similar in children and adults. Oral weekly DAY101 is well-tolerated and shows anti-tumor activity. The amended protocol explores differential dosing to achieve similar responses across a variety of body surface areas.

scholarly journals IMG-05. INITIAL RADIOGRAPHIC ASSESSMENT OF DWI AND ADC VALUES IN CHILDREN AND YOUNG ADULTS TREATED WITH DAY101 (TAK-580) FOR RECURRENT LOW-GRADE GLIOMAS (LGG) HARBORING MAPK ALTERATIONS

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii355-iii356
Author(s):  
Emily Krzykwa ◽  
Ronald L Korn ◽  
Samuel C Blackman ◽  
Karen D Wright
Keyword(s):  
Young Adults ◽  
Mapk Pathway ◽  
Quantitative Measure ◽  
Imaging Biomarker ◽  
Low Grade ◽  
Low Grade Gliomas ◽  
Molecular Image ◽  
Tissue Organization ◽  
Adc Values ◽  
Children And Young Adults

Abstract BACKGROUND Apparent diffusion coefficient (ADC) is a quantitative measure reflecting observed net movement of water calculated from a diffusion-weighted image (DWI), correlating with tumor cellularity. The higher cellularity of high-grade gliomas results in diffusion restriction and reduced ADC values, whereas the lower cellularity of low-grade gliomas (LGGs) gives higher ADC values. Here we examine changes in ADC values in patients with LGGs treated with the type 2 RAF inhibitor DAY101 (formerly TAK580). METHODS Historical, baseline, and on-treatment brain MRIs for 9 patients enrolled on a phase 1 study of DAY101 in children and young adults with radiographically recurrent or progressive LGG harboring MAPK pathway alterations were obtained, de-identified and independently evaluated for ADC changes. Time points included baseline, first follow-up, and best response. Data processing of ADC estimates was performed using pmod molecular image software package. ADC changes were displayed as a histogram with mean values. Results were based upon a single read paradigm. RESULTS There was a clear shift to lower ADC values for the solid component of tumors, reflecting changes in cellularity and tissue organization, while necrosis correlated with a shift toward higher ADC values. DWI reveals reduced ADCs in responding tumors, with the percent change in ADC from baseline correlating with deeper RANO responses. CONCLUSION DWI analysis reveals reductions in ADC values that correlates with treatment response and a shift toward more normal cellularity in tumors treated with DAY101. Changes in ADC may represent a novel imaging biomarker, reflecting biological response to DAY101 treatment.

Phase I Study of a Weekly Schedule of Irinotecan, High-Dose Leucovorin, and Infusional Fluorouracil as First-Line Chemotherapy in Patients With Advanced Colorectal Cancer

1999 ◽  
Vol 17 (3) ◽  
pp. 907-907 ◽  
Author(s):  
Udo Vanhoefer ◽  
Andreas Harstrick ◽  
Claus-Henning Köhne ◽  
Wolf Achterrath ◽  
Youcef M. Rustum ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Phase I ◽  
Dose Level ◽  
Phase I Study ◽  
Advanced Colorectal Cancer ◽  
High Dose ◽  
Weekly Schedule ◽  
First Line ◽  
Dose Levels ◽  
Line Chemotherapy

PURPOSE: To determine the maximum-tolerated dose (MTD) of a weekly schedule of irinotecan (CPT-11), leucovorin (LV), and a 24-hour infusion of fluorouracil (5-FU24h) as first-line chemotherapy in advanced colorectal cancer and to assess preliminary data on the antitumor activity. PATIENTS AND METHODS: Twenty-six patients with measurable metastatic colorectal cancer were entered onto this phase I study. In the first six dose levels, fixed doses of CPT-11 (80 mg/m2) and LV (500 mg/m2) in combination with escalated doses of 5-FU24h ranging from 1.8 to 2.6 g/m2 were administered on a weekly-times-four (dose levels 1 to 4) or weekly-times-six (dose levels 5 to 6) schedule. The dose of CPT-11 was then increased to 100 mg/m2 (dose level 7). RESULTS: Seventy-nine cycles of 5-FU24h/LV with CPT-11 were administered in an outpatient setting. No dose-limiting toxicities were observed during the first cycle at dose levels 1 to 6, but diarrhea of grade 4 (National Cancer Institute common toxicity criteria) was observed in three patients after multiple treatment cycles. Other nonhematologic and hematologic side effects, specifically alopecia and neutropenia, did not exceed grade 2. With the escalation of CPT-11 to 100 mg/m2 (dose level 7), diarrhea of grade 3 or higher was observed in four of six patients during the first cycle; thus, the MTD was achieved. Sixteen of 25 response-assessable patients (64%; 95% confidence interval, 45% to 83%) achieved an objective response. CONCLUSION: The recommended doses for further studies are CPT-11 80 mg/m2, LV 500 mg/m2, and 5-FU24h 2.6 g/m2 given on a weekly-times-six schedule followed by a 1-week rest period. The addition of CPT-11 to 5-FU24h/LV seems to improve the therapeutic efficacy in terms of tumor response with manageable toxicity.

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