scholarly journals EPCT-16. LENALIDOMIDE ACTIVITY IN PILOCYTIC ASTROCYTOMA AND OPTIC PATHWAY GLIOMAS: REPORT ON CHILDREN’S ONCOLOGY GROUP ACNS1022

2021 ◽  
Vol 23 (Supplement_1) ◽  
pp. i50-i50
Author(s):  
Katherine Warren ◽  
Gilbert Vezina ◽  
Linda Springer ◽  
Allen Buxton ◽  
Cody Peer ◽  
...  
Keyword(s):  
Pilocytic Astrocytoma ◽  
Low Dose ◽  
Objective Response ◽  
Low Grade Glioma ◽  
Activity Level ◽  
High Dose ◽  
Low Grade ◽  
Optic Pathway ◽  
Long Term Effects ◽  
Optic Pathway Gliomas

Abstract Children with low-grade glioma have excellent survival rates but often suffer from the morbidity of treatment, particularly from cytotoxic chemotherapies. Targeted agents appear to have some activity but the long-term effects of inhibiting normal developmental pathways are unknown. Lenalidomide is an oral immunomodulatory agent with additional properties including anti-angiogenesis. Phase I studies indicated greater tolerability of this agent compared to adults, and a potential dose-response effect. We performed a Phase 2 trial of lenalidomide in children with pilocytic astrocytoma and optic pathway gliomas who failed initial therapy. The primary objective was to determine the objective response rate of children randomized to Regimen A low-dose (20 mg/m2 /dose) or Regimen B high-dose (115 mg/m2 /dose) lenalidomide, each administering lenalidomide daily x 21 days of each 28-day course. Secondary objectives included estimation of event-free survival (EFS) in this population and correlation of plasma lenalidomide concentration with toxicity and outcome. Results 74 eligible patients were enrolled (n=37 to each arm). The pre-defined activity level of interest was achieved for both arms. Objective responses were observed in both arms, with 4 partial responses in each. A total of n=18 patients completed 26 courses of therapy (Arm A, n=12, Arm B, n=6) The median number of courses on each arm was 14 (range 2–26) for Arm A and 11 for Arm B (range 1- 26). Of the 74 eligible patients who received study drug, 30 required a dose reduction for toxicity (Arm A, n=6, Arm B, n=24) and 16 discontinued treatment on protocol due to toxicity (Arm A, n=2, Arm B, n=14). Conclusion Lenalidomide demonstrates a sufficient level of activity in children with low-grade glioma to warrant further exploration in Phase 3 studies. Low-dose (20 mg/m2) lenalidomide appears to have better tolerability.

scholarly journals ACTR-07. LONG-TERM OUTCOMES FROM INTERGROUP NCCTG 86-72-51 (ALLIANCE): FINAL REPORT OF A PHASE III PROSPECTIVE RANDOMIZED TRIAL OF HIGH DOSE VERSUS LOW DOSE RADIATION IN ADULT SUPRATENTORIAL LOW-GRADE GLIOMA

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi13-vi14
Author(s):  
William Breen ◽  
S Keith Anderson ◽  
Xiomara Carrero ◽  
Paul Brown ◽  
Karla Ballman ◽  
...  
Keyword(s):  
Low Dose ◽  
Low Grade Glioma ◽  
Phase Iii ◽  
High Dose ◽  
Low Grade ◽  
Tumor Diameter ◽  
Low Dose Radiation ◽  
Dose Radiation

Abstract PURPOSE To provide a final update on oncologic and cognitive outcomes of high dose versus low dose radiation for low-grade glioma. METHODS Between 1986 and 1994, 203 patients with supratentorial low grade glioma were randomized to 50.4 Gy in 28 fractions versus 64.8 Gy in 36 fractions after any degree of resection. Histologic subtype was oligodendroglioma (71%) or astrocytoma (29%). Primary outcome was overall survival (OS). Cognitive status was followed using Folstein Mini-Mental State Examination (MMSE). RESULTS For the entire cohort of 203 patients, median OS was 8.4 years (95% CI: 7.2 – 10.8). Median progression-free survival (PFS) was 5.2 years (95% CI: 4.3 – 6.6). Median follow-up is 17.2 years for the 33 patients still alive. High-dose radiation did not improve OS (15-yr OS: 22.4% vs. 24.9%, log rank p=0.978) or PFS (15-yr PFS: 15.2% vs. 9.5%, p=0.7142). OS was significantly better for patients with pre-operative tumor diameter < 5 cm (15-yr OS: 39.4% vs. 15.2%, p< 0.001), baseline MMSE > 27 (15-yr OS: 27.3% vs. 9.8%, p=0.001), and for patients who underwent gross total resection (GTR) (15-yr OS: 39.3% GTR vs. 16.4% subtotal resection vs. 24.5% biopsy only, p=0.0119). PFS was improved for patients with oligodendroglioma versus astrocytoma (15-yr PFS: 13.8% vs. 8.6%, p=0.0221). PFS was also improved for patients with pre-operative tumor diameter < 5 cm, patients who had GTR, and patients with baseline MMSE > 27. For patients who had normal MMSE at baseline, at 7 years only 1 patient (5%) had a clinically significant decrease in MMSE from the previous time point, with the remainder (95%) stable. None had decrease in MMSE at 10, 12, or 15 years. CONCLUSIONS Long-term follow-up indicates no benefit to high-dose over low-dose radiation for low-grade gliomas. Minimal late decline in cognitive function after radiation was seen by MMSE. SUPPORT: U10CA180821,U10CA180882. https://acknowledgments.alliancefound.org

scholarly journals Final report from Intergroup NCCTG 86-72-51 (Alliance): a phase III randomized clinical trial of high-dose versus low-dose radiation for adult low-grade glioma

2020 ◽  
Vol 22 (6) ◽  
pp. 830-837 ◽  
Author(s):  
William G Breen ◽  
S Keith Anderson ◽  
Xiomara W Carrero ◽  
Paul D Brown ◽  
Karla V Ballman ◽  
...  
Keyword(s):  
Low Dose ◽  
Low Grade Glioma ◽  
Gross Total Resection ◽  
High Dose ◽  
Low Grade ◽  
Tumor Diameter ◽  
Low Dose Radiation ◽  
Total Resection ◽  
Dose Radiation

Abstract Background The optimal radiation dose for adult supratentorial low-grade glioma is unknown. The aim of this study was to provide a final update on oncologic and cognitive outcomes of high-dose versus low-dose radiation for low-grade glioma. Methods Between 1986 and 1994, 203 patients with supratentorial low-grade glioma were randomized (1:1) to 50.4 Gy in 28 fractions versus 64.8 Gy in 36 fractions after any degree of resection. Results For all patients, median overall survival (OS) was 8.4 years (95% CI: 7.2–10.8). Median progression-free survival (PFS) was 5.2 years (95% CI: 4.3–6.6). Median follow-up is 17.2 years for the 33 patients still alive. High-dose radiation did not improve 15-year OS (22.4%) versus low-dose radiation (24.9%, log-rank P = 0.978) or 15-year PFS (high dose, 15.2% vs low dose, 9.5%; P = 0.7142). OS was significantly better for patients with preoperative tumor diameter &lt;5 cm and baseline Mini-Mental State Examination (MMSE) &gt;27 and who underwent gross total resection. PFS was improved for patients with oligodendroglioma versus astrocytoma, preoperative tumor diameter &lt;5 cm, patients who had gross total resection, and patients with baseline MMSE &gt;27. For patients who had normal MMSE at baseline, at 7 years only 1 patient (5%) had a clinically significant decrease in MMSE from the previous time point, with the remainder (95%) stable. None had decrease in MMSE at 10, 12, or 15 years. Conclusions Long-term follow-up indicates no benefit to high-dose over low-dose radiation for low-grade gliomas. Cognitive function appeared to be stable after radiation as measured by MMSE.

scholarly journals LG-28THREAT TO VISION SCORE (TTV SCORE) IN CHILDREN WITH OPTIC PATHWAY GLIOMAS (OPGS): UK EXPERIENCE FROM PROSPECTIVE LOW GRADE GLIOMA (LGG2) TRIAL

2016 ◽  
Vol 18 (suppl 3) ◽  
pp. iii85.1-iii85
Author(s):  
Evangelos Drimtzias ◽  
Susan Picton ◽  
David Richards ◽  
Kevin Falzon ◽  
Janice Hoole ◽  
...  
Keyword(s):  
Low Grade Glioma ◽  
Low Grade ◽  
Optic Pathway ◽  
Optic Pathway Gliomas

scholarly journals High-dose radiation associated with improved survival in IDH-wildtype low-grade glioma

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Shuai Liu ◽  
Yanwei Liu ◽  
Guanzhang Li ◽  
Jin Feng ◽  
Li Chen ◽  
...  
Keyword(s):  
Overall Survival ◽  
Survival Analysis ◽  
Radiation Dose ◽  
Frontal Lobe ◽  
Low Grade Glioma ◽  
Molecular Characteristics ◽  
High Dose ◽  
Low Grade ◽  
Multivariate Survival ◽  
Dose Radiation

Abstract Background As molecular advances have deepened the knowledge on low-grade glioma (LGG), we investigated the effect of higher radiation dose on the survival of IDH-wildtype (IDHwt) LGG. Methods In the current study, 52 IDHwt LGG patients who received radiotherapy were enrolled from the Chinese Glioma Genome Atlas dataset. Radiation doses > 54 Gy were defined as high-dose, whereas doses ≤ 54 Gy were defined as low-dose. We performed univariate and multivariate survival analyses to examine the prognostic role of high-dose radiotherapy. Results In total, the radiation dose ranged from 48.6 Gy to 61.2 Gy, with a median of 55.8 Gy, and 31 patients were grouped into high-dose radiation. Univariate survival analysis indicated that high-dose radiotherapy (p = 0.015), tumors located in the frontal lobe (p = 0.009), and pathology of astrocytoma (p = 0.037) were significantly prognostic factors for overall survival. In multivariate survival analysis, high-dose radiotherapy (p = 0.028) and tumors located in the frontal lobe (p = 0.016) were independently associated with better overall survival. Conclusions In conclusion, high-dose radiotherapy independently improved the survival of IDHwt LGG. This can guide treatments for glioma with known molecular characteristics.

A multicenter open-label phase 1 study evaluating the safety and tolerability of HMPL-306 in patients with locally advanced or metastatic solid tumors with IDH mutations.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS3159-TPS3159
Author(s):  
Filip Janku ◽  
John S. Kauh ◽  
Christopher Tucci ◽  
Zhao Yang ◽  
Marek K. Kania ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Tricarboxylic Acid Cycle ◽  
Phase 1 ◽  
Objective Response ◽  
Locally Advanced ◽  
Low Grade Glioma ◽  
Statistical Hypothesis ◽  
Low Grade ◽  
Open Label ◽  
Idh Mutations

TPS3159 Background: Isocitrate dehydrogenase (IDH) is a rate-limiting tricarboxylic acid cycle enzyme with 3 isoforms. Mutations in IDH1 and IDH2 result in gain-of-function activity that can cause tumor formation and/or progression and have been associated with various tumor types. Therefore, selective, single mutant IDH (mIDH) isotype inhibitors (mIDH1 or mIDH2) can lead to insufficient efficacy and the potential for tumor resistance. HMPL-306 is an innovative, small-molecule, orally available, highly selective, potent inhibitor of both mIDH1 and mIDH2. Clinical development of a compound that concurrently targets, inhibits, and suppresses multiple mIDHs could lead to significant and durable clinical benefit for patients (pts) with solid tumors harboring IDH mutations. Methods: This is a phase 1, open-label, dose escalation (Part 1) and dose expansion (Part 2) study to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of HMPL-306 in pts ≥18 years with locally advanced or metastatic solid tumors with any IDH mutations. HMPL-306 will be administered orally, once daily in a 28-day continuous dosing treatment cycle. The HMPL-306 dose will be escalated in Part 1 according to the modified toxicity probability interval-2 (mTPI-2) design in 4 cohorts in approximately 15-20 pts: 50, 100, 150, and 200 mg. Eligible pts must have locally advanced or metastatic solid tumors with IDH1 or IDH2 mutations. The primary objectives are to evaluate safety, dose limiting toxicities (DLTs), tolerability, maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), and PK. Approximately 95 pts will be enrolled at the RP2D in Part 2 to further characterize the safety, tolerability, PK, PD, and preliminary anti-tumor activities of HMPL-306. Part 2 will include 5 dose expansion cohorts: cholangiocarcinoma (n = 20), skeletal chondrosarcoma (n = 20), low-grade glioma (n = 20), perioperative low-grade glioma (n = 15), any other solid tumor harboring an IDH1/2 mutation (n = 20). All pts will continue treatment until disease progression, unacceptable toxicity, withdrawal of consent, or at the investigator’s discretion. Safety will be assessed based on reports of adverse events including clinical laboratory testing, vital signs, physical examinations, and electrocardiograms. All pts who receive any study treatment will be included in safety and efficacy analyses. Antitumor activity based on investigator-assessed overall response will be evaluated using descriptive analyses. Objective response rate will be calculated with 95% confidence interval using the Clopper-Pearson method. The Kaplan-Meier method will be used to summarize the time-to-event data such as progression-free survival and duration of response. No statistical hypothesis testing is planned. Enrollment started February 2021.

Cisplatin and VP16 in Metastatic Breast Carcinoma as a Third-Line Chemotherapy: A Randomized Study Comparing Low versus High Doses of Cisplatin

1995 ◽  
Vol 81 (4) ◽  
pp. 241-244 ◽  
Author(s):  
Guido Ceci ◽  
Giancarlo Bisagni ◽  
Giorgio Cocconi ◽  
Carmelina Rodinò ◽  
Virginio Belsanti ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Advanced Breast Cancer ◽  
Low Dose ◽  
Objective Response ◽  
Metastatic Breast ◽  
Advanced Breast ◽  
High Dose ◽  
Severe Toxicity ◽  
Third Line ◽  
Line Chemotherapy

Aims and background The study was designed to define the activity of the combination of cisplatin and etoposide as third-line chemotherapy for advanced breast cancer and to investigate the role of the dosage of cisplatin on the effectiveness of the combination. Methods Ninety-five eligible patients with advanced breast cancer who had failed or relapsed on two previous lines of chemotherapy were randomized to receive cisplatin at a high dose (100 mg/m2 i.v. day 1, arm A) or a low dose (60 mg/m2 day 1, arm B), combined with etoposide (100 mg/m2 i.v. days 4, 6 and 8). Cycles were repeated every 3 weeks. Results Of the 78 patients evaluable for response (39 in arm A and 39 in arm B), 9 (12%) showed complete or partial response, 5 (13%) in the high-dose arm and 4 (10%) in the low-dose arm. One complete response was seen in the high-dose arm and none in the low-dose arm. The only 2 patients with brain involvement showed an objective response (one CR in arm A and one PR in arm B). Median time to progression was 14 weeks in arm A and 10 weeks in arm B, median duration of remission 28 and 34 weeks, and survival 36 and 35 weeks, respectively. The differences were not significant. As expected, the patients in the high-dose arm experienced more severe toxicity. One toxic death was observed in each arm due to sepsis in agranulocytosis. The difference was statistically significant regarding nausea and vomiting. Neurotoxicity and ototoxicity were not relevant problems in this patient setting. Conclusions Considering the very poor prognostic factors presented by these patients, the combination showed a certain activity, and further evaluation in earlier stages of disease is warranted. A particular responsiveness on brain metastases is suggested. The dose of cisplatin was not proven to be of significant importance.

Adverse long-term effects of brain radiotherapy in adult low-grade glioma patients

Neurology ◽  
2001 ◽  
Vol 56 (10) ◽  
pp. 1285-1290 ◽  
Author(s):  
O. Surma-aho ◽  
M. Niemela ◽  
J. Vilkki ◽  
M. Kouri ◽  
A. Brander ◽  
...  
Keyword(s):  
Low Grade Glioma ◽  
Low Grade ◽  
Long Term Effects ◽  
Brain Radiotherapy

scholarly journals Activation of mTORC1/mTORC2 signaling in pediatric low-grade glioma and pilocytic astrocytoma reveals mTOR as a therapeutic target

2013 ◽  
Vol 15 (12) ◽  
pp. 1604-1614 ◽  
Author(s):  
Marianne Hütt-Cabezas ◽  
Matthias A. Karajannis ◽  
David Zagzag ◽  
Smit Shah ◽  
Iren Horkayne-Szakaly ◽  
...  
Keyword(s):  
Pilocytic Astrocytoma ◽  
Therapeutic Target ◽  
Low Grade Glioma ◽  
Low Grade

Carboplatin treatment of progressive optic pathway gliomas to delay radiotherapy

1993 ◽  
Vol 79 (2) ◽  
pp. 223-227 ◽  
Author(s):  
Albert Moghrabi ◽  
Henry S. Friedman ◽  
Peter C. Burger ◽  
Robert Tien ◽  
W. Jerry Oakes
Keyword(s):  
Low Grade ◽  
Optic Pathway ◽  
Radiographic Evidence ◽  
Content Type ◽  
The Third ◽  
Arrest Growth ◽  
Unacceptable Toxicity ◽  
Optic Pathway Gliomas ◽  
Fine Print ◽  
Do So

✓ Six patients with optic pathway gliomas who were previously managed with surgery and/or chemotherapy were treated with carboplatin (560 mg/sq m) after radiographic evidence of disease progression. The median age at diagnosis was 2 years (range 4 months to 7 years), and the interval between diagnosis and carboplatin therapy ranged between 7 months and 6.5 years (median 1.8 years). Treatment was given at 4-week intervals and continued until unacceptable toxicity supervened, the disease progressed, or the disease was stable for 12 months. All patients demonstrated disease stability at the outset of the third cycle and continued to do so at the time of this writing. Two patients are 16 and 32 months from initial carboplatin therapy and have been off treatment for 5 and 14 months, respectively; two patients are still receiving therapy at 7 and 11 months after their initial treatment. During the study, two patients developed hypersensitivity to the drug, requiring its discontinuation. Toxicity was minimal, consisting mainly of thrombocytopenia, requiring a one-dose reduction in four of the six treated patients. No platelet transfusions were needed. These results suggest that carboplatin can arrest growth of progressive optic pathway gliomas in children and can allow delay of radiotherapy. A larger trial will be required to define the optimal use of carboplatin in the treatment of low-grade gliomas in children.

A phase II prospective study of selumetinib in children with recurrent or refractory low-grade glioma (LGG): A Pediatric Brain Tumor Consortium (PBTC) study.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 10504-10504 ◽  
Author(s):  
Jason R. Fangusaro ◽  
Arzu Onar-Thomas ◽  
Tina Young-Poussaint ◽  
Shengjie Wu ◽  
Azra H Ligon ◽  
...  
Keyword(s):  
Phase Ii ◽  
Pediatric Brain Tumor ◽  
Braf V600e Mutation ◽  
Low Grade Glioma ◽  
Braf V600e ◽  
Low Grade ◽  
Optic Pathway ◽  
Grade 3 ◽  
Molecular Aberrations

10504 Background: A greater understanding of the Ras-MAP kinase-signaling pathway in pediatric low-grade glioma (LGG) paired with the availability of potent selective inhibitors has enhanced the ability to target this pathway with therapeutic intent. Methods: The PBTC conducted a multi-institutional phase II study (NCT01089101) evaluating selumetinib (AZD6244, ARRY-142886), a MEK I/II inhibitor, in children with recurrent/refractory LGG assigned to 6 strata and treated at 25 mg/m2/dose PO BID for up to two years. Here we present the data from three of these strata. The remaining strata are still accruing patients. Results: Stratum I included children with non-NF-1 and non-optic pathway recurrent/refractory pilocytic astrocytoma (PA) harboring BRAF aberrations (BRAF V600e mutation or the BRAF-KIAA 1549 fusion). Eight of 25 (32%) patients achieved a partial response (PR) with 2-year PFS of 66+/-11%. Two of 7 (29%) patient tumors with a BRAF V600e mutation and 6/18 (33%) with a BRAF KIAA-1549 fusion had a PR. Stratum 3 enrolled NF-1-associated LGG. Tissue for tumor BRAF evaluation was not required for eligibility. Ten of 25 (40%) achieved PR with a 2-year PFS of 96+/-4%. Only one patient progressed while on treatment. Stratum 4 included children with non-NF-1 optic pathway/hypothalamic LGG. Tissue for tumor BRAF evaluation was not required for eligibility. Two of 16 (12.5%) had a PR with a 2-year PFS of 65+/-13%. The BRAF aberration status of the responders in strata 3 and 4 is mostly unknown. All responses were confirmed centrally and seven patients remain on treatment. The most common toxicities were grade 1/2 CPK elevation, diarrhea, hypoalbuminemia, elevated AST and rash. Rare grade 3/4 toxicities included elevated CPK, rash, neutropenia, emesis and paronychia. Conclusions: Selumetinib was effective in treating children with recurrent/refractory LGG, including those with NF-1 associated LGG and PA harboring BRAF V600e mutation or BRAF-KIAA 1549 fusion. Larger prospective studies are necessary to determine the future, specific role of this agent in treating children with LGG harboring specific molecular aberrations. Clinical trial information: NCT01089101.

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