scholarly journals LGG-30. TRAMETINIB-ASSOCIATED HYPONATREMIA IN A CHILD WITH LOW GRADE GLIOMA IS NOT SEEN FOLLOWING TREATMENT WITH ALTERNATIVE MEK INHIBITOR

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii372-iii372
Author(s):  
Margot A Lazow ◽  
Sarah A Lawson ◽  
Ralph Salloum ◽  
Trent R Hummel ◽  
Natasha Pillay Smiley ◽  
...  
Keyword(s):  
Dose Reduction ◽  
Fluid Intake ◽  
Single Agent ◽  
Mek Inhibitor ◽  
Tumor Control ◽  
Low Grade ◽  
Pituitary Dysfunction ◽  
Adequate Understanding ◽  
Pediatric Patient Population ◽  
Inhibitor Combination

Abstract Molecularly targeted therapy with MEK inhibitors is increasingly being incorporated into the treatment of pediatric low-grade gliomas (LGGs). Trametinib is an orally available MEK1/2 inhibitor that has demonstrated tumor control in LGGs with BRAF alterations. Safe expansion of MEK inhibitor therapy within the pediatric patient population demands adequate understanding of and surveillance for potential MEK-inhibitor specific toxicities, especially among young children. Hyponatremia has been reported in adult patients receiving BRAF/MEK inhibitor combination treatment as well as in two pediatric patients with known diabetes insipidus treated with trametinib monotherapy. To our knowledge, single-agent trametinib has not previously been reported to be associated with hyponatremia in children in the absence of an underlying endocrinopathy. We present a case of hyponatremia associated with trametinib use in an infant with progressive LGG without known endocrine dysfunction, which recurred after significant dose reduction. Therapy with an alternative MEK1/2 inhibitor, binimetinib, provided excellent tumor response without hyponatremia. Hyponatremia is a rare but serious side effect of trametinib, even without underlying pituitary dysfunction. Infants and patients lacking the ability to quickly regulate fluid intake in response to osmolality changes are at particular risk of suffering severe consequences from hyponatremia and should be monitored closely with initiation of trametinib. Switching to a different drug within the same class may offer an alternative to significant dose reduction or discontinuation due to this toxicity.

Skin events (SE) among 1,126 patients (Pts) treated with lapatinib (L), an oral dual ErbB1/2 tyrosine kinase inhibitor (TKI)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 9102-9102 ◽  
Author(s):  
R. Sweetman ◽  
M. E. Lacouture ◽  
M. Koehler ◽  
S. Laabs ◽  
A. Preston ◽  
...  
Keyword(s):  
Dose Reduction ◽  
Drug Eruption ◽  
Kinase Inhibitor ◽  
Treatment Time ◽  
Single Agent ◽  
Skin Toxicity ◽  
Drug Discontinuation ◽  
Low Grade ◽  
Tumor Type ◽  
Grade 3

9102 Background: Lapatinib (L) is active as a single agent and in combination with capecitabine in pts with ErbB2+ve breast cancer. Safety profile from > 5,000 pts demonstrates infrequent Grade (G)3/4 (10%) adverse events, with drug discontinuation (disc) required in (<2%) events. SEs were commonly reported and were likely due to ErbB1 inhibition in the epidermis, as hypothesized with the other ErbB1 TKIs. However, the SE with L appear to differ clinically from other TKIs. Methods: SE in 1,126 pts reported in 8 L trials ( EGF20001 , EGF20002 , EGF20003 , EGF20004 , EGF20008 , EGF20009 , EGF20014 , + EGF100151) were pre-defined as dermatitis, drug eruption, dry skin, pruritus/urticaria, skin disorder, skin infection, nail, and hair disorder. SE were characterized based on CTC grading, and examined as to their relationship to L dose, length of L exposure, tumor type, concurrent treatment, time to onset from L initiation, and time to resolution with L dose- reduction or disc. Furthermore clinical management, skin biopsies, photos, and outcome were examined. Results: Pts were treated with L monotherapy 1,000–1,500mg daily (N=928), or in combination with capecitabine (C) (N=198). Non-L containing arms of studies EGF100151 (N=191; C alone) and EGF20001 (N=197; tamoxifen alone) served as controls. Among all L treated pts, 54% experienced SE mostly as G1/2, and 69% L+C pts experienced G1–3 SE with 50% G2. Majority of SE were deemed not specific to L and were rarely severe (no G4). Only 1% required drug disc. Most frequently reported SEs were dermatitis/drug eruption (38% all grade; 3% G3) (8% all grade, 1% G3). The frequency of SE with L at 1,500 mg QD was 57%, 1250 mg QD was 41%, and 500 BID was 63%. Most SE developed early (45% day 1–14) and persisted a median of 29 days. The majority of L pts (82%) did not require intervention (ie, dose reduction, hold, or withdraw). Conclusions: This large collection of L treated pts demonstrates that SE related to L therapy are low grade, infrequently require intervention or dose reduction, and rarely cause drug disc. Further attempts to identify pts at high risk for skin toxicity, its management, and the pathophysiology of L related SE are ongoing. No significant financial relationships to disclose.

Pediatric ganglioglioma of the brainstem and cervicomedullary junction: a retrospective cohort study

2020 ◽  
Vol 25 (1) ◽  
pp. 30-36
Author(s):  
Soliman Oushy ◽  
Avital Perry ◽  
Christopher S. Graffeo ◽  
Aditya Raghunathan ◽  
Lucas P. Carlstrom ◽  
...  
Keyword(s):  
Tertiary Care ◽  
Significant Risk ◽  
Foot Drop ◽  
Cranial Neuropathy ◽  
Primary Study ◽  
Tumor Control ◽  
Subtotal Resection ◽  
Low Grade ◽  
Surgical Morbidity ◽  
Cervicomedullary Junction

OBJECTIVEGanglioglioma is a low-grade central nervous system neoplasm with a pediatric predominance, accounting for 10% of all brain tumors in children. Gangliogliomas of the cervicomedullary junction (GGCMJs) and brainstem (GGBSs) present a host of management challenges, including a significant risk of surgical morbidity. At present, understanding of the prognostic factors—including BRAF V600E status—is incomplete. Here, the authors report a single-institution GGCMJ and GGBS experience and review the pertinent literature.METHODSA prospectively maintained neurosurgical database at a large tertiary care academic referral center was retrospectively queried for cases of GGCMJ pathologically confirmed in the period from 1995 to 2015; appropriate cases were defined by diagnosis codes and keywords. Secondary supplemental chart review was conducted to confirm or capture relevant data. The primary study outcome was treatment failure as defined by evidence of radiographic recurrence or progression and/or clinical or functional decline. A review of the literature was conducted as well.RESULTSFive neurosurgically managed GGBS patients were identified, and the neoplasms in 4 were classified as GGCMJ. All 5 patients were younger than 18 years old (median 15 years, range 4–16 years) and 3 (60%) were female. One patient underwent gross-total resection, 2 underwent aggressive subtotal resection (STR), and 2 underwent stereotactic biopsy only. All patients who had undergone STR or biopsy required repeat resection for tumor control or progression. Progressive disease was treated with radiotherapy in 2 patients, chemotherapy in 2, and chemoradiotherapy alone in 1. Immunostaining for BRAF V600E was positive in 3 patients (60%). All 5 patients experienced at least one major complication, including wound infection, foot drop, hemiparesis, quadriparesis, cranial neuropathy, C2–3 subluxation, syringomyelia, hydrocephalus, aspiration, and coma. Overall mortality was 20%, with 1 death observed over 11 years of follow-up.CONCLUSIONSGGBS and GGCMJ are rare, benign posterior fossa tumors that carry significant perioperative morbidity. Contemporary management strategies are heterogeneous and include combinations of resection, radiotherapy, and chemotherapy. The BRAF V600E mutation is frequently observed in GGBS and GGCMJ and appears to have both prognostic and therapeutic significance with targeted biological agents.

Combination of microsurgery and Gamma Knife surgery for the treatment of intracranial chondrosarcomas

2006 ◽  
Vol 105 (Supplement) ◽  
pp. 18-25 ◽  
Author(s):  
Petter Förander ◽  
Tiit Rähn ◽  
Lars Kihlström ◽  
Elfar Ulfarsson ◽  
Tiit Mathiesen
Keyword(s):  
Gamma Knife ◽  
Cranial Nerve ◽  
Residual Tumor ◽  
Local Tumor Control ◽  
Gamma Knife Surgery ◽  
Long Term Results ◽  
Tumor Control ◽  
Low Grade ◽  
Cranial Nerve Palsies ◽  
Tumor Volume Reduction

ObjectIntracranial chondrosarcomas have a high risk of recurrence after surgery. This retrospective study of patients with intracranial chondrosarcoma was conducted to determine the long-term results of microsurgery followed by Gamma Knife surgery (GKS) for residual tumor or recurrence.MethodsThe authors treated nine patients whose median age was 36 years. Seven patients had low-grade chondrosarcomas (LGCSs), whereas mesenchymal chondrosarcomas (MCSs) were diagnosed in two. Radiosurgery was performed in eight patients, whereas one patient declined further surgical intervention and tumor-volume reduction necessary for the GKS.The patients were followed up for 15 to 173 months (median 108 months) after diagnosis and 3 to 166 months (median 88 months) after GKS. Seven patients had residual tumor tissue after microsurgery, and two operations appeared radical. In the two latter cases, tumors recurred after 25 and 45 months. Thus, definite tumor control was not achieved after surgery alone in any patient, whereas the addition of radiosurgery allowed tumor control in all six patients with LGCSs. Two of these patients experienced an initial tumor regrowth after GKS; in both cases the recurrences were outside the prescribed radiation field. The patients underwent repeated GKS, and subsequent tumor control was observed. An MCS was diagnosed in the remaining two patients. Complications after microsurgery included diplopia, facial numbness, and paresis. After GKS, one patient had radiation necrosis, which required microsurgery, and two patients had new cranial nerve palsies.Conclusions Tumor control after microsurgery alone was not achieved in any patient, whereas adjuvant radiosurgery provided local tumor control in six of eight GKS-treated patients. Tumor control was not achieved in the two patients with MCS. Similar to other treatments for intracranial chondrosarcoma, morbidity after micro- and radiosurgical combination therapy was high and included severe cranial nerve palsies.

scholarly journals COVD-01. VINBLASTINE MONOTHERAPY INDUCTION FOR LOCALISED CNS GERMINOMA DURING THE COVID-19 PANDEMIC

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii282-iii282
Author(s):  
Rafael Moleron ◽  
Sara Stoneham ◽  
Thankamma Ajithkumar ◽  
Justin Cross ◽  
James Nicholson ◽  
...  
Keyword(s):  
Germ Cell ◽  
Treatment Options ◽  
Single Agent ◽  
Germ Cell Tumour ◽  
Research Priorities ◽  
Tumour Volume ◽  
Cell Tumour ◽  
Low Grade ◽  
Testicular Seminoma

Abstract INTRODUCTION Patients with localised CNS-germinoma have excellent survival. More recently, intensive inpatient chemotherapy (carboPEI=carboplatin/etoposide/ifosfamide in Europe) has been effectively employed to reduce radiotherapy fields and/or dose. Current research priorities focus on reducing treatment burden and long-term sequelae. Of note, outpatient-based single-agent carboplatin chemotherapy is associated with excellent outcomes in metastatic testicular seminoma (an identical pathology) [Alifrangis,EJC,2020]. Recently, successful vinblastine monotherapy was reported in localised CNS-germinoma [Murray,Neurooncol-Adv,2020]. METHODS Due to the COVID-19 pandemic, adapted UK guidelines for germ-cell-tumour management were distributed, including potential non-standard treatment options that would reduce hospital visits/admissions. A 30-year-old patient presented with a 32mmx30mmx35mm diameter solid+multi-cystic localised pineal CNS lesion, consistent radiologically with a germ-cell-tumour with prominent teratoma component. Investigation revealed negative AFP/HCG markers and biopsy-proven pure germinoma. After appropriate consent, the patient commenced 12-week induction with weekly vinblastine monotherapy (low-grade-glioma dosing [Lassaletta,JCO,2016]), with wk6&12 MRI re-assessment prior to definitive radiotherapy. RESULTS Vinblastine was well-tolerated. After initial 4mg/m2 test-dosing (wk1), standard 6mg/m2 was delivered for wk2, but resulted in asymptomatic neutropenia (nadir 0.3x10^9/l) and missed dosing at wk3. Subsequent doses were 4mg/m2, with no further neutropenia. As expected, MRI showed moderate 40% tumour volume reduction by wk12. Surgical resection of the residual presumed teratoma component was undertaken prior to radiotherapy. CONCLUSION Patients with CNS-germinoma have excellent outcomes and reduction of treatment-effects remains a priority. The exquisite chemosensitivity of germinoma, excellent results from monotherapy for metastatic testicular disease, and early promise of vinblastine monotherapy lend itself to further exploration for CNS-germinoma.

scholarly journals CTNI-15. CLINICAL EFFICACY OF ONC201 IN NEWLY DIAGNOSED DIPG AND IN PREVIOUSLY IRRADIATED PEDIATRIC H3 K27M-MUTANT GLIOMAS

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii45-ii45
Author(s):  
Sharon Gardner ◽  
Carl Koschmann ◽  
Rohinton S Tarapore ◽  
Jeffrey Allen ◽  
Wafik Zaky ◽  
...  
Keyword(s):  
Body Weight ◽  
Single Agent ◽  
Biologically Active ◽  
Pharmacokinetic Analysis ◽  
Low Grade ◽  
Newly Diagnosed ◽  
Liquid Formulation ◽  
Phase Ii Trials ◽  
Body Weights ◽  
Post Radiation

Abstract ONC201, an anti-cancer DRD2 antagonist and ClpP agonist, is in Phase II trials for adult H3 K27M-mutant diffuse midline gliomas. In adults, the recommended phase 2 dose (RP2D) of 625mg ONC201 once a week has been established as a biologically active dose that is well tolerated. Radiographic regressions with single agent ONC201 have been reported in adult recurrent H3 K27M-mutant glioma patients. This multi-arm, dose-escalation and dose-expansion trial determined the pediatric RP2D of ONC201 administered as an oral capsule (Arm A) or liquid formulation (Arm E) in post-radiation H3 K27M-mutant glioma (Arm A) or in newly diagnosed DIPG (Arm B) patients. Molecular assessments include intratumoral ONC201 concentrations (Arm C) and CSF H3 K27M DNA levels (Arm D). Enrollment as of April 30, 2020 is complete in Arm A (22) and Arm E (26) and continues in Arm B (18/24), Arm C (5/12), and Arm D (22/24). The RP2D of weekly 625mg ONC201 scaled by body weight was confirmed when administered as a capsule or a liquid formulation as a single agent or in combination with radiation without dose-limiting toxicity. The most frequent adverse events regardless of attribution to the drug were predominantly low grade: ONC201 capsule alone was headache (54.5%), nausea (36.4%), and fatigue (36.4%); ONC201 liquid formulation was vomiting (31.8%), headache (22.7%), VIth nerve disorder (22.7%); ONC201 capsules in combination with radiation (Arm B) was headache (47.1%), vomiting (52.9%), nausea (41.2%). Pharmacokinetic analysis in plasma of Arm A patients revealed T1/2: 8.4h; Tmax: 2.1h; Cmax: 2.3ug/mL; AUC0-tlast: 16.4ug/mL, with similar exposure across body weights. In conclusion, when scaled by body weight the ONC201 capsule or liquid formulation alone or in combination with radiation were associated with safety and pharmacokinetic profiles in pediatric H3 K27M-mutant diffuse midline glioma patients that are similar to the experience in adults.

scholarly journals Bcl-2 antagonist apogossypol (NSC736630) displays single-agent activity in Bcl-2–transgenic mice and has superior efficacy with less toxicity compared with gossypol (NSC19048)

Blood ◽  
2008 ◽  
Vol 111 (6) ◽  
pp. 3211-3219 ◽  
Author(s):  
Shinichi Kitada ◽  
Christina L. Kress ◽  
Maryla Krajewska ◽  
Lee Jia ◽  
Maurizio Pellecchia ◽  
...  
Keyword(s):  
B Cells ◽  
Transgenic Mice ◽  
Parent Compound ◽  
Single Agent ◽  
Maximum Tolerated Dose ◽  
Low Grade ◽  
Altered Expression ◽  
Cell Counts

Abstract Altered expression of Bcl-2 family proteins plays central roles in apoptosis dysregulation in cancer and leukemia, promoting malignant cell expansion and contributing to chemoresistance. In this study, we compared the toxicity and efficacy in mice of natural product gossypol and its semisynthetic derivative apo-gossypol, compounds that bind and inhibit antiapoptotic Bcl-2 family proteins. Daily oral dosing studies showed that mice tolerate doses of apogossypol 2- to 4-times higher than gossypol. Hepatotoxicity and gastrointestinal toxicity represented the major adverse activities of gossypol, with apogossypol far less toxic. Efficacy was tested in transgenic mice in which Bcl-2 is overexpressed in B cells, resembling low-grade follicular lymphoma in humans. In vitro, Bcl-2–expressing B cells from transgenic mice were more sensitive to cytotoxicity induced by apogossypol than gossypol, with LD50 values of 3 to 5 μM and 7.5 to 10 μM, respectively. In vivo, using the maximum tolerated dose of gossypol for sequential daily dosing, apogossypol displayed superior activity to gossypol in terms of reducing splenomegaly and reducing B-cell counts in spleens of Bcl-2–transgenic mice. Taken together, these studies indicate that apogossypol is superior to parent compound gossypol with respect to toxicology and efficacy, suggesting that further development of this compound for cancer therapy is warranted.

Phase I study of the combination of fludarabine, mitoxantrone, and dexamethasone in low-grade lymphoma.

1994 ◽  
Vol 12 (3) ◽  
pp. 575-579 ◽  
Author(s):  
P McLaughlin ◽  
F B Hagemeister ◽  
F Swan ◽  
F Cabanillas ◽  
O Pate ◽  
...  
Keyword(s):  
Overall Response Rate ◽  
Response Rate ◽  
Single Agent ◽  
Active Agent ◽  
Large Cell ◽  
Maximum Tolerated Dose ◽  
Low Grade ◽  
Overall Response ◽  
Nonhematologic Toxicity ◽  
High Fraction

PURPOSE Fludarabine is an active agent for patients with low-grade lymphoma (LGL) but has mainly been used as a single agent. This trial was designed to define the maximum-tolerated dose (MTD) of a combination of fludarabine, mitoxantrone, and dexamethasone (FND), to identify the toxicities of these agents in combination, and to make preliminary observations about the efficacy of this combination. PATIENTS AND METHODS Twenty-one patients with recurrent LGL or follicular large-cell lymphoma were treated, in cohorts of three, at stepwise escalating doses. Patients were required to have adequate marrow function and normal renal, hepatic, and cardiac function. RESULTS The MTD of the combination was found to be as follows: fludarabine, 25 mg/m2/d (days 1 to 3); mitoxantrone, 10 mg/m2 (day 1); and dexamethasone, 20 mg/d (days 1 to 5). Each course was administered monthly, and up to eight courses were given. Dose-limiting toxicities were neutropenia and infections. Thrombocytopenia was modest. Nonhematologic toxicity was very modest. Responses were seen at every dose level. The overall response rate was 71%, with a 43% complete remission (CR) rate. The median duration of CR was 18 months (with follow-up duration from 13 to 28+ months). CONCLUSION FND was well tolerated in this population. While our primary aim was to define the MTD, our preliminary observations on the efficacy of the regimen were favorable. The overall response rate was high, there was a high fraction of CRs, and our early impression is that these responses are durable.

scholarly journals LGG-26. DIFFUSE LEPTOMENINGEAL GLIONEURONAL TUMOR (DLGNT) IN CHILDREN: DIFFERENT CLINICAL PRESENTATIONS AND OUTCOMES

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii371-iii371
Author(s):  
Andge Valiakhmetova ◽  
Ludmila Papusha ◽  
Ludmila Yasko ◽  
Alexander Druy ◽  
Alexander Karachunsky ◽  
...  
Keyword(s):  
Mapk Pathway ◽  
Braf Inhibitor ◽  
Complete Response ◽  
Mek Inhibitor ◽  
Braf V600e ◽  
Glioneuronal Tumor ◽  
Low Grade ◽  
Conventional Chemotherapy ◽  
Diffuse Leptomeningeal Glioneuronal Tumor ◽  
Braf Fusion

Abstract Diffuse leptomeningeal glioneuronal tumor (DLGNT) is an extremely rare disease, newly recognized in the 2016 WHO classification of tumors of the CNS. Most DLGNTs are low-grade neuroepithelial tumors with variable elements of neuronal/neurocytic and glial differentiation, have diffuse leptomeningeal enhancement on MRI, and typically harbor KIAA1549-BRAF fusions. Other alterations, such as the BRAF V600E substitution, are less common. Here, we present three cases of DLGNT with different presentations and outcomes. The first patient is a 2yr-old male with KIAA1549-BRAF fusion, and was treated with Carbo/VCR chemotherapy after a biopsy, with resultant ongoing stable disease for 3.5 years. The second patient, an 8yr-old male had the BRAF V600E point mutation and was treated with conventional chemotherapy (VCR/carboplatin). On progression, he received the BRAF inhibitor vemurafenib, achieving a complete response which last 14 month. The third patient, a 27 month old male, harbored a KIAA1549-BRAF fusion and was treated at diagnosis with the MEK inhibitor trametinib. The tumor has been radiographically stable in the context of clinical improvement for 21 months since the treatment initiation, ongoing 24 month. In summary, we present further evidence of MAPK pathway alterations in children with DLGNT. We describe a range of molecular presentations and clinical outcomes, including one patient treated with conventional chemotherapy with further stabilization of disease during 3.5 years and two patients who were successfully treated with targeted therapy.

scholarly journals LGG-52. BINIMETINIB IN CHILDREN WITH PROGRESSIVE OR RECURRENT LOW-GRADE GLIOMA NOT ASSOCIATED WITH NEUROFIBROMATOSIS TYPE 1: INITIAL RESULTS FROM A MULTI-INSTITUTIONAL PHASE II STUDY

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii376-iii376
Author(s):  
Nathan Robison ◽  
Jasmine Pauly ◽  
Jemily Malvar ◽  
Sharon Gardner ◽  
Jeffrey Allen ◽  
...  
Keyword(s):  
Creatine Kinase ◽  
Dose Reduction ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Neurofibromatosis Type ◽  
Primary Objective ◽  
Preclinical Model ◽  
Low Grade ◽  
Type I ◽  
Open Label

Abstract BACKGROUND RAS/RAF/MEK/ERK pathway activation is the primary driver for most pediatric low-grade gliomas (LGG). Binimetinib is an orally bioavailable MEK1/2 inhibitor found to have significant central nervous system penetration in a preclinical model. OBJECTIVE The primary objective of this multi-institutional open-label phase II study was to assess preliminary efficacy of binimetinib in progressive pediatric LGG. The study included strata for both neurofibromatosis type I (NF1) and non-NF1 associated tumors, as well as a target validation (surgical) stratum. NF1 and surgical strata remain open to enrollment and will be reported separately. METHODS Children aged 1–18 years with previously treated recurrent or progressive LGG were eligible. The dose of binimetinib was 32 mg/m2/dose twice daily. Partial and minor responses were defined, respectively, as 50% and 25% decrease in maximal two-dimensional measurements. RESULTS Fifty-seven eligible patients without NF1, median age 8 years, were enrolled and began treatment; 26 were female; 28 had documented KIAA1549-BRAF fusion. Eleven patients discontinued drug in the first year due to toxicity, and an additional 27 required dose reduction. The most common drug-attributable grade 3 toxicities included creatine kinase elevation (n=9 patients), rash (n=8), and truncal weakness (n=8). Truncal weakness improved or resolved with dose reduction or cessation. Grade 4 toxicities included creatine kinase elevation (n=2) and transient colitis (n=1). Of 44 patients with preliminary response data available, 22 (50%) showed a minor (n=7) or partial (n=15) response. CONCLUSION Binimetinib is active, with manageable toxicities, in children without NF1 with progressive LGG.

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