CTNI-22. A PHASE 0/1 ‘TRIGGER’ TRIAL OF RIBOCICLIB PLUS EVEROLIMUS IN RECURRENT HIGH-GRADE GLIOMA

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi64-vi64
Author(s):  
Nader Sanai ◽  
An-Chi Tien ◽  
Jun Jiang ◽  
Yu-Wei Chang ◽  
Chelsea Pennington-Krygier ◽  
...  
Keyword(s):  
High Grade Glioma ◽  
High Grade ◽  
Mtor Inhibition ◽  
Who Grade ◽  
Expansion Phase ◽  
Pik3ca Mutations ◽  
Pten Loss ◽  
Drug Concentrations ◽  
Phase 0 ◽  
Unbound Concentration

Abstract BACKGROUND mTOR activation is a mechanism of resistance in CDK4/6 targeting. We evaluated tumor pharmacokinetics (PK) and tumor pharmacodynamics (PD) of combined CDK4/6 and mTOR inhibition in recurrent high-grade glioma (HGG) patients. METHODS Recurrent HGG patients with (1) intact RB, (2) CDKN2A/B deletion or CDK4/6 amplification, and (3) PTEN loss or PIK3CA mutations receive five days of presurgical ribociclib plus everolimus prior to resection at 2, 8 or 24 hours after the final dose. Beginning at 400mg QD ribociclib plus 2.5mg QD everolimus, six dose-escalations summit at 600mg QD plus 60mg QW. Gadolinium [Gd]-enhancing and nonenhancing tumor regions, CSF, and plasma are collected. Total and unbound drug concentrations are determined using validated LC-MS/MS methods. RB and S6 phosphorylation are compared to matched archival tissue. To select patients for a therapeutic expansion phase of combined drug therapy, the protocol includes a PK ‘trigger’ (i.e., for each drug, unbound concentration in Gd-nonenhancing tumor > 5-fold biochemical IC50) and a PD ‘trigger’ (i.e., for each tumor, > 30% decrease in pRB and pS6). RESULTS 21 patients with WHO Grade III (n=2) and IV (n=19) gliomas were enrolled into the Phase 0 component of the study. No dose-limiting toxicities were observed. In Gd-nonenhancing tumor regions, the median unbound concentration of ribociclib was 719 nM, whereas unbound everolimus tumor concentrations were undetectable. Across all dose-levels, 62% (13/21) and 22% (5/21) of tumors demonstrated decreased tumor RB and S6 phosphorylation, respectively. Tumor proliferation (MIB-1) was decreased in 67% (14/21) of all patients. No patients qualified for the therapeutic expansion phase. CONCLUSION In adult HGG, ribociclib achieves pharmacologically-relevant concentrations in Gd-nonenhancing tumor whereas everolimus exhibits no meaningful tumor penetration. These findings support further clinical development of ribociclib, but not everolimus, for the treatment of high-grade glioma patients.

OS05.8.A A Phase 0/1 ‘Trigger’ Trial of Ribociclib Plus Everolimus in Recurrent High-Grade Glioma

2021 ◽  
Vol 23 (Supplement_2) ◽  
pp. ii8-ii8
Author(s):  
N Sanai ◽  
A Tien ◽  
J Jiang ◽  
Y Chang ◽  
C Pennington-Krygier ◽  
...  
Keyword(s):  
Tumor Resection ◽  
High Grade Glioma ◽  
High Grade ◽  
Mtor Inhibition ◽  
Who Grade ◽  
Pik3ca Mutations ◽  
Drug Concentrations ◽  
Limit Of Quantitation ◽  
Unbound Concentration ◽  
Dose Levels

Abstract BACKGROUND The RB-CDK4/6 and mTOR signaling pathways are deregulated in high-grade glioma (HGG) and mTOR activation is a potential mechanism of resistance to CDK4/6 inhibition. This study evaluates the tumor pharmacokinetics (PK) and tumor pharmacodynamics (PD) of combined CDK4/6 and mTOR inhibition in recurrent HGG patients. MATERIAL AND METHODS Eligible patients had recurrent HGG with (1) intact RB expression, (2) CDKN2A/B deletion or CDK4/6 amplification, and (3) PTEN loss or PIK3CA mutations. Six patients received five days of presurgical ribociclib (400mg QD) plus everolimus (2.5mg QD) and then underwent tumor resection at 2, 8 or 24 hours following the last dose. Five subsequent dose-escalation cohorts each enrolled three additional patients, reaching a maximum dose-level of ribociclib (600mg QD) plus everolimus (60mg QW). Tumor tissue (gadolinium [Gd]-enhancing and nonenhancing regions), CSF, and plasma were collected. Total and unbound drug concentrations were determined using validated LC-MS/MS methods. Tumor PD effects, including RB and S6 phosphorylation, were compared to matched archival tissue. A PK ‘trigger’ (i.e., unbound concentration > 5-fold biochemical IC50) and a PD ‘trigger’ (>30% decrease in both pRB and pS6) were set for each drug. Gd-nonenhancing tissue exhibiting both PK and PD effects in excess of these thresholds qualified patients for postoperative combination therapy. RESULTS 21 patients with WHO Grade III (n=2) and WHO Grade IV (n=19) gliomas were enrolled. No dose-limiting toxicities were observed. Following presurgical drug, all patients demonstrated marked decrease in Gd-enhancement on preoperative MRI. In Gd-nonenhancing tumor regions, the median unbound concentration of ribociclib was 719 nM (i.e., > 5-fold biochemical IC50 for CDK4/6 inhibition), whereas the unbound everolimus tumor concentrations in all patients were below the lower limit of quantitation (i.e., < 0.2 nM). The median total concentrations of everolimus in tumors at dose-levels 0 to 5 were 2.9, 8.8, 10.3, 5.0, 15.7, and 13.7 nM, respectively. Across all dose-levels, 62% (13/21) and 22% (5/21) of tumors demonstrated decreased tumor RB and S6 phosphorylation, respectively. Tumor proliferation (MIB-1) was decreased in 67% (14/21) of all patients. CONCLUSION In adult HGG, ribociclib achieves pharmacologically-relevant concentrations in Gd-nonenhancing tumor, consistent with the observed tumor PD effects. Everolimus exhibits very limited penetration into human glioma tissue. Our study supports further development of ribociclib, but not everolimus, for the treatment of glioma patients.

scholarly journals CTIM-06. DENDRITIC CELL VACCINE STUDY FOR RECURRENT, HIGH-GRADE GLIOMA: TISSUE-BASED RNA SEQUENCING AND SERUM CYTOKINE LEVELS AS POTENTIAL BIOMARKERS

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii33-ii34
Author(s):  
Macarena De La Fuente ◽  
Tulay Koru-Sengul ◽  
Deborah Heros ◽  
Feng Miao ◽  
Alain Fernandez Marrero ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Rna Sequencing ◽  
Tumor Antigens ◽  
High Grade Glioma ◽  
Treatment Discontinuation ◽  
Sequencing Analysis ◽  
High Grade ◽  
Who Grade ◽  
Cytokine Levels ◽  
Grade 3

Abstract BACKGROUND Glioblastoma is the most common primary malignant brain tumor. Despite multimodality treatment approach, median progression-free survival (PFS) is only 8 months, median overall-survival (OS) 14 months and 5-year survival rate of under 10%. Dendritic cells (DCs) are the professional antigen presenting cells of the immune system. The rationale for sensitizing dendritic cells to a pool of non-selected tumor antigens is based on the marked heterogeneity present within glioblastoma tumor cells. METHODS Phase 1/feasibility study of DC vaccine for recurrent high-grade glioma was conducted. Pooled, non-selected tumor antigens collected via tumor cell lysate were used for DC sensitization. RNA sequencing analysis was performed on all tumor samples. Cytokine levels in serum were detected using a Luminex cytokine panel. RESULTS A total of 20 patients were enrolled onto this study (median age 58yrs, range: 39–74, 65% male). Pathology showed WHO grade IV glioblastoma in 14 (70%) and grade III anaplastic astrocytoma in 6 (30%) patients. IDH wild type in 19 (95%) patients. Treatment emergent adverse events (all grades, regardless of attribution) occurred in more than 15% of the patients (20% fatigue, 15% dizziness, 15% headache, none leading to treatment discontinuation). There were five grade 3–4 and none grade 5 events. One grade 4 event (seizure) probable related to investigational treatment leading to treatment discontinuation. Four grade 3 events (dysphasia, possible related; intracranial hemorrhage unrelated; muscle weakness, unlikely related and hematoma, unrelated). Median PFS was 3.8 months. Median OS was 11 months. RNA sequencing in tumor samples and correlation with cytokine levels in serum is currently been analyzed. CONCLUSION Tumor lysate pulsed DC vaccination demonstrates acceptable safety and tolerability in high-grade glioma patients. Evaluations of integrating molecular profiling RNA sequencing information and cytokine levels to identify potential subset of patients with significant clinical benefit will be provided.

scholarly journals Convection Enhanced Delivery in the Setting of High-Grade Gliomas

Pharmaceutics ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 561
Author(s):  
Chibueze D. Nwagwu ◽  
Amanda V. Immidisetti ◽  
Michael Y. Jiang ◽  
Oluwasegun Adeagbo ◽  
David C. Adamson ◽  
...  
Keyword(s):  
Rapid Development ◽  
Systemic Exposure ◽  
Therapeutic Index ◽  
High Grade Glioma ◽  
High Grade ◽  
Clinical Experiences ◽  
Convection Enhanced Delivery ◽  
Drug Concentrations ◽  
Infiltrative Growth Pattern ◽  
High Grade Gliomas

Development of effective treatments for high-grade glioma (HGG) is hampered by (1) the blood–brain barrier (BBB), (2) an infiltrative growth pattern, (3) rapid development of therapeutic resistance, and, in many cases, (4) dose-limiting toxicity due to systemic exposure. Convection-enhanced delivery (CED) has the potential to significantly limit systemic toxicity and increase therapeutic index by directly delivering homogenous drug concentrations to the site of disease. In this review, we present clinical experiences and preclinical developments of CED in the setting of high-grade gliomas.

scholarly journals High-grade glioma with anterior skull base erosion and intranasal extension: case report

2017 ◽  
Vol 126 (5) ◽  
pp. 1484-1487 ◽  
Author(s):  
Matthew T. Stib ◽  
Michael Johnson ◽  
Alan Siu ◽  
M. Isabel Almira-Suarez ◽  
Zachary Litvack ◽  
...  
Keyword(s):  
Nasal Cavity ◽  
Skull Base ◽  
Radiation Treatment ◽  
High Grade Glioma ◽  
Brain Parenchyma ◽  
Anterior Skull Base ◽  
High Grade ◽  
Who Grade ◽  
Who Grade Iii ◽  
Grade Iii

The authors describe the case of a large WHO Grade III anaplastic oligoastrocytoma extending through the anterior skull base and into the right nasal cavity and sinuses. Glial neoplasms are typically confined to the intracranial compartment within the brain parenchyma and rarely extend into the nasal cavity without prior surgical or radiation therapy. This 42-year-old woman presented with progressive headaches and sinus congestion. MR imaging findings revealed a large intracranial lesion with intranasal extension. Endoscopic nasal biopsy revealed pathology consistent with an infiltrating glioma. The patient subsequently underwent a combined transcranial/endonasal endoscopic approach for resection of this lesion. Pathological diagnosis revealed a WHO Grade III oligoastrocytoma. This report reviews the mechanisms of extradural glioma extension. To the authors' knowledge, it is the second report of a high-grade glioma exhibiting nasal extension without prior surgical or radiation treatment.

High-grade gliomas and molecular biology of neurosurgical oncology

2019 ◽  
pp. 89-106
Author(s):  
Stephen J Price ◽  
Harry Bulstrode ◽  
Richard Mair
Keyword(s):  
Molecular Markers ◽  
Who Classification ◽  
High Grade Glioma ◽  
High Grade ◽  
Optimal Management ◽  
Who Grade ◽  
Normal Human ◽  
Who Grade Iii ◽  
Grade Iii

The term high-grade glioma (HGG) encompasses a number of histological entities that are considered by the WHO Classification as WHO Grade III and IV tumours. They have traditionally been considered as having similar behaviour and had been treated in a similar manner but recent advances in our understanding of tumour biology have led to the identification of molecular markers that are now central to the classification of these tumours. Normal human cells develop into cancer cells through a stepwise accumulation of genomic and epigenomic alterations and this chapter considers the molecular markers of gliomas and explains their significance before going on to discuss the optimal management.

Evaluation of laboratory disturbance risk when adding low-dose cotrimoxazole for PJP prophylaxis to regimens of high-grade glioma patients taking RAAS inhibitors

2018 ◽  
Vol 25 (6) ◽  
pp. 1366-1373 ◽  
Author(s):  
Roland Coppens ◽  
Johanna Yang ◽  
Sunita Ghosh ◽  
John Gill ◽  
Carole Chambers ◽  
...  
Keyword(s):  
Low Dose ◽  
Elevated Serum ◽  
High Grade Glioma ◽  
Pneumocystis Jirovecii ◽  
Binary Logistic Regression Analysis ◽  
Pneumocystis Jirovecii Pneumonia ◽  
High Grade ◽  
Who Grade ◽  
Renin Angiotensin Aldosterone System ◽  
Renin Angiotensin

Background Cotrimoxazole is associated with the development of hyponatremia, hyperkalemia and elevated serum creatinine, especially when combined with inhibitors of the renin–angiotensin–aldosterone system (RAAS). Pneumocystis jirovecii pneumonia (PJP) prophylaxis is the standard of care for high-grade glioma (HGG) patients receiving temozolomide concurrently with radiotherapy, low-dose cotrimoxazole being the preferred agent. Many of these patients are also taking renin–angiotensin–aldosterone system inhibitors, however the risk of significant laboratory disturbance in these patients remains undescribed. Objective We evaluated whether high-grade glioma patients taking renin–angiotensin–aldosterone system inhibitors receiving low-dose cotrimoxazole for Pneumocystis jirovecii pneumonia prophylaxis are at additional risk of laboratory disturbances in comparison with their non-renin–angiotensin–aldosterone system counterparts. Methods We conducted a retrospective chart review of adult neuro-oncology patients treated for WHO Grade III or IV glioma between 2013 and 2016. Patient serum Na, K, creatinine, and eGFR were compared (renin–angiotensin–aldosterone system vs. non-renin–angiotensin–aldosterone system) using the chi-square test. Binary logistic regression analysis was then performed to account for differences between cohorts. Results Of 63 patients (35 non-renin–angiotensin–aldosterone system, 28 renin–angiotensin–aldosterone system), patients in the renin–angiotensin–aldosterone system cohort were more likely to experience a laboratory disturbance (odds ratio=3.17, p = 0.03). Overall, these disturbances were moderate, but were slightly more common and slightly more severe in the renin–angiotensin–aldosterone system cohort. Conclusion Adding low-dose cotrimoxazole for Pneumocystis jirovecii pneumonia prophylaxis to the regimens of patients with high-grade glioma taking renin–angiotensin–aldosterone system inhibitors increases the risk of laboratory disturbances. While these are generally moderate, some patients are at risk of significant electrolyte abnormalities requiring intervention.

scholarly journals P14.60 FET PET response upon radiochemotherapy followed by Tumor Treating Fields (TTFields) in a patient with progressive high-grade glioma

2019 ◽  
Vol 21 (Supplement_3) ◽  
pp. iii81-iii81
Author(s):  
A F Keßler ◽  
J Weiland ◽  
T Linsenmann ◽  
R Ernestus ◽  
C Hagemann ◽  
...  
Keyword(s):  
Tumor Progression ◽  
Treatment Response ◽  
High Grade Glioma ◽  
High Grade ◽  
Who Grade ◽  
Fet Pet ◽  
Tumor Treating Fields ◽  
Grade Ii ◽  
The Right ◽  
Pet Scans

Abstract BACKGROUND The addition of Tumor Treating Fields (TTFields) to the first-line therapy in glioblastoma (GBM) demonstrated significantly improved progression free survival, overall survival and longterm survival rates in the EF-14 phase 3 trial. However, responder analysis of patients with recurrent GBM (rGBM) treated with TTFields monotherapy (in the EF-11 trial) revealed delayed response monitored by MRI analysis. More recent data suggests that O-(2-18F-fluoroethyl)-L-tyrosine (FET) PET may add valuable information for monitoring therapy response of glioblastoma patients treated with TTFields. Here, we report on FET PET response in a patient with progressive anaplastic astrocytoma WHO grade III (AA) treated with TTFields in combination with temozolomide (TMZ) chemotherapy. METHODS We present a 38-year old patient with an initial diagnosis of a diffuse astrocytoma WHO grade II in 2011, and malignisation to an AA on progression. The treatment regimen included initially radio-chemotherapy (RCT) with TMZ. On further progression of the AA in 2017, TTFields were added to another 6 cycles of TMZ. Several FET PET scans for differentiation of tumor progression from treatment-related changes were performed over time. The definitive diagnosis (tumor progression and grading) was confirmed by histopathology after stereotactic biopsy (SB). RESULTS In 2012, the patient was first diagnosed with a low grade astrocytoma WHO grade II of the right frontal, temporal and parietal lobe including infiltration of thalamus and corpus was confirmed by SB, followed by irradiation. On progression in 2015, a FET PET Scan showed FET avidity in all tumor affected regions of the brain. SB confirmed an AA, while FET PET scans showed only a mild response in the temporoparietal region after 6 cycles of TMZ. In 2017, the next progression without further malignisation was confirmed by SB and treated RCT with 41.4 Gy and TMZ chemotherapy, followed by application of TTFields with an average usage rate of 85.7 % over 6 months. Thus, the TTFields adherence was well above the independent prognostic threshold of 75 %. No additional adverse events due to the combined therapy of TTFields and TMZ were observed. Due to a new contrast enhancing lesion in the right frontal lobe (10x7mm), another FET PET scan was performed 1.5 years later. In this scan, obtained after combined TTFields and RCT therapy a strong response regarding FET avidity was observed. CONCLUSION In summary, FET PET is able to add important additional information for evaluation of treatment response in high grade glioma patients, in particular for TTFields treated patients, while adding TTFields to radiochemotherapy might even enhance treatment response of high grade glioma. Further studies might elucidate the role of FET PET imaging for therapy monitoring in high grade glioma patients treated with TTFields.

Safety of nivolumab in combination with dendritic cell vaccines in recurrent high-grade glioma.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e13526-e13526
Author(s):  
Katherine B. Peters ◽  
Gerald E. Archer ◽  
Pamela Norberg ◽  
Weihua Xie ◽  
Stevie Threatt ◽  
...  
Keyword(s):  
Dendritic Cell ◽  
Surgical Resection ◽  
Phase 1 ◽  
Randomized Study ◽  
High Grade Glioma ◽  
Checkpoint Blockade ◽  
Phase Iii ◽  
High Grade ◽  
Who Grade ◽  
Dc Vaccine

e13526 Background: Recurrence of high-grade glioma (HGG) (WHO grade III-IV) is a nearly universal phenomenon and necessitates the development of new therapeutic modalities. Two possible immunotherapeutic modalities are checkpoint blockade with agents such as nivolumab, a blocking antibody against the inhibitory checkpoint programmed cell death-1 (PD-1), and dendritic cell (DC) vaccination. We have shown in phase 1 and 2 trials that DC vaccination against the glioblastoma (GBM)-associated antigen human cytomegalovirus pp65-lysosomal-associated membrane protein (CMVpp65) is safe and possesses potential benefit. We hypothesized that nivolumab-induced immune checkpoint blockade could enhance efficacy of DC vaccination. Therefore, we undertook a phase 1 study to evaluate safety of nivolumab in combination with CMVpp65 mRNA pulsed DC vaccination in subjects with first or second recurrence of resectable HGG. Methods: We performed a phase 1, single-center, randomized study of nivolumab alone versus nivolumab + DC vaccination prior to planned surgical resection for both groups. We administered nivolumab 3 mg/kg IV q2weeks for 8 weeks followed by surgery and planned continuation of nivolumab. For the group receiving nivolumab + DC vaccination, we administered 3 vaccines before surgical resection with both groups receiving 5 planned post-resection DC vaccines. Primary endpoint was safety assessment using NCI-CTCAE 4.03. Results: We enrolled 6 subjects (4: GBM, 1: anaplastic astrocytoma, 1: anaplastic oligodendroglioma) with 3 receiving nivolumab alone and 3 receiving nivolumab + DC vaccination. Age range was 45-63 years subjects. We documented similar adverse events in both groups with most common grade 1-2 toxicities being fatigue (2 subjects, nivolumab alone) and thrombocytopenia (2 subjects, nivolumab + DC vaccine). Grade 4 toxicities included wound infection (2 subjects, nivolumab + DC vaccine) and meningitis (1 subject, nivolumab + DC vaccine). While we designed the study to enroll 66 subjects, we terminated the study early in light of CheckMate 143 phase III data showing nivolumab did not improve overall survival in recurrent GBM. Conclusions: Safety of nivolumab + DC vaccination in recurrent HGG is similar to nivolumab alone. Continued evaluation of new therapeutics including immunotherapy is underway for this patient population. Clinical trial information: NCT02529072.

BMX-HGG: Phase II trial of newly diagnosed high-grade glioma treated with concurrent radiation therapy, temozolomide, and BMX-001.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS2577-TPS2577
Author(s):  
Katherine B. Peters ◽  
Adam Louis Cohen ◽  
Nicholas A. Butowski ◽  
John L. Villano ◽  
Pierre Giglio ◽  
...  
Keyword(s):  
Radiation Therapy ◽  
White Matter ◽  
Cancer Therapy ◽  
Phase Ii ◽  
Functional Assessment ◽  
Phase Ii Study ◽  
High Grade Glioma ◽  
High Grade ◽  
Newly Diagnosed ◽  
Who Grade

TPS2577 Background: Patients diagnosed with malignant high-grade gliomas (WHO grade III-IV) experience significant morbidity and mortality associated with these cancers. While the mainstay of therapy for patients with newly diagnosed high-grade glioma is surgery followed by concurrent chemotherapy and radiation therapy (RT), the outcomes remain very poor. BMX-001 (MnTnBuOE-2-PyP5+) is a metalloporphyrin with differential action in response to radiation therapy and chemotherapy-induced oxidative stress. Early preclinical studies demonstrated BMX-001’s ability to act as a radioprotectant to healthy tissue such as a central nervous white matter and as a radiosensitizer to cancer cells, in particular, human glioblastoma xenografts. We evaluated the safety of BMX-001 in combination with concurrent RT and temozolomide (TMZ) in a phase I study of newly diagnosed high-grade glioma patients, and we found that BMX-001 is safe and well-tolerated in this population. The maximum tolerated dose of BMX-001 during concurrent RT and TMZ was determined to be 28 mg delivered subcutaneously (SC) followed by 16 biweekly SC doses at 14 mg (Peters et al., Neuro-Oncology 2018). Methods: For this multi-site, open-label, phase II study (NCT02655601), we will randomize approximately 160 patients 1:1 to concurrent RT and TMZ with BMX-001 versus concurrent RT and TMZ alone. Key eligibility criteria include newly diagnosed histologically confirmed high-grade glioma (WHO III-IV), 18 ≥ years, and Karnofsky performance status ≥ 70%. The primary endpoint is overall survival. Secondary endpoints include cognitive performance as assessed by standardized cognitive testing, bone marrow protection, safety and tolerability, progression-free survival, overall tumor response rate, and plasma pharmacokinetics. Exploratory endpoints are health-related quality of life (as assessed by Functional Assessment of Cancer Therapy–Brain, Functional Assessment of Cancer Therapy-Cognition, and Functional Assessment of Chronic Illness Therapy-Fatigue), qualitative hair loss, and white matter integrity (as measured by MRI diffusion tensor/susceptibility imaging). Since November 2018, this phase II study has enrolled 64 of 160 high-grade glioma patients at six sites with future sites planned to be implemented. Clinical trial information: NCT02655601 .

Effect of temozolomide chronotherapy in patients with high-grade glioma.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e14525-e14525 ◽  
Author(s):  
Himachandana Atluri ◽  
Jian Li Campian ◽  
Grayson Talcott ◽  
Melissa Meyer ◽  
Emily Slat ◽  
...  
Keyword(s):  
Statistical Significance ◽  
Biological Rhythms ◽  
Progression Free Survival ◽  
High Grade Glioma ◽  
Well Being ◽  
Current Therapy ◽  
High Grade ◽  
Who Grade ◽  
Significant Difference ◽  
Morning Administration

e14525 Background: High grade gliomas (HGG) (the most common being glioblastoma) are the most common primary CNS malignancy in adults. Mainstay of therapy is surgical resection followed by concurrent radiation and temozolomide (TMZ) followed by adjuvant TMZ. Unfortunately, prognosis remains poor and optimization of current therapy is critical. Chronotherapy is defined as improvement in treatment outcomes by maximizing treatment efficacy and minimizing toxicity by administering medications in accordance with biological rhythms of the patient. In a mouse model, there was greater anti-tumor efficacy during morning administration of TMZ. This trial was designed to determine the feasibility and potential clinical impact of chrono-therapeutically administering TMZ in patients with HGG. Methods: Adult patients ( > 18 years) with HGG (WHO Grade III/IV) were eligible. Patients were screened and consented prior to initiation of monthly TMZ therapy. Eligible patients were randomized to TMZ in the morning (AM) before 10AM or in the evening (PM) after 8PM. Pill diaries were recorded for drug administration time and compliance. Fact-Br Quality of Life (QoL) surveys were administered to patients at the time of enrollment in the trial and at the end of treatment to measure differences in QoL in both groups. Circadian rhythm was recorded by Actiwatch. Adverse events (AE), overall survival (OS) and progression free survival (PFS) were measured for each group. Results: At the time of submission, a total of 28 patients were evaluated. 15 patients were in AM group and 13 in PM group. It is feasible for participants to take TMZ per study assignment. There was no significant difference in the QoL based on the Fact-Br dataset in the four main categories of physical well-being, social/family well-being, functional well-being and emotional well-being. The Friedman’s two-way nonparametric ANOVA tests were used to analyze the differences across time points. Cytopenias are a known adverse effect of TMZ. There was a trend towards worsening lymphocyte counts in the AM group compared to PM group, although not statistically significant. There was no statistical significance in PFS or OS in patients with newly diagnosed glioblastoma. Conclusions: Chronotherapy with TMZ is feasible. A trend of worsening lymphocyte counts is noted in AM treatment group compared to PM group but was not statistically significant. No difference in OS or PFS was noted, although sample size was too small to effectively assess this. A larger study will need to be conducted to effectively assess the effect of chronotherapy on survival. Clinical trial information: NCT02781792.

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