Dataset Information

First-in-Human Phase I Clinical Trial of Pharmacologic Ascorbate Combined with Radiation and Temozolomide for Newly Diagnosed Glioblastoma.

ABSTRACT: PURPOSE:Standard treatment for glioblastoma (GBM) includes surgery, radiation therapy (RT), and temozolomide (TMZ), yielding a median overall survival (OS) of approximately 14 months. Preclinical models suggest that pharmacologic ascorbate (P-AscH-) enhances RT/TMZ antitumor effect in GBM. We evaluated the safety of adding P-AscH- to standard RT/TMZ therapy. PATIENTS AND METHODS:This first-in-human trial was divided into an RT phase (concurrent RT/TMZ/P-AscH-) and an adjuvant (ADJ) phase (post RT/TMZ/P-AscH- phase). Eight P-AscH- dose cohorts were evaluated in the RT phase until targeted plasma ascorbate levels were achieved (?20 mmol/L). In the ADJ phase, P-AscH- doses were escalated in each subject at each cycle until plasma concentrations were ?20 mmol/L. P-AscH- was infused 3 times weekly during the RT phase and 2 times weekly during the ADJ phase continuing for six cycles or until disease progression. Adverse events were quantified by CTCAE (v4.03). RESULTS:Eleven subjects were evaluable. No dose-limiting toxicities occurred. Observed toxicities were consistent with historical controls. Adverse events related to study drug were dry mouth and chills. Targeted ascorbate plasma levels of 20 mmol/L were achieved in the 87.5 g cohort; diminishing returns were realized in higher dose cohorts. Median progression-free survival (PFS) was 9.4 months and median OS was 18 months. In subjects with undetectable MGMT promoter methylation (n = 8), median PFS was 10 months and median OS was 23 months. CONCLUSIONS:P-AscH-/RT/TMZ is safe with promising clinical outcomes warranting further investigation.

SUBMITTER: Allen BG

PROVIDER: S-EPMC6858950 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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First-in-Human Phase I Clinical Trial of Pharmacologic Ascorbate Combined with Radiation and Temozolomide for Newly Diagnosed Glioblastoma.

Allen Bryan G BG Bodeker Kellie L KL Smith Mark C MC Monga Varun V Sandhu Sonia S Hohl Raymond R Carlisle Thomas T Brown Heather H Hollenbeck Nancy N Vollstedt Sandy S Greenlee Jeremy D JD Howard Matthew A MA Mapuskar Kranti A KA Seyedin Steven N SN Caster Joseph M JM Jones Karra A KA Cullen Joseph J JJ Berg Daniel D Wagner Brett A BA Buettner Garry R GR TenNapel Mindi J MJ Smith Brian J BJ Spitz Douglas R DR Buatti John M JM

Clinical cancer research : an official journal of the American Association for Cancer Research 20190819 22

<h4>Purpose</h4>Standard treatment for glioblastoma (GBM) includes surgery, radiation therapy (RT), and temozolomide (TMZ), yielding a median overall survival (OS) of approximately 14 months. Preclinical models suggest that pharmacologic ascorbate (P-AscH<sup>-</sup>) enhances RT/TMZ antitumor effect in GBM. We evaluated the safety of adding P-AscH<sup>-</sup> to standard RT/TMZ therapy.<h4>Patients and methods</h4>This first-in-human trial was divided into an RT phase (concurrent RT/TMZ/P-AscH< ...[more]

PMID: 31427282

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Project description:Treatment of glioblastoma xenografts with chloroquine results in macroautophagy/autophagy inhibition, resulting in a reduction of tumor hypoxia and sensitization to radiation. Preclinical data show that EGFRvIII-expressing glioblastoma may benefit most from chloroquine because of autophagy dependency. This study is the first to explore the safety, pharmacokinetics and maximum tolerated dose of chloroquine in combination with radiotherapy and concurrent daily temozolomide in patients with a newly diagnosed glioblastoma. This study is a single-center, open-label, dose-finding phase I trial. Patients received oral chloroquine daily starting one week before the course of chemoradiation (temozolomide 75 mg/m2/d) until the end of radiotherapy (59.4 Gy/33 fractions). Thirteen patients were included in the study (n = 6: 200 mg, n = 3: 300 mg, n = 4: 400 mg chloroquine). A total of 44 adverse events, possibly related to chloroquine, were registered including electrocardiogram QTc prolongation, irreversible blurred vision and nausea/vomiting resulting in cessation of temozolomide or delay of adjuvant cycles. The maximum tolerated dose was 200 mg chloroquine. Median overall survival was 16 months (range 2-32). Median survival was 11.5 months for EGFRvIII- patients and 20 months for EGFRvIII+ patients. A daily dose of 200 mg chloroquine was determined to be the maximum tolerated dose when combined with radiotherapy and concurrent temozolomide for newly diagnosed glioblastoma. Favorable toxicity and promising overall survival support further clinical studies.Abbreviations: AE: adverse events; CQ: chloroquine; DLT: dose-limiting toxicities; EGFR: epidermal growth factor receptor; GBM: glioblastoma; HCQ: hydroxychloroquine; IDH1/2: isocitrate dehydrogenase (NADP(+)) 1/2; MTD: maximum tolerated dose; CTC: National Cancer Institute Common Toxicity Criteria; MGMT: O-6-methylguanine-DNA methyltransferase; OS: overall survival; po qd: per os quaque die; SAE: serious adverse events; TMZ: temozolomide; WHO: World Health Organization.

Project description:PurposeDespite intensive treatment with surgery, radiation therapy, temozolomide (TMZ) chemotherapy, and tumor-treating fields, mortality of newly diagnosed glioblastoma (nGBM) remains very high. SurVaxM is a peptide vaccine conjugate that has been shown to activate the immune system against its target molecule survivin, which is highly expressed by glioblastoma cells. We conducted a phase IIa, open-label, multicenter trial evaluating the safety, immunologic effects, and survival of patients with nGBM receiving SurVaxM plus adjuvant TMZ following surgery and chemoradiation (ClinicalTrials.gov identifier: NCT02455557).MethodsSixty-four patients with resected nGBM were enrolled including 38 men and 26 women, in the age range of 20-82 years. Following craniotomy and fractionated radiation therapy with concurrent TMZ, patients received four doses of SurVaxM (500 μg once every 2 weeks) in Montanide ISA-51 plus sargramostim (granulocyte macrophage colony-stimulating factor) subcutaneously. Patients subsequently received adjuvant TMZ and maintenance SurVaxM concurrently until progression. Progression-free survival (PFS) and overall survival (OS) were reported. Immunologic responses to SurVaxM were assessed.ResultsSurVaxM plus TMZ was well tolerated with no serious adverse events attributable to SurVaxM. Of the 63 patients who were evaluable for outcome, 60 (95.2%) remained progression-free 6 months after diagnosis (prespecified primary end point). Median PFS was 11.4 months and median OS was 25.9 months measured from first dose of SurVaxM. SurVaxM produced survivin-specific CD8+ T cells and antibody/immunoglobulin G titers. Apparent clinical benefit of SurVaxM was observed in both methylated and unmethylated patients.ConclusionSurVaxM appeared to be safe and well tolerated. The combination represents a promising therapy for nGBM. For patients with nGBM treated in this manner, PFS may be an acceptable surrogate for OS. A large randomized clinical trial of SurVaxM for nGBM is in progress.

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Project description:BackgroundThe impact of prolonging temozolomide (TMZ) maintenance beyond six cycles in newly diagnosed glioblastoma (GBM) remains a topic of discussion. We investigated the effects of prolonged TMZ maintenance on progression-free survival (PFS) and overall survival (OS).Patients and methodsIn this retrospective single-center cohort study, we included patients with GBM who were treated with radiation therapy with concomitant and adjuvant TMZ. For analysis, patients were considered who either completed six TMZ maintenance cycles (group B), continued with TMZ therapy beyond six cycles (group C), or stopped TMZ maintenance therapy within the first six cycles (group A). Patients with progression during the first six TMZ maintenance cycles were excluded.ResultsClinical data from 107 patients were included for Kaplan-Meier analyses and 102 for Cox regressions. Median PFS times were 8.1 months (95% confidence interval [CI] 6.1-12.4) in group A, 13.7 months (95% CI 10.6-17.5) in group B, and 20.9 months (95% CI 15.2-43.5) in group C. At first progression, response rates of TMZ/lomustine rechallenge were 47% in group B and 13% in group C. Median OS times were 12.7 months (95% CI 10.3-16.8) in group A, 25.2 months (95% CI 17.7-55.5) in group B, and 28.6 months (95% CI 24.4-open) in group C. Nevertheless, multivariate Cox regression for patients in group C compared with group B that accounted for imbalances of other risk factors showed no different relative risk (RR) for OS (RR 0.77, p = .46).ConclusionOur data do not support a general extension of TMZ maintenance therapy beyond six cycles. The Oncologist 2017;22:570-575 IMPLICATIONS FOR PRACTICE: Radiation therapy with concomitant and adjuvant temozolomide (TMZ) maintenance therapy is still the standard of care in patients below the age of 65 years in newly diagnosed glioblastoma. However, in clinical practice, many centers continue TMZ maintenance therapy beyond six cycles. The impact of this continuation is controversial and has not yet been addressed in prospective randomized clinical trials. We compared the effect of more than six cycles of TMZ in comparison with exactly six cycles on overall survival (OS) and progression-free survival (PFS) by multivariate analysis and found a benefit in PFS but not OS. Thus, our data do not suggest prolonging TMZ maintenance therapy beyond six cycles, which should be considered in neurooncological practice.

Dataset Information

First-in-Human Phase I Clinical Trial of Pharmacologic Ascorbate Combined with Radiation and Temozolomide for Newly Diagnosed Glioblastoma.

Publications

First-in-Human Phase I Clinical Trial of Pharmacologic Ascorbate Combined with Radiation and Temozolomide for Newly Diagnosed Glioblastoma.

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