scholarly journals Phase I trial of convection-enhanced delivery of IL13-Pseudomonas toxin in children with diffuse intrinsic pontine glioma

2019 ◽  
Vol 23 (3) ◽  
pp. 333-342 ◽  
Author(s):  
John D. Heiss ◽  
Aria Jamshidi ◽  
Smit Shah ◽  
Staci Martin ◽  
Pamela L. Wolters ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Phase I ◽  
Disease Progression ◽  
Performance Status ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Pontine Glioma ◽  
Convection Enhanced Delivery ◽  
Antitumor Effects ◽  
Radiographic Findings ◽  
Long Term Treatment

OBJECTIVEIn this clinical trial report, the authors analyze safety and infusion distribution of IL13-Pseudomonas exotoxin, an antitumor chimeric molecule, administered via intratumoral convection enhanced delivery (CED) in pediatric patients with diffuse intrinsic pontine glioma (DIPG).METHODSThis was a Phase I single-institution, open-label, dose-escalation, safety and tolerability study of IL13-PE38QQR infused via single-catheter CED into 5 pediatric DIPG patients. IL13-PE38QQR was administered to regions of tumor selected by radiographic findings. Two escalating dose levels were evaluated: 0.125 µg/mL in cohort 1 and 0.25 µg/mL in cohort 2. Real-time MRI was performed during intratumoral infusions, and MRI and MR spectroscopy were performed before and after the infusions. Clinical evaluations, including parent-reported quality of life (QOL), were assessed at baseline and 4 weeks post-infusion.RESULTSDirect infusion of brainstem tumor with IL13-PE using the CED technique in patients with DIPG produced temporary arrest of disease progression in 2 of 5 patients, both of whom subsequently received a second infusion. All 5 patients showed signs of disease progression by 12 weeks after initial infusion. Two patients experienced transient cranial nerve deficits and lethargy after infusion, and these deficits resolved with corticosteroid treatment in both cases. No patient had radiographic evidence of acute or long-term treatment toxicity. Parent-reported QOL was consistent with medical outcomes.CONCLUSIONSEven though IL13-PE delivered by CED did not reach the entire MRI-defined tumor volume in any patient, short-term radiographic antitumor effects were observed in 2 of the 5 patients treated. The patients’ performance status did not improve. Drug delivery using multiple catheters may produce improved outcomes.Clinical trial registration no.: NCT00088061 (clinicaltrials.gov)

ProCAID: A phase I clinical trial to combine the AKT inhibitor AZD5363 with docetaxel and prednisolone (DP) chemotherapy for metastatic castration resistant prostate cancer (mCRPC).

2016 ◽  
Vol 34 (2_suppl) ◽  
pp. 228-228 ◽  
Author(s):  
Simon J. Crabb ◽  
Alison J. Birtle ◽  
Karen Martin ◽  
Nichola Downs ◽  
Megan Bowers ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Protein Kinase ◽  
Phase I ◽  
Disease Progression ◽  
Phase Ii ◽  
Performance Status ◽  
Research Network ◽  
Castration Resistant Prostate Cancer ◽  
Akt Inhibitor ◽  
Clinical Resistance

228 Background: DP extends survival in mCRPC. However emergent clinical resistance is effectively inevitable. Serine/threonine protein kinase AKT (protein kinase B) pathway activation is highly prevalent in mCRPC contributing to disease progression and DP therapeutic resistance. AZD5363 is a potent oral pan-AKT inhibitor. Pre-clinical data suggest activity in mCRPC and synergy with docetaxel. This phase I trial was to develop a DP/AZD5363 combination in mCRPC. Methods: Eligibility included chemotherapy naive histologically/cytologically proven measurable/evaluable mCRPC, PSA or radiographic disease progression, ECOG performance status 0 or 1, serum testosterone <1.7 nmol/L. Treatment comprised DP up to 10 cycles (75 mg/m2, IV, day 1; prednisolone 5 mg BID, PO, day 1–21) and AZD5363 to disease progression. Planned AZD5363 dose levels were 320 mg (DL1), 400 mg (DL2) and 480 mg (DL3), BID, PO, 4 days on/3 days off, from cycle 1, day 2. We utilised a conventional 3+3 dose escalation to determine a recommended phase II dose (RP2D) for AZD5363 combined with DP according to defined dose limiting toxicity (DLT) using CTCAEv4. Results: 10 patients were recruited (4 DL1, 6 DL2), median age 67.5 (Range: 56-72). A median of 6.5 cycles (Range: 3-10) of DP and 4 cycles (Range: 1-13) of AZD5363 were administered. No DLTs were seen in DL1. 2 patients in DL2 experienced DLTs (G3 rash, G3 diarrhoea). 7 pts (70%) had at least one G3/4 IMP-related AE with neutropenia (n=3) and maculo-papular rash (n=3) the most common. G3/4 AEs considered related to AZD5363 occurred in 3 patients (0 DL1, 3 DL2) including maculo-papular rash, diarrhoea and neutropenia. Transient hyperglycaemia occurred in all patients (Random glucose C1D2 pre dose mean 6.0 mmol/L, 2 hour mean 8.7 mmol/L, 4 hour mean 9.5 mmol/L, 8 hour mean 6.5 mmol/L). Conclusions:The RP2D for AZD5363 is 320 mg bd 4 days on/3 days off in combination with full dose DP for mCRPC. A placebo controlled randomised phase II trial for this approach has commenced recruitment. This work was supported by CRUK [C9317/A16029]. CRUK Reference: CRUK/12/042. This research was conducted with support from the Investigator-Sponsored Study Collaboration between AstraZeneca and the National Cancer Research Network. Clinical trial information: NCT02121639.

A phase I study of convection enhanced delivery (CED) of 124I-8H9 radio-labeled monoclonal antibody in children with diffuse intrinsic pontine glioma (DIPG).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 2010-2010 ◽  
Author(s):  
Mark M. Souweidane ◽  
Kim Kramer ◽  
Neeta Pandit-Taskar ◽  
Pat Zanzonico ◽  
Zhiping Zhou ◽  
...  
Keyword(s):  
Phase I ◽  
Brain Stem ◽  
Absorbed Dose ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Pontine Glioma ◽  
Open Label ◽  
Convection Enhanced Delivery ◽  
Dose Escalation Study ◽  
The Mean ◽  
The Brain

2010 Background: Diffuse intrinsic pontine glioma (DIPG) represents one of the most deadly central nervous system tumors of childhood with a median survival of less than 12 months. Convection-enhanced delivery (CED) has been recently hypothesized as a means for augmenting distribution of therapeutic agents within the brain stem. We conducted this study to evaluate CED in children with DIPG. Methods: We performed a standard 3+3 phase I, open-label, dose escalation study in patients with non-progressive DIPG 4 to 14 weeks post-completion or radiation therapy. Seven dose levels of a single injection of 124I-8H9 (range 0.25 to 4.0 mCi, 250 to 4000 mcl) were studied. Results: 25 children were treated. The average age at enrollment 8 years old (range 3-17). There was no dose limiting toxicity (DLT) and adverse events were limited to grade 1 or 2 (CTCAE v4.0). Estimations of distribution volumes were dose dependent and ranged from 1.5 to 20.1 cm3. The mean volume of distribution/volume of infusion (Vd/Vi) was 3.4 (SD 1.2). The mean lesion absorbed dose was 1527 rad/mCi. The mean tumor coverage on dose level 7 was 107%. Conclusions: CED in the brain stem of children with DIPG who were previously irradiated is a safe therapeutic strategy. Up to 4 mCi of 124I-8H9 was well tolerated. An infusion volume of 4000 mcl appears to be a reasonable single dose for good tumor coverage. PET-based dosimetry validates the conceptual basis for direct drug delivery. Based on our finding CED merits further exploration in early phase clinical trials for children with DIPG. Clinical trial information: NCT01502917.

scholarly journals DIPG-40. TARGETING MASTER REGULATOR DEPENDENCIES IN DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii294-iii295
Author(s):  
Jovana Pavisic ◽  
Chankrit Sethi ◽  
Chris Jones ◽  
Stergios Zacharoulis ◽  
Andrea Califano
Keyword(s):  
Gene Expression ◽  
Expression Profiles ◽  
Treatment Options ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Low Grade ◽  
Precision Oncology ◽  
Pontine Glioma ◽  
Convection Enhanced Delivery ◽  
Master Regulator

Abstract Diffuse intrinsic pontine glioma (DIPG) remains a fatal disease with no effective drugs to date. Mutation-based precision oncology approaches are limited by lack of targetable mutations and genetic heterogeneity. We leveraged systems biology methodologies to discover common targetable disease drivers—master regulator proteins (MRs)—in DIPG to expand treatment options. Using the metaVIPER algorithm, we interrogated an integrated low grade glioma and GBM gene regulatory network with 31 DIPG-gene expression signatures to identify tumor-specific MRs by differential expression of their transcriptional targets. Unsupervised clustering identified MR signatures of upregulated activity in RRM2/TOP2A in 13 patients, CD3D in 5 patients, and MMP7, TACSTD2, RAC2 and SLC15A1/SLC34A2 in individual patients, all of which can be targeted. Notably, intratumoral administration of etoposide by convection enhanced delivery was effective in murine proneural gliomas in which TOP2 was identified as a MR while RRM2—targetable by drugs such as cladribine—has been shown to be a positive regulator of glioma progression whose knock-down inhibits tumor growth. We also prioritized drugs by their ability to reverse MR-activity signatures using a large drug-perturbation database. Patients clustered by predicted drug sensitivities with distinct groups of tumors predicted to respond to proteasome inhibitors, Thiotepa or Volasertib all of which have early evidence in treating gliomas. We will refine this analysis in a multi-institutional study of &gt;100 patient gene expression profiles to define MR signatures driving known biological/molecular disease subtypes, use DIPG cell lines recapitulating common MR architectures to optimize therapy prioritization, and validate our findings in vivo.

scholarly journals EPCT-06. A PHASE I STUDY OF MULTI-TARGETED THERAPY IN NEWLY DIAGNOSED OR PROGRESSIVE DIFFUSE INTRINSIC PONTINE GLIOMA

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii304-iii305
Author(s):  
Muhammad Baig ◽  
Jason Johnson ◽  
Sumit Gupta ◽  
Zsila Sadighi ◽  
Wafik Zaky ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Maintenance Therapy ◽  
Phase I ◽  
Phase I Study ◽  
Diffusion Tensor ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Newly Diagnosed ◽  
Pontine Glioma ◽  
Dose Limiting Toxicity

Abstract BACKGROUND Diffuse intrinsic pontine glioma (DIPG) constitutes 80% of pediatric brain stem tumors with a median survival of 12 months. The PI3K/AKT/mTOR pathway is a key oncogenic driver of this tumor. Targeting the chromatin dysregulation through HDAC inhibition, demonstrated benefit in vivo and vitro studies. We completed the first study as a multi-targeted therapy using SAHA and temsirolimus in pediatric DIPG. METHODS After receiving institutional IRB approval, we enrolled 6 patients on this phase I study using a 3 + 3 statistical design. Patients were divided into stratum 1 and stratum 2, based on newly diagnosed or relapsed DIPG respectively. Stratum I patients received radiation therapy concurrently with vorinostat, followed by maintenance therapy with vorinostat and temsirolimus for 10 cycles (28 day cycle), while in stratum II patients received vorinostat and temsirolimus for 12 cycles. Neuroimaging including diffusion tensor imaging were evaluated where feasible. RESULTS Three patients were enrolled in each of the stratum. One patient in stratum 1 completed therapy, 2 other demonstrated progressive disease (PD) after 4th and 1st cycle of maintenance therapy respectively. In stratum 2 all patients progressed 2 months after the start of therapy. However no dose-limiting toxicity (DLT) was noted. The patient in stratum 1 who completed therapy, remained free of PD 21 months after diagnosis with continued improvements in the volume of enhancing and T2 hyperintense disease. CONCLUSION Although no significant benefit was seen as compared to historical controls during this study, no dose limiting toxicity was noticed with this treatment.

scholarly journals A novel magnetic resonance imaging segmentation technique for determining diffuse intrinsic pontine glioma tumor volume

2016 ◽  
Vol 18 (5) ◽  
pp. 565-572 ◽  
Author(s):  
Ranjodh Singh ◽  
Zhiping Zhou ◽  
Jamie Tisnado ◽  
Sofia Haque ◽  
Kyung K. Peck ◽  
...  
Keyword(s):  
Confidence Limit ◽  
Interobserver Agreement ◽  
Tumor Volume ◽  
Correlation Coefficients ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Pontine Glioma ◽  
Convection Enhanced Delivery ◽  
Subjective Judgment ◽  
Low Degree ◽  
Picture Archiving And Communication

OBJECTIVE Accurately determining diffuse intrinsic pontine glioma (DIPG) tumor volume is clinically important. The aims of the current study were to 1) measure DIPG volumes using methods that require different degrees of subjective judgment; and 2) evaluate interobserver agreement of measurements made using these methods. METHODS Eight patients from a Phase I clinical trial testing convection-enhanced delivery (CED) of a therapeutic antibody were included in the study. Pre-CED, post–radiation therapy axial T2-weighted images were analyzed using 2 methods requiring high degrees of subjective judgment (picture archiving and communication system [PACS] polygon and Volume Viewer auto-contour methods) and 1 method requiring a low degree of subjective judgment (k-means clustering segmentation) to determine tumor volumes. Lin's concordance correlation coefficients (CCCs) were calculated to assess interobserver agreement. RESULTS The CCCs of measurements made by 2 observers with the PACS polygon and the Volume Viewer auto-contour methods were 0.9465 (lower 1-sided 95% confidence limit 0.8472) and 0.7514 (lower 1-sided 95% confidence limit 0.3143), respectively. Both were considered poor agreement. The CCC of measurements made using k-means clustering segmentation was 0.9938 (lower 1-sided 95% confidence limit 0.9772), which was considered substantial strength of agreement. CONCLUSIONS The poor interobserver agreement of PACS polygon and Volume Viewer auto-contour methods highlighted the difficulty in consistently measuring DIPG tumor volumes using methods requiring high degrees of subjective judgment. k-means clustering segmentation, which requires a low degree of subjective judgment, showed better interobserver agreement and produced tumor volumes with delineated borders.

scholarly journals Provider Recommendations for Phase I Clinical Trials Within a Shared Decision-Making Model in Phase I Cancer Clinical Trial Discussions

2020 ◽  
Vol 16 (9) ◽  
pp. e859-e867
Author(s):  
Rachel S. Hianik ◽  
Gavin P. Campbell ◽  
Eli Abernethy ◽  
Colleen Lewis ◽  
Christina S. Wu ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Decision Making ◽  
Clinical Trials ◽  
Phase I ◽  
Shared Decision Making ◽  
Phase I Trial ◽  
Performance Status ◽  
Shared Decision ◽  
Phase I Clinical Trials ◽  
Decision Making Model

PURPOSE: Debate continues over whether explicit recommendations for a clinical trial should be included as an element of shared decision making within oncology. We aimed to determine if and how providers make explicit recommendations in the setting of phase I cancer clinical trials. METHODS: Twenty-three patient/provider conversations about phase I trials were analyzed to determine how recommendations are made and how the conversations align with a shared decision-making framework. In addition, 19 providers (9 of whose patient encounters were observed) were interviewed about the factors they consider when deciding whether to recommend a phase I trial. RESULTS: We found that providers are comprehensive in the factors they consider when recommending clinical trials. The two most frequently stated factors were performance status (89%) and patient preferences (84%). Providers made explicit recommendations in 19 conversations (83%), with 12 of those being for a phase I trial (12 [63%] of 19). They made these recommendations in a manner consistent with a shared decision-making model; 18 (95%) of the 19 conversations during which a recommendation was made included all steps, or all but 1 step, of shared decision making, as did 11 of the 12 conversations during which a phase I trial was recommended. In 7 (58%) of these later conversations, providers also emphasized the importance of the patient’s opinion. CONCLUSION: We suggest that providers not hesitate to make explicit recommendations for phase I clinical trials, because they are able to do so in a manner consistent with shared decision making. With further research, these results can be applied to other clinical trial settings.

scholarly journals ABC Transporter Inhibition Plus Dexamethasone Enhances the Efficacy of Convection Enhanced Delivery in H3.3K27M Mutant Diffuse Intrinsic Pontine Glioma

Neurosurgery ◽  
2019 ◽  
Vol 86 (5) ◽  
pp. 742-751 ◽  
Author(s):  
Vadim Tsvankin ◽  
Rintaro Hashizume ◽  
Hiroaki Katagi ◽  
James E Herndon ◽  
Christopher Lascola ◽  
...  
Keyword(s):  
Abc Transporter ◽  
Kinase Inhibitor ◽  
Mutant Cell ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Pontine Glioma ◽  
Convection Enhanced Delivery ◽  
P Glycoprotein ◽  
Magnetic Resonance Imaging Mri

Abstract BACKGROUND An impermeable blood–brain barrier and drug efflux via ATP-binding cassette (ABC) transporters such as p-glycoprotein may contribute to underwhelming efficacy of peripherally delivered agents to treat diffuse intrinsic pontine glioma (DIPG). OBJECTIVE To explore the pharmacological augmentation of convection-enhanced delivery (CED) infusate for DIPG. METHODS The efficacy of CED dasatinib, a tyrosine kinase inhibitor, in a transgenic H3.3K27M mutant murine model was assessed. mRNA expression of ABCB1 (p-glycoprotein) was analyzed in 14 tumor types in 274 children. In Vitro viability studies of dasatinib, the p-glycoprotein inhibitor, tariquidar, and dexamethasone were performed in 2 H3.3K27M mutant cell lines. Magnetic resonance imaging (MRI) was used to evaluate CED infusate (gadolinium/dasatinib) distribution in animals pretreated with tariquidar and dexamethasone. Histological assessment of apoptosis was performed. RESULTS Continuous delivery CED dasatinib improved median overall survival (OS) of animals harboring DIPG in comparison to vehicle (39.5 and 28.5 d, respectively; P = .0139). Mean ABCB1 expression was highest in K27M gliomas. In Vitro, the addition of tariquidar and dexamethasone further enhanced the efficacy of dasatinib (P &lt; .001). In Vivo, MRI demonstrated no difference in infusion dispersion between animals pretreated with dexamethasone plus tariquidar prior to CED dasatinib compared to the CED dasatinib. However, tumor apoptosis was the highest in the pretreatment group (P &lt; .001). Correspondingly, median OS was longer in the pretreatment group (49 d) than the dasatinib alone group (39 d) and no treatment controls (31.5 d, P = .0305). CONCLUSION ABC transporter inhibition plus dexamethasone enhances the efficacy of CED dasatinib, resulting in enhanced tumor cellular apoptosis and improved survival in H3.3K27M mutant DIPG.

scholarly journals Correction to: A phase I/II study of gemcitabine during radiotherapy in children with newly diagnosed diffuse intrinsic pontine glioma

2017 ◽  
Vol 136 (1) ◽  
pp. 219-220
Author(s):  
Sophie E. M. Veldhuijzen van Zanten ◽  
Fatma E. El‑Khouly ◽  
Marc H. A. Jansen ◽  
Dewi P. Bakker ◽  
Esther Sanchez Aliaga ◽  
...  
Keyword(s):  
Phase I ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Newly Diagnosed ◽  
Pontine Glioma
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