scholarly journals DDRE-10. METABOLIC TARGETING OF HUMAN GLIOBLASTOMA USING 5-AMINOLEVULINIC ACID (ALA)-MEDIATED SONODYNAMIC THERAPY: A FIRST-IN-HUMAN STUDY

2020 ◽  
Vol 3 (Supplement_1) ◽  
pp. i8-i8
Author(s):  
Stuart Marcus ◽  
Nader Sanai
Keyword(s):  
Brain Tumor ◽  
Internal Control ◽  
Tumor Tissue ◽  
Aminolevulinic Acid ◽  
Clinical Care ◽  
Human Study ◽  
Time Interval ◽  
Sonodynamic Therapy ◽  
Phase 0 ◽  
Recurrent Gbm

Abstract Heme biosynthesis is altered in glioblastoma (GBM). Systemic dosing with ALA, the first committed molecule in the heme pathway, results in accumulation of the fluorescent intermediate, protoporphyrin IX (PpIX) only within tumor tissue (Gleolan label, 2019). PpIX is a photosensitizer that is effective in photodynamic therapy (PDT); in recurrent GBM patients, the safety and feasibility of ALA PDT has been demonstrated (Johansson A, et al. Lasers Surg Med 2013;45:225), although the practicality of this strategy in clinical care remains uncertain. Importantly, preclinical models of GBM show that PpIX is also a sonosensitizer and, in combination with transcranial MRI-guided focused ultrasound (MRgFUS), leads to non-ablative cytotoxic effects in vivo (Jeong EJ et al, Ultrasound in Medicine and Biology 2013:38;2143, Suehiro S et al, J Neurosurg 2018: 1377, Wu et al Nature Sci Reports 2019: 9;10465). The Ivy Brain Tumor Center is conducting a first-in-human study of 5-ALA sonodynamic therapy (SDT) for recurrent GBM (NCT 04559685). In this Phase 0/1 clinical trial, nontherapeutic, single-treatment SDT is administered prior to planned tumor resection. A Dose-Escalation Arm varies the power/energy of the MRgFUS while using a fixed time-interval from exposure to surgery. A subsequent Time-Escalation Arm varies the interval between MRgFUS and surgical resection, but fixes the power/energy of the delivered ultrasound. In both Arms, patient tumor tissue is assessed for sonodynamic and pharmacodynamic effects. In each patient, half of the tumor volume is not targeted with SDT and serves as an internal control. This first-in-human study will demonstrate the safety and feasibility of ALA sonodynamic therapy in GBM and may provide the first-ever biological evidence of sonosensitization in a brain tumor patient. If successful, this Phase 0 trial will introduce a new, metabolically-driven, GBM treatment modality that may be applicable to any brain tumor that selectively accumulates PpIX after ALA administration.

CTNI-48. A PHASE 0 ‘TRIGGER’ TRIAL OF CDK4/6 PLUS ERK1/2 INHIBITORS IN RECURRENT GLIOBLASTOMA

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi70-vi71
Author(s):  
Nader Sanai ◽  
Yu-Wei Chang ◽  
Tigran Margaryan ◽  
Anita DeSantis ◽  
Mackenna Elliott ◽  
...  
Keyword(s):  
Tumor Tissue ◽  
Drug Dose ◽  
Recurrent Glioblastoma ◽  
Optimal Time ◽  
Time Interval ◽  
Tumor Proliferation ◽  
Drug Concentrations ◽  
Phase 0 ◽  
Recurrent Gbm ◽  
Dual Drug

Abstract BACKGROUND This dual-drug Phase 0 study (NCT04391595) evaluates the tumor pharmacokinetics (PK) and tumor pharmacodynamics (PD) of abemaciclib, a selective CDK4/6-inhibitor, plus LY3214996, a selective ERK1/2 inhibitor, in recurrent GBM patients. METHODS Adult recurrent GBM patients (n=10) with intact RB expression, > 30% pERK expression, and CDKN2A/B deletion or CDK4/6 amplification received six days of abemaciclib (150mg BID) plus LY3214996 (200mg QD) prior to a planned resection at 3-5 or 7-9 hour time interval after the final drug dose in a Time-Escalation Arm. Tumor tissue (gadolinium [Gd]-enhancing and nonenhancing regions), cerebrospinal fluid (CSF), and plasma were collected. Total and unbound drug concentrations were measured using validated LC-MS/MS methods. Tumor PD effects, including RB and RSK phosphorylation, were compared to matched archival or pre-treatment biopsied tissue. A PK ‘trigger’ (i.e., unbound concentration > 5x biochemical IC50) was set for each drug. Gd-nonenhancing tumor tissue exhibiting abemaciclib and LY3214996 concentrations in excess of their trigger threshold qualified patients for postoperative dual-drug therapy. RESULTS No dose-limiting toxicities were observed. In Gd-nonenhancing tumor regions, median unbound concentrations of abemaciclib were 31.2 nM (3-5 hour cohort) and 25.1 nM (7-9 hour cohort) while median unbound concentrations of LY3214996 were 52.0 nM (3-5 hour cohort) and 10.2 nM (7-9 hour cohort). Tumor RB and RSK phosphorylation decreased in 6/10 and 2/10 patients, respectively. Tumor proliferation (MIB-1) was decreased in 8/10 patients. 5/10 patients exceeded PK thresholds for both abemaciclib (12 nM) and LY3214996 (25 nM), thereby entering the study’s therapeutic expansion phase. CONCLUSION Abemaciclib and LY3214996 achieve pharmacologically-relevant concentrations in Gd-non-enhancing GBM tissue and are associated with suppression of RB pathway and tumor proliferation. The Optimal Time Interval (OTI) for tissue sampling was 3-5 hours after the final drug dose. Based on this interim analysis, the trial will accrue an additional 25 patients at this OTI.

A Phase 0 ‘trigger’ trial of CDK4/6 plus ERK1/2 inhibitors in recurrent glioblastoma.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2005-2005
Author(s):  
Nader Sanai ◽  
Yu-Wei Chang ◽  
Tigran Margaryan ◽  
Anita DeSantis ◽  
Mackenna Elliott ◽  
...  
Keyword(s):  
Interim Analysis ◽  
Tumor Tissue ◽  
Mapk Signaling ◽  
Drug Dose ◽  
Time Interval ◽  
Tumor Proliferation ◽  
Drug Concentrations ◽  
Phase 0 ◽  
Recurrent Gbm ◽  
Dual Drug

2005 Background: The RB-CDK4/6 and MAPK signaling pathways are dysregulated in glioblastoma (GBM). Our recent phase 0 study of ribociclib in recurrent GBM patients suggested that CDK4/6 inhibitor monotherapy is not durable. In this ongoing, dual-drug phase 0 study (NCT04391595), we evaluate the tumor pharmacokinetics (PK) and tumor pharmacodynamics (PD) of abemaciclib, a selective CDK4/6-inhibitor, plus LY3214996, a selective ERK1/2 inhibitor, in recurrent GBM patients. Methods: Adult patients eligible for this open-label, multi-center phase 0 protocol had recurrent GBM with (1) intact RB expression, (2) >30% pERK expression, and (3) CDKN2A/B deletion or CDK4/6 amplification. Prior to a planned resection, patients received six days of abemaciclib (150mg BID) plus LY3214996 (200mg QD). In a Time-Escalation Arm, ten patients were assigned to 3-5 hour or 7-9 hour intervals from final drug dose to tumor removal. Tumor tissue (gadolinium [Gd]-enhancing and nonenhancing regions), cerebrospinal fluid (CSF), and plasma were collected. Total and unbound drug concentrations were measured using validated LC-MS/MS methods. Tumor PD effects, including RB and RSK phosphorylation, were compared to matched archival or pre-treatment biopsied tissue. A PK ‘trigger’ ( i.e., unbound concentration > 5x biochemical IC50) was set for each drug. Gd-nonenhancing tumor tissue exhibiting abemaciclib and LY3214996 concentrations in excess of their trigger threshold qualified patients for postoperative dual-drug therapy. Results: In this interim analysis, no dose-limiting toxicities were observed. In Gd-nonenhancing tumor regions, median unbound concentrations of abemaciclib (including its equipotent M2 and M20 metabolites) were 31.2 nM (3-5 hour cohort) and 25.1 nM (7-9 hour cohort). In the same tissue, median unbound concentrations of LY3214996 were 52.0 nM (3-5 hour cohort) and 10.2 nM (7-9 hour cohort). Tumor RB and RSK phosphorylation decreased in 6/10 and 2/10 patients, respectively. Gd-enhancing tumor proliferation (MIB-1) was decreased in 8/10 patients. 5/10 patients exceeded PK thresholds for both abemaciclib (12 nM) and LY3214996 (25 nM), thereby entering the study’s therapeutic expansion phase. Conclusion: Abemaciclib and LY3214996 achieve pharmacologically-relevant concentrations in Gd-non-enhancing GBM tissue and are associated with suppression of the RB pathway and tumor proliferation. Following 6 days of presurgical drug exposure, the Optimal Time Interval (OTI) for tissue sampling was 3-5 hours after the final drug dose. Based on this interim analysis, the trial will accrue an additional 25 patients at this OTI. Clinical trial information: NCT04391595.

CTNI-23. A FIRST-IN-HUMAN PHASE 0/1 CLINICAL TRIAL OF 5-AMINOLEVULINIC ACID SONODYNAMIC THERAPY IN RECURRENT GLIOBLASTOMA

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi64-vi64
Author(s):  
Nader Sanai ◽  
An-Chi Tien ◽  
Artak Tovmasyan ◽  
Yu-Wei Chang ◽  
Tigran Margaryan ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Tumor Cell ◽  
Internal Control ◽  
Aminolevulinic Acid ◽  
Biological Effects ◽  
Recurrent Glioblastoma ◽  
Tumor Cell Death ◽  
Sonodynamic Therapy ◽  
Phase 0

Abstract 5-Aminoleveulinic acid sonodynamic therapy (5-ALA SDT) is a drug-device strategy that exploits the metabolic liabilities of cancer. Following systemic administration of 5-ALA, aberrant tumor metabolism leads to accumulation of protoporphyrin-IX (PpIX). Activation of PpIX by non-invasive, non-ablative magnetic resonance-guided focused ultrasound (MRgFUS) induces reactive oxygen species and tumor cell death. This first-in-human Phase 0/1 study investigates the feasibility, safety, and biological effects of 5-ALA SDT in recurrent glioblastoma (GBM) patients. Six hours prior to SDT, adult patients with recurrent GBM are administered Sonala-001 (10mg/kg), an IV formulation of 5-ALA. In a Dose-Escalation Arm, 9-18 patients are assigned to one of three ascending acoustic energy doses of MRgFUS (200J/400J/800J, measured at transducer surface), followed by a four-day interval to planned tumor resection. In each patient, half the tumor volume, including Gadolinium-enhancing and nonenhancing tumor, is targeted with MRgFUS and the other half serves as an internal control. Using tumor pharmacodynamic endpoints, the Minimum Biological Dose (MBD) associated with 5-ALA SDT response is identified. In a subsequent Time-Escalation Arm, 12 patients are treated at the MBD and assigned to one of two time-intervals between SDT and resection. As of May 1, accrual to the 200J dose level (n=3) is complete without significant drug- or device-related adverse events. No cellular or radiographic changes to non-targeted tissue were detected. The median Cmax for 5-ALA and PpIX were 307 µM and 319 nM, respectively. The oxidative stress biomarkers 4-hydroxynonenal, glutathione, cysteine, and thiol were significantly elevated in treated tissue vs. control. Similarly, the apoptosis biomarker cleaved caspase-3 was increased in treated tumor vs. control (median, 48.6% vs. 29.6%, p=0.05). This first-in-human experience with a new therapeutic modality for recurrent glioblastoma patients demonstrates that 5-ALA SDT is safe at 200J. Sonodynamic therapy leads to targeted oxidative stress and tumor cell death in human glioblastoma tissue.

scholarly journals Phase 0 and window of opportunity clinical trial design in neuro-oncology: a RANO review

2020 ◽  
Vol 22 (11) ◽  
pp. 1568-1579 ◽  
Author(s):  
Michael A Vogelbaum ◽  
Daria Krivosheya ◽  
Hamid Borghei-Razavi ◽  
Nader Sanai ◽  
Michael Weller ◽  
...  
Keyword(s):  
Brain Tumor ◽  
Trial Design ◽  
Human Study ◽  
Clinical Trial Design ◽  
Drug Level ◽  
New Drugs ◽  
Window Of Opportunity ◽  
Surgical Specimen ◽  
Number Of Patients ◽  
Phase 0

Abstract Glioblastoma is a devastating disease with poor prognosis. Few effective chemotherapeutics are currently available, and much effort has been expended to identify new drugs capable of slowing tumor progression. The phase 0 trial design was developed to facilitate early identification of promising agents for cancer that should undergo accelerated approval. This design features an early in-human study that enrolls a small number of patients who receive subtherapeutic doses of medication with the goals of describing pharmacokinetics through drug blood level measurements and determining intratumoral concentrations of the investigational compound as well as pharmacodynamics by studying the biochemical and physiological effects of drugs. In neuro-oncology, however, the presence of the blood–brain barrier and difficulty in obtaining brain tumor tissue warrant a separate set of considerations. In this paper, we critically reviewed the protocols used in all brain tumor related in-human phase 0 and phase 0–like (“window of opportunity”) studies between 1993 and 2018, as well as ongoing clinical trials, and identified major challenges in trial design as applied to central nervous system tumors that include surgical specimen collection and storage, brain tumor drug level analysis, and confirmation of drug action. We therefore propose that phase 0 trials in neuro-oncology should include (i) only patients in whom a resection of the tumor is planned, (ii) use of clinical doses of an investigational agent, (iii) tissue sampling from enhancing and non-enhancing portions of the tumor, and (iv) assessment of drug-specific target effects. Standardization of clinical protocols for phase 0/window of opportunity studies can help accelerate the development of effective treatments for glioblastoma.

scholarly journals Macroscopic fluorescence-lifetime imaging of NADH and protoporphyrin IX improves the detection and grading of 5-aminolevulinic acid-stained brain tumors

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Mikael T. Erkkilä ◽  
David Reichert ◽  
Johanna Gesperger ◽  
Barbara Kiesel ◽  
Thomas Roetzer ◽  
...  
Keyword(s):  
Brain Tumor ◽  
Brain Tumors ◽  
Fluorescence Lifetime ◽  
Tumor Tissue ◽  
Aminolevulinic Acid ◽  
Protoporphyrin Ix ◽  
Low Grade ◽  
Wide Field ◽  
Fluorescence Lifetime Imaging ◽  
Lifetime Imaging

AbstractMaximal safe tumor resection remains the key prognostic factor for improved prognosis in brain tumor patients. Despite 5-aminolevulinic acid-based fluorescence guidance the neurosurgeon is, however, not able to visualize most low-grade gliomas (LGG) and infiltration zone of high-grade gliomas (HGG). To overcome the need for a more sensitive visualization, we investigated the potential of macroscopic, wide-field fluorescence lifetime imaging of nicotinamide adenine dinucleotide (NADH) and protoporphyrin IX (PPIX) in selected human brain tumors. For future intraoperative use, the imaging system offered a square field of view of 11 mm at 250 mm free working distance. We performed imaging of tumor tissue ex vivo, including LGG and HGG as well as brain metastases obtained from 21 patients undergoing fluorescence-guided surgery. Half of all samples showed visible fluorescence during surgery, which was associated with significant increase in PPIX fluorescence lifetime. While the PPIX lifetime was significantly different between specific tumor tissue types, the NADH lifetimes did not differ significantly among them. However, mainly necrotic areas exhibited significantly lower NADH lifetimes compared to compact tumor in HGG. Our pilot study indicates that combined fluorescence lifetime imaging of NADH/PPIX represents a sensitive tool to visualize brain tumor tissue not detectable with conventional 5-ALA fluorescence.

scholarly journals 347MO 5-Aminolevulinic acid sonodynamic therapy in recurrent glioblastoma: A first-in-human phase 0/1 clinical trial

2021 ◽  
Vol 32 ◽  
pp. S518-S519
Author(s):  
N. Sanai ◽  
A-C. Tien ◽  
A. Tovmasyan ◽  
Y-W. Chang ◽  
T. Margaryan ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Aminolevulinic Acid ◽  
Recurrent Glioblastoma ◽  
Sonodynamic Therapy ◽  
Phase 0

Feasibility and phase I trial of tandutinib in patients with recurrent glioblastoma

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 2039-2039 ◽  
Author(s):  
J. G. Supko ◽  
S. A. Grossman ◽  
D. M. Peereboom ◽  
S. Chowdhary ◽  
G. J. Lesser ◽  
...  
Keyword(s):  
Brain Tumor ◽  
Phase I ◽  
Dose Level ◽  
Phase Ii ◽  
Phase I Study ◽  
Tumor Tissue ◽  
Recurrent Glioblastoma ◽  
The Mean ◽  
Grade 3 ◽  
Recurrent Gbm

2039 Background: Platelet-derived growth factor signaling is important in gliomagenesis and PDGFR-β is expressed on >90% of endothelial cells in glioblastoma specimens. Methods: We report the results of a feasibility and phase I study of tandutinib (MLN518), an orally bioavailable, quinazoline-based inhibitor of type III receptor tyrosine kinases including PDGFR-β, FLT-3, and c-Kit, in patients with recurrent glioblastoma (GBM) conducted in the New Approaches to Brain Tumor Therapy (NABTT) consortium. Results: A feasibility study was conducted in 6 recurrent GBM patients in whom resection was clinically indicated. These patients received tandutinib 500-mg BID for 7 days prior to resection. In these patients, the drug was measured in tumor tissue and plasma samples obtained shortly before and after the resection by LC/MS. The mean ± SD concentration of tandutinib in tumor tissue was 7.2 ± 3.2 μg/mL and the mean ratio of its concentration in brain tumor-to-plasma was 9.6 ± 7.7. A phase I study was conducted in 19 patients to determine the MTD in this recurrent GBM population with sequential assessment of the following dose levels: 500-, 600-, and 700-mg BID. Four patients were replaced due to early withdrawal unrelated to toxicity. Dose limiting toxicities were observed in 1/6 patients at 500-mg BID (grade 3 phosphorous, grade 3 fatigue, grade 3 somnolence in 1 patient); 1/6 patients at 600-mg BID (grade 3 phosphorous); 2/3 patients at 700-mg BID (grade 3 fatigue, grade 3 weakness). 600-mg BID was declared the MTD and a phase II study has been initiated at this dose level. Conclusions: The mean brain tumor tissue-to-plasma ratio of tandutinib in GBM patients receiving 500-mg BID exceeded the estimated threshold ratio of 0.33 that was considered as being necessary to achieve local cytotoxic concentrations in brain tumors. The MTD of tandutinib in the recurrent GBM population is 600-mg BID. A phase II trial has been initiated at this dose level. [Table: see text]

A phase 0 first-in-human study using NU-0129: A gold base spherical nucleic acid (SNA) nanoconjugate targeting BCL2L12 in recurrent glioblastoma patients.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 3012-3012 ◽  
Author(s):  
Priya Kumthekar ◽  
Alfred Rademaker ◽  
Caroline Ko ◽  
Karan Dixit ◽  
Margaret A. Schwartz ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Tumor Tissue ◽  
Human Study ◽  
Tumor Resection ◽  
Brain Barrier ◽  
Open Label ◽  
Apoptotic Markers ◽  
Blood Brain ◽  
Phase 0 ◽  
Grade 3

3012 Background: Glioblastoma is a difficult to treat tumor with therapeutics limited by their ability to cross the blood brain barrier. SNAs, i.e., gold nanoparticle cores covalently conjugated with a corona of densely packed, highly oriented siRNA oligonucleotides targeted to the GBM oncogene BCL2L12, represent a novel class of blood-brain and blood-tumor barrier-permeable nanomedicinal conjugates, for suppressing gene expression in the tumors of GBM patients. Methods: This is a single-arm, open-label, “window of opportunity” phase 0 first-in-human trial to determine the safety and bioavailability of a novel nanotherapeutic compound, NU-0129. Enrolled patients were treated with intravenous NU-0129 at the dose of 0.04mg/kg. This treatment dosing was considered microdosing defined as 1/50ththe NOAEL (no observed adverse event level) from non-human primate studies. Treatment was followed by tumor resection 8-48 hours later. Primary outcome patient safety and toxicity was monitored weekly for 3 weeks post-infusion. Secondary objectives included biodistribution of NU0129 in tissue, evaluation of pharmacokinetics of NU0129 and the feasibility of NU0129 administration. Exploratory objectives included Bcl2L12 expression and post treatment apoptotic markers as well as progression free survival and overall survival rates. Results: 8 patients were enrolled, treated and subsequently underwent surgical resection. No significant treatment related toxicities were seen. Severe ( > grade 3) adverse events were observed in two patients: hypophosphatemia (one grade 3, one grade 4) and one patient with grade 3 lymphopenia, all were considered as “possibly related” by treating oncologists. In 6 of the 8 patients sufficient tumor tissue was available for analysis of gold accumulation by ICP-MS (inductively coupled plasma-mass spectrometry), and gold accumulation was seen in the tumor tissue of all 6 of these patients. Conclusions: Macrodosing of the nanotherapeutic NU-0129 was well tolerated in glioblastoma patients with no unexpected adverse effects and showed initial evidence of crossing blood brain barrier. Immunohistochemistry for Bcl2L12 expression, apoptotic markers, and PK studies are pending. The demonstration of gold nanoparticles in the tumor tissue validates this approach for drug delivery. Clinical trial information: NCT03020017.

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