- Giuseppe Minniti (Siena, Italy)
- Dieta Brandsma (Amsterdam, Netherlands)
277O - The ReSPECT-GBM™ phase I/IIa trial of rhenium-186 nanoliposome (186RNL) in recurrent glioma via convection enhanced delivery (CED) and planned phase IIb trial
- Andrew J. Brenner (San Antonio, United States of America)
Abstract
Background
A phase I/IIa dose escalation trial was initiated to determine the safety and recommended phase II dose (RP2D) of 186RNL in patients with recurrent glioma. 186RNL is a source of high energy beta and gamma particles. We report the safety, feasibility, overall survival (OS), RP2D and proposed phase IIb clinical plan.
Methods
All recurrent glioma patients had computerized treatment planning and up to 4 intracranial catheter(s) placed. Each patient received a single administration of 186RNL by CED. Whole body planar and SPECT/CT imaging on days 1-8 following treatment assessed dosimetry and radiation distribution. Patients were followed for safety, sufficiency of radiation delivery and OS.
Results
Twenty-one patients across 6 dose cohorts received 1.0-22.3mCi in 0.6-8.8mL. Mean tumor volume was 8.3mL. Patients had a mean of 1.7 recurrences and poor prognostic factors. Mean absorbed radiation dose to the tumor (MARDT) was 271Gy with negligible systemic exposure. There were no dose limiting toxicities and the overall safety profile was favorable. Patients were stratified by MARDT. Those receiving >100Gy MARDT (n=12) had a median and mean OS of 129.7 (95% CI 35 to 169.1) and 106.4±19.7 weeks respectively with 4 patients alive. Patients receiving ≤100Gy MARDT (n=9) had a median and mean OS of 22.3 (95% CI 6.4 to 45.3) and 24.6±4.8 weeks respectively, none are alive. Kaplan Meier analysis of patients receiving MARDT >100Gy vs. those with ≤100Gy showed a statistically significant difference in OS (p<0.001).
MARDT (Gy) Median OS (w) 95% CI (w) Mean±SE (w) ≤100 22.3 6.4, 45.3 24.6±4.8 >100 129.7 35, 169.1 100.8±19
Conclusions
A single administration of 186RNL by CED in recurrent glioma patients with poor prognosis is feasible, safe, and potentially effective in increasing OS when >100Gy radiation is delivered to the tumor. A RP2D of 22.3mCi/8.8mL was selected for patients with tumors of up to 15mL in the PIIb trial planned for 2022. The PIIb trial design and comparative survival data (synthetic control arm) will also be presented.
Clinical trial identification
NCT011906385.
Legal entity responsible for the study
The authors.
Funding
NIH/National Cancer Institute, Plus Therapeutics.
Disclosure
A.J. Brenner: Financial Interests, Personal, Ownership Interest: NanoTx; Financial Interests, Personal and Institutional, Research Grant: NIH/NCI; Financial Interests, Personal, Advisory Role: Plus Therapeutics. W.T. Phillips, A. Bao: Financial Interests, Personal, Ownership Interest: NanoTX; Financial Interests, Personal, Advisory Role: Plus Therapeutics. M.H.H. Hedrick: Financial Interests, Personal and Institutional, Member of the Board of Directors: Plus Therapeutics. N. LaFrance: Financial Interests, Personal, Full or part-time Employment: Plus. All other authors have declared no conflicts of interest.
278O - Preliminary results of a phase II study of retifanlimab (PD-1 inhibitor) plus or minus epacadostat (IDO1 inhibitor) in combination with bevacizumab and hypofractionated radiotherapy for recurrent glioblastoma: NCT03532295
- Jian L. Campian (Rochester, United States of America)
Abstract
Background
Immunotherapies targeting the PD-1 pathway in recurrent glioblastoma (rGBM) have failed. We hypothesize that combining therapies targeting multiple immunosuppressive pathways with cytotoxic and antiangiogenic therapies will improve survival. Here, we evaluate the safety and efficacy of an anti-PD-1 monoclonal antibody (retifanlimab), hypofractionated radiotherapy (HFRT), and bevacizumab, with or without an oral IDO1 inhibitor (epacadostat), in patients with rGBM in a nonrandomized, noncomparative sequential two-arm phase II study.
Methods
This is an open-label phase II study of 2 sequential cohorts. Cohort A first examines retifanlimab (500mg IV Q4W)+ bevacizumab (10mg/kg IV Q2W) + HFRT (3.5Gy/day x10) in patients with
Results
We have completed accrual for cohort A and the interim analysis results are presented here: 25 rGBM enrolled, with 23 evaluable. Median age is 64.3 years (42.1-81.8), 30.4% female, 30.4%
Conclusions
Interim analysis suggests retifanlimab combined with HFRT and bevacizumab in patients with rGBM is well-tolerated and had encouraging OS and PFS at the time of data cutoff. Cohort B, which adds epacadostat, is currently enrolling.
Clinical trial identification
NCT03532295.
Editorial acknowledgement
NA
Legal entity responsible for the study
The authors.
Funding
Incyte.
Disclosure
J.L. Campian: Non-Financial Interests, Institutional, Principal Investigator: Merck. A. Kim: Non-Financial Interests, Institutional, Funding: Monteris. M. Ciorba: Non-Financial Interests, Institutional, Funding: Incyte. M. Chheda: Non-Financial Interests, Institutional, Research Grant, PI for Orbus, Incyte and Merck trials: NeoImmuneTech. All other authors have declared no conflicts of interest.
Invited Discussant 277O and 278O
- Giuseppe Minniti (Siena, Italy)
Q&A
- All Speakers (Lugano, Switzerland)
279O - ctDNA detection in cerebrospinal fluid and concordance with the primary tumor in a multicenter prospective study of patients with glioma
- Santiago Cabezas-Camarero (Madrid, Spain)
Abstract
Background
Gliomas are the most common primary brain tumors, but there are currently many limitations for the implementation of liquid biopsy in this disease. Cerebrospinal fluid (CSF) is emerging as the most reliable reservoir for ctDNA analysis, although evidence is still limited.
Methods
Prospective study of patients with gliomas diagnosed at Hospital Clinico Universitario San Carlos and Hospital Universitario La Paz (Madrid, Spain). High throughput next generation sequencing (NGS) using a customized gene panel (Illumina, Inc.) of 8 genes (IDH1, IDH2, ATRX, TP53, PTEN, PIK3CA, EGFR, BRAF) was used in paired CSF and FFPE and/or fresh tumor samples, and run in an Illumina Miseq instrument (Illumina, Inc.). Only confirmed pathogenic mutations were considered as valid and are reported here. Mutation concordance occurred when the same pathogenic gene variants were detected in tumor and CSF.
Results
Between February 2017 and March 2020, 31 glioma patients (pts) were enrolled in which 2-5 ml of CSF were collected intraoperatively prior to surgical manipulation of the tumor. M:F ratio: 22:9. Median age 51 (Min-Max: 20-78). CSF collected at new diagnosis (n=22); relapse (n=9). WHO 5th Ed: IDHMUT astrocytoma (n=9), IDHMUT oligodendroglioma (n=6), IDHWT glioblastoma (n=16). CSF-ctDNA-positive: 18/31 (58%). CSF-ctDNA-negative: 13/31 (42%). No. of mutations in CSF: 1 (9/18), 2 (7/18), 3 (2/18). Frequency of CSF-ctDNA mutated genes: EGFR (8/18: 44%), PTEN (7/18: 39%), TP53 (6/18: 33%), IDH1 (4/18: 22%), PIK3CA (4/18: 22%). Tumor-CSF mutation concordance: 15/18 (83%). After a median follow-up since CSF collection of 20 months (m) (Min-Max: 0-57), median OS was not reached (NR) (95%CI NR-NR). No correlation was found between detection of ctDNA in CSF and distance from closest CSF reservoir, tumor size or IDH status.
Conclusions
CSF is a reliable reservoir for ctDNA analyses in patients with gliomas. Larger, prospective studies should be conducted in order to refine the potential role of liquid biopsy in this disease.
Legal entity responsible for the study
The authors.
Funding
Study funded thanks to the BECA GEINO 2016 from Grupo Español de Investigación en Neuro-Oncología (GEINO).
Disclosure
S. Cabezas-Camarero: Financial Interests, Personal, Invited Speaker: BMS, Merck Serono, MSD; Financial Interests, Personal, Expert Testimony: MSD, BMS, Merck Serono; Financial Interests, Personal, Advisory Board: Merck Serono; Financial Interests, Institutional, Funding: Merck Serono. All other authors have declared no conflicts of interest.
280O - Pharmacokinetics and pharmacodynamics of paxalisib in newly diagnosed glioblastoma patients with unmethylated MGMT promoter status: Final phase II study results
- John F. De Groot (Houston, United States of America)
Abstract
Background
Paxalisib is being developed for the treatment of glioblastoma multiforme (GBM). Post hoc analysis of phase 1 fluorodeoxyglucose-positron emission tomography (FDG-PET) scans suggested that paxalisib crosses the blood-brain barrier with a uniform distribution throughout the brain.
Methods
The recently completed phase 2 trial (NCT03522298) enrolled patients with newly diagnosed GBM with unmethylated MGMT promoter status following surgical resection and chemotherapy (Stupp Regimen). Study outcomes comprised maximum tolerated dose (MTD), safety, preliminary efficacy, pharmacokinetics (PK) at the MTD under fed and fasted conditions and change in FDG-PET uptake in patients with measurable disease.
Results
Patients (n=30; 70.0% males, mean age 58.5 years) received between 1 and 29 treatment cycles. At the MTD (60 mg/day), paxalisib prolonged median progression free survival (8.4 months [RANO], 8.6 months [mRANO]) and improved median overall survival (15.7 months). Paxalisib was steadily absorbed (median Tmax 2.5 and 4 hours postdose) and declined with a mean elimination half-life ranging from 20.2 to 29.0 hours. Mean half-life (20.2 to 29.0 hours) was similar across dose levels and under fed and fasted conditions. Systemic exposure to paxalisib appeared slightly higher for the 60 mg fed status compared to 60 mg fasted status. Comparison of fed versus fasted treatment was statistically significant for Cmax at the 90% level (geometric least squares mean ratios: AUC0-last 1.33, AUC0-inf 1.06, and Cmax 1.52). Ten patients underwent FDG-PET imaging, 8 (80%) had a decrease in FDG uptake on Day 3 and/or Day 7 in Cycle 1 and 4 (40%) had a metabolic partial response.
Conclusions
PK parameters were consistent with prior clinical experience and there was no evidence of a deviation from dose-proportionality. At the MTD FDG-PET data provide evidence that paxalisib has the ability to exert biological effect in tumour tissue, irrespective of fed or fasted status. Further evaluation is ongoing in GBM AGILE (NCT03970447).
Clinical trial identification
NCT03522298.
Editorial acknowledgement
Hazel Palmer ISMP CMPP, Scriptix Pty Ltd., Sydney, NSW, Australia.
Legal entity responsible for the study
Kazia Therapeutics Limited.
Funding
Kazia Therapeutics Limited.
Disclosure
P. Wen: Financial Interests, Personal, Advisory Role: Agios, AstraZeneca, Vascular Biogenics, VBI Vaccines, Tocagen, Bayer, Blue Earth Diagnostics, Karyopharm Therapeutics, Voyager Therapeutics, QED Therapeutics, Imvax, ElevateBio, Integral Health, Prelude Therapeutics, Novocure, Mundipharma, Black Diamond Therapeutics, Day One Biopharmaceuticals, Sapience Therapeutics, Nuvation Bio, Celularity, Novartis, Merck, Boston Pharmaceuticals, Chimerix; Financial Interests, Institutional, Funding, Research Funding: Agios, AstraZeneca, Merck, Novartis, Oncoceutics, Lilly, Beigene, Kazia Therapeutics, MediciNova, Vascular Biogenics, VBI Vaccines, Puma Biotechnology, Celgene, Bayer, Nuvation Bio, Chimerix, Karyopharm Therapeutics. J.F. de Groot: Other, Personal, Full or part-time Employment, Recipient is Immediate Family Member: ZIOPHARM Oncology; Financial Interests, Personal, Advisory Role: Genetech/Roche, AbbVie, Merck, Mundipharma Research, GenomiCare, KIYATEC, resTORbio, Janssen, Bioasis Technologies, InSightec, DelMar Pharmaceuticals, Samus Therapeutics, Magnolia Innovation, Karyopharm Therapeutics, Prelude Therapeutics, Cure Brain Cancer Foundation, Sapience Therapeutics, GlaxoSmithKline, Tocagen, Voyager Therapeutics, Novartis, Debiopharm Group, Agios, Monteris Medical; Other, Personal, Leadership Role, Recipient is Immediate Family Member: ZIOPHARM Oncology; Financial Interests, Personal, Other: VBI Vaccines; Financial Interests, Personal, Stocks/Shares: Gilead Sciences, WuXi Biologics; Other, Personal, Ownership Interest, Recipient is Immediate Family Member: ZIOPHARM Oncology; Financial Interests, Personal, Funding, Research funding: CarThera, Haihe Pharmaceutical, Taiho Pharmaceutical. J. Battiste: Financial Interests, Personal, Other: SVN Med. S. Goldlust: Financial Interests, Personal, Full or part-time Employment: Regional Cancer Care Associates; Financial Interests, Personal, Advisory Role: NovoCure, Boston Biomedical, Sumitomo Dainippon Pharma Oncology, Cellevolve; Financial Interests, Personal, Leadership Role: Cellevolve; Financial Interests, Personal, Speaker’s Bureau: NovoCure; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: NovoCure, Caris Life Sciences, Kyowa Kirin International; Financial Interests, Personal, Stocks/Shares: COTA; Financial Interests, Personal, Other, Honoraria: Cornerstone Specialty Network, Daiichi Sankyo/AstraZeneca, Physicans' Education Resource; Financial Interests, Institutional, Funding, Research Funding: NovoCure, Celldex, Cortice Biosciences, Acerta Pharma, Bristol Myers Squibb, Tocagen, Wex Pharmaceuticals, Northwest Biotherapeutics, AbbVie, Celgene, Boston Biomedical, Cantex Pharmaceuticals, Diffusion Pharmaceuticals, Amgen, CNS Healthcare, Karyopharm Therapeutics, Novogen, Pfizer, Sanofi, Kazia Therapeutics, Imvax, Merck, Regeneron, Boehringer Ingelheim, Ono Pharmaceutical, Sumitomo Dainippon Pharma Oncology, Celularity; Financial Interests, Institutional, Funding, Research fundingResearch Funding: ImmunoCellular Therapeutics. D. Damek: Financial Interests, Institutional, Funding, Research Funding: Kazia Therapeutics, NovoCure. B. Ellingson: Financial Interests, Personal, Advisory Role: Siemens, Medicenna, MedQIA, Imaging Endpoints, Neosoma, Kazia Therapeutics, VBL Therapeutics, Global Coalition for Adaptive Research, Servier, Janssen, Chimerix, Sumitomo Dainippon Pharma Oncology, ImmunoGenesis, Ellipses Pharma, Monteris Medical, Alpheus Medical; Financial Interests, Personal, Funding, Research funding: Siemens, Jansssen; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Siemens. J. Garner: Financial Interests, Personal, Full or part-time Employment: Kazia Therapeutics; Financial Interests, Personal, Leadership Role: Kazia Therapeutics; Financial Interests, Personal, Stocks/Shares: Kazia Therapeutics. J. Friend: Financial Interests, Personal, Full or part-time Employment: Helsinn Therapeutics, Kazia Therapeutics; Financial Interests, Personal, Leadership Role: Helsinn Therapeutics, Kazia Therapeutics; Financial Interests, Personal, Stocks/Shares: Kazia Therapeutics. J. Simpson: Financial Interests, Personal, Full or part-time Employment: Kazia Therapeutics; Financial Interests, Personal, Leadership Role: Kazia Therapeutics; Financial Interests, Personal, Stocks/Shares: Kazia Therapeutics. A. Olivero: Financial Interests, Personal, Advisory Role: Genentech/Roche, ORIC Pharmaceuticals, Imugene, Kazia Therapeutics, Genentech; Financial Interests, Personal, Royalties, Has patents fro employment with Genentech/Roche: Genentech/Roche; Financial Interests, Personal, Stocks/Shares: Roche, Kazia Therapeutics; Financial Interests, Personal, Full or part-time Employment: Genentech; Financial Interests, Personal, Leadership Role: Genentech; Financial Interests, Personal, Other, Research funding in the form of medical writing support, furnished by Daniel Clyde, PhD, of Health Interactions,: F. Hoffmann-La Roche Ltd.; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Kazia Therapeutics, Genentech. T. Cloughesy: Financial Interests, Personal, Advisory Role: Roche/Genentech, Tocagen, VBL Therapeutics, Novartis, Agios, AbbVie, Pfizer, Bristol Myers Squibb, Merck, GW Pharmaceuticals, Boehringer Ingelheim, KIYATEC, VBI Vaccines, Bayer, DelMar Pharmaceuticals, QED Therapeutics, Amgen, Pascal Biosciences, Karyopharm Therapeutics, Katmai Pharmaceuticals, Global Coalition for Adaptive Research, DNAtrix, Inovio Pharmaceuticals, Sapience Therapeutics; Financial Interests, Personal, Royalties, U.S. Provisional Application No.: 62/819,322 Title: COMPOSITIONS AND METHODS FOR TREATING CANCER Filing Date: March 15, 2019 Inventor(s): David A. Nathanson et al. FH Reference No.: UCH-17760 (32246-17760) Your Reference No.: [UCLA 2019-630-1] US: UCLA; Financial Interests, Personal, Other: Global Coalition for Adaptive Research, Break Through Cancer; Financial Interests, Personal, Stocks/Shares: Notable Labs, Katmai Pharmaceuticals, Chimerix.
Invited Discussant 279O and 280O
- Filip Y. De Vos (Utrecht, Netherlands)
Q&A
- All Speakers (Lugano, Switzerland)