342O Intracranial administration of CTLA-4 and PD-1 immune checkpoint blocking monoclonal antibodies in recurrent glioblastoma (rGB): A multi-cohort adaptive phase I clinical trial

AbstractA conditionally replication-defective human cytomegalovirus (HCMV) vaccine, V160, was shown to be safe and immunogenic in a two-part, double-blind, randomized, placebo-controlled phase I clinical trial (NCT01986010). However, the specificities and functional properties of V160-elicited antibodies remain undefined. Here, we characterized 272 monoclonal antibodies (mAbs) isolated from single memory B cells of six V160-vaccinated subjects. The mAbs bind to diverse HCMV antigens, including multiple components of the pentamer, gB, and tegument proteins. The most-potent neutralizing antibodies target the pentamer-UL subunits. The binding sites of the antibodies overlap with those of antibodies responding to natural HCMV infection. The majority of the neutralizing antibodies target the gHgL subunit. The non-neutralizing antibodies predominantly target the gB and pp65 proteins. Sequence analysis indicated that V160 induced a class of gHgL antibodies expressing the HV1-18/KV1-5 germline genes in multiple subjects. This study provides valuable insights into primary targets for anti-HCMV antibodies induced by V160 vaccination.

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A phase I clinical trial on intratumoral and intracavitary administration of ipilimumab and nivolumab in patients with recurrent glioblastoma.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.2534 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. 2534-2534

Author(s):

Julia Katharina Schwarze ◽

Johnny Duerinck ◽

Ines Dufait ◽

Gil Awada ◽

Samuel Klein ◽

...

Keyword(s):

Clinical Trial ◽

Phase I ◽

Bacterial Colonization ◽

Recurrent Glioblastoma ◽

Phase I Clinical Trial ◽

Pharmacokinetic Analysis ◽

Historical Cohort ◽

Idh1 R132h ◽

R132h Mutation ◽

Clinical Trial Information

2534 Background: Intravenous (IV) administration of ipilimumab (IPI) and nivolumab (NIVO) has low activity in recurrent glioblastoma (rGB). Intratumoral (IT) and intracavitary (IC) administration of IPI and NIVO is under evaluation in the GlITIpNi phase I clinical trial. Methods: Patients (pts) with resectable rGB were recruited to cohorts C1, C2 and C4; pts with non-resectable rGB were recruited in C3 (biopsy only). IT administration (brain tissue lining the resection cavity during surgery) of IPI (10 mg)(C1), or IPI (5 mg) plus NIVO (10 mg)(C2, C3 and C4), was followed by IC administration of NIVO at escalating doses of 1, 5 or 10 mg Q2w in both C3 and C4 (via an Ommaya reservoir). In all cohorts, pts received 10 mg NIVO IV Q2w (6x in C1/C2, and 12x in C3/C4). Corticosteroids were contraindicated. Results: Forty-six pts (31 male; median age 56y (38-74); IDH1 R132H mutation in 2 pts in C1/C2; NGS somatic mutation analysis for C3/C4 ongoing) with rGB following resection, RT and temozolomide were enrolled (3, 24, 13 and 6 pts in C1, C2, C3 and C4, respectively). All pts received IT administrations. Pts in C1/C2 received a median of 5 IV NIVO administrations. Study treatment has been completed in all pts in C1/C2, in 9 pts in C3, and in 3 pts in C4; pts received a median of 4 (0-10) and 3 (0-7) postoperative IC/IV administrations in C3 and C4, respectively. Two pts in C2 and 1 pt in C3 had an increased perilesional cerebral edema (G3) with neurological deterioration after surgery/IT-injection, that was reversible with steroids. Most frequent AE were fatigue (32 pts, 64%), fever (20 pts, 44%), and headache (25 pts, 50%). In 4 pts from C3, the Ommaya was removed because of bacterial colonization (asymptomatic). There were no G5 AE. There was no dose/AE correlation with increasing IC NIVO doses in C3/C4. Repetitive CSV analysis during therapy (C3/C4) revealed increased lymphocyte counts in 4 pts; scRNA- and TCR-sequencing is ongoing. Gene expression profiling for C1/C2, and pharmacokinetic analysis of NIVO and IPI in CSV for C3/C4 are ongoing. After a median FU of 62w (16-165) for pts in C1/C2, 16 pts have died; median OS is 71w (95% CI 8-134), 1- and 2y-OS% are respectively 51% (95% CI 31-71), and 34% (95% CI 10-59). OS compares favorably to a historical cohort of Belgian rGB pts (n = 469; Log-Rank p .001). After a median FU of 10w (1-37) for pts in C3/C4, 2 pts have died; median OS has not been reached. One pt in C3 achieved a PR that is ongoing at 12m. Conclusions: IT/IC administration of NIVO and IPI is feasible and sufficiently safe to warrant further investigation in pts with rGB. Clinical trial information: NCT03233152 .

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Phase I clinical trial of temsirolimus and perifosine for recurrent glioblastoma

Annals of Clinical and Translational Neurology ◽

10.1002/acn3.51009 ◽

2020 ◽

Vol 7 (4) ◽

pp. 429-436 ◽

Cited By ~ 3

Author(s):

Thomas J. Kaley ◽

Katherine S. Panageas ◽

Elena I. Pentsova ◽

Ingo K. Mellinghoff ◽

Craig Nolan ◽

...

Keyword(s):

Clinical Trial ◽

Phase I ◽

Recurrent Glioblastoma ◽

Phase I Clinical Trial

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ONCOLYTIC POLIO/RHINOVIRUS RECOMBINANT (PVSRIPO) IN RECURRENT GLIOBLASTOMA (GBM): FIRST PHASE I CLINICAL TRIAL EVALUATING THE INTRATUMORAL ADMINISTRATION

Neuro-Oncology ◽

10.1093/neuonc/nou209.5 ◽

2014 ◽

Vol 16 (suppl 3) ◽

pp. iii43-iii43 ◽

Cited By ~ 4

Author(s):

A. Desjardins ◽

J. H. Sampson ◽

K. B. Peters ◽

T. Ranjan ◽

G. Vlahovic ◽

...

Keyword(s):

Clinical Trial ◽

Phase I ◽

Recurrent Glioblastoma ◽

Phase I Clinical Trial ◽

Intratumoral Administration

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Intracerebral administration of CTLA-4 and PD-1 immune checkpoint blocking monoclonal antibodies in patients with recurrent glioblastoma: a phase I clinical trial

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-002296 ◽

2021 ◽

Vol 9 (6) ◽

pp. e002296

Author(s):

Johnny Duerinck ◽

Julia Katharina Schwarze ◽

Gil Awada ◽

Jens Tijtgat ◽

Freya Vaeyens ◽

...

Keyword(s):

Clinical Trial ◽

Phase I ◽

Intravenous Administration ◽

Recurrent Glioblastoma ◽

Phase I Clinical Trial ◽

Fixed Dose ◽

Rank Test ◽

Central Nervous System Toxicity ◽

Historical Cohort ◽

Significant Difference

BackgroundPatients with recurrent glioblastoma (rGB) have a poor prognosis with a median overall survival (OS) of 30–39 weeks in prospective clinical trials. Intravenous administration of programmed cell death protein 1 and cytotoxic T-lymphocyte-associated antigen 4 inhibitors has low activity in patients with rGB. In this phase I clinical trial, intracerebral (IC) administration of ipilimumab (IPI) and nivolumab (NIVO) in combination with intravenous administration of NIVO was investigated.MethodsWithin 24 hours following the intravenous administration of a fixed dose (10 mg) of NIVO, patients underwent a maximal safe resection, followed by injection of IPI (10 mg; cohort-1), or IPI (5 mg) plus NIVO (10 mg; cohort-2) in the brain tissue lining the resection cavity. Intravenous administration of NIVO (10 mg) was repeated every 2 weeks (max. five administrations). Next generation sequencing and RNA gene expression profiling was performed on resected tumor tissue.ResultsTwenty-seven patients were enrolled (cohort-1: n=3; cohort-2: n=24). All patients underwent maximal safe resection and planned IC administrations and preoperative NIVO. Thirteen patients (cohort-1: n=3; cohort-2: n=10) received all five postoperative intravenous doses of NIVO. In cohort-2, 14 patients received a median of 3 (range 1–4) intravenous doses. Subacute postoperative neurological deterioration (n=2) was reversible on steroid treatment; no other central nervous system toxicity was observed. Immune-related adverse events were infrequent and mild. GB recurrence was diagnosed in 26 patients (median progression-free survival (PFS) is 11.7 weeks (range 2–152)); 21 patients have died due to progression. Median OS is 38 weeks (95% CI: 27 to 49) with a 6-month, 1-year, and 2-year OS-rate of, respectively, 74.1% (95% CI: 57 to 90), 40.7% (95% CI: 22 to 59), and 27% (95% CI: 9 to 44). OS compares favorable against a historical cohort (descriptive Log-Rank p>0.003). No significant difference was found with respect to PFS (descriptive Log-Rank test p>0.05). A higher tumor mRNA expression level of B7-H3 was associated with a significantly worse survival (multivariate Cox logistic regression, p>0.029).ConclusionIC administration of NIVO and IPI following maximal safe resection of rGB was feasible, safe, and associated with encouraging OS.Trial registrationNCT03233152.

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