Final results of controlled IL-12 monotherapy in adults with grade III or IV gliomas

Autor: John Loewy, Christina Amidei, Jill Buck, E. Antonio Chiocca, John S. Yu, Yunxia Wang, Nira Hadar, Arnold Gelb, Nathan Demars, Bakhtiar Yamini, Nancy Ann Oberheim Bush, Rimas V. Lukas, Taylor Estupinan, Laurence J.N. Cooper, John Miao
Rok vydání: 2020
Předmět:
Zdroj: Journal of Clinical Oncology. 38:3040-3040
ISSN: 1527-7755
0732-183X
DOI: 10.1200/jco.2020.38.15_suppl.3040
Popis: 3040 Background: Interleukin-12 (IL-12), a master regulator of the immune system, results in anti-tumor responses in preclinical models, but safe use requires tightly controlled production. This phase 1 trial (NCT02026271) is the first to evaluate the safety and tolerability of Ad-RTS-hIL-12 (Ad) under transcriptional control with veledimex (V) in adults with grade III or IV gliomas. Methods: Multicenter, phase 1, open-label, 3 + 3 dose escalation study of Ad (a single intratumoral injection, 2 × 1011 viral particles, Day 0) with oral V dosing (Days 0 to 14) of 10, 20, 30, and 40 mg in subjects with rGBM. Results: 38 subjects were treated (resection group: V 10 mg (n = 6); 20 mg (n = 15); 30 mg (n = 4); 40 mg (n = 6); and, stereotactic group: V 20 mg, n = 7). The adverse event profile of Ad+ V, was predictable and controllable, with the main adverse reactions (ARs) being mild to moderate. All ARs were manageable and reversible upon withholding V. We observed increased peak (mean ± SEM) serum recombinant IL-12 and downstream endogenous IFN-g: V 10mg 21.4 ± 11.7 pg/mL and 14.6 ± 7.1 pg/mL; V 20 mg 25.8 ± 7.1 pg/mL and 57.0 ± 26.5 pg/mL; V 30 mg 65.7 ± 45.5 pg/mL and 60.7 ± 50.0 pg/mL; V 40mg 108.8 ± 41.0 pg/mL and 167.5 ± 70.9 pg/mL, V 20mg (stereotactic) 25.1 ± 7.2 pg/mL and 69.8 ± 48.5 pg/mL, respectively. In the V 20 mg cohort , there was an increase in tumor-associated T cells (CD3+CD8+%) from pre-Ad (mean ± SEM) 0.6 ± 0.4 to biopsy (~5 mons) 6.3 ± 5.0 and production of IFN-g 97.2 ± 85.3 pg/g (n = 2). Median overall survival (mOS) in the V 20 mg cohort (resection, n = 15) was 12.7 mons (mean follow-up, 13.1 mons). Subjects with unifocal disease (n = 6) who received low-dose (≤ 20mg total) dexamethasone during active dosing (Days 0-14) had an mOS of 17.8 mons. Tumor response data will be presented. Conclusions: Results of Controlled IL-12 in rGBM are promising, with V-dependent and proportional increases in IL-12 and IFN-g resulting in immune activation, with a favorable safety profile and encouraging survival. The 20 mg V dose is the recommended phase 2 dose. Controlled IL-12 is being evaluated in a monotherapy substudy (n = 36, V 20 mg) and two combination studies with immune checkpoint inhibitors for rGBM. Clinical trial information: NCT02026271 .
Databáze: OpenAIRE
Externí odkaz: