Toll-like receptor-7 agonist administered subcutaneously in a prolonged dosing schedule in heavily pretreated recurrent breast, ovarian, and cervix cancers.
BACKGROUND
The primary objective was to study the antitumor activity of prolonged subcutaneous dosing of systemic 852A, a Toll-like receptor-7 agonist (TLR-7), in recurrent breast, ovarian and cervix cancer. Secondary objectives included assessment of safety and immune system activation.


METHODS
Adults with recurrent breast, ovarian or cervix cancer failing multiple therapies received 0.6 mg/m(2) of 852A subcutaneously twice weekly for 12 weeks. Doses increased by 0.2 mg/m(2)/week to a maximum of 1.2 mg/m(2). Serum was collected to assess immune activation.


RESULTS
Fifteen patients enrolled: 10 ovarian, 2 cervix and 3 breast. Three completed all 24 injections. There were two grade 2 (decreased ejection fractions), nine grade 3 (1 cardiovascular, 1 anorexia, 3 dehydration, 2 infections, 2 renal) and two grade 4 (hepatic and troponin elevation) unanticipated toxicities. Cardiac toxicities included three cardiomyopathies (2 asymptomatic) and one stress-related non-ST elevated myocardial infarction. Five patients discontinued therapy due to possibly associated side effects. One who had stable disease (SD) following 24 doses received 17 additional doses. A cervix patient with SD following 24 doses received chemotherapy after progressing 3 months later, and remains disease free at 18 months. Immune activation, as evidenced by increased IP-10 and IL-1ra, was observed.


CONCLUSIONS
In this first human experience of a TLR-7 agonist delivered subcutaneously using a prolonged dosing schedule, 852A demonstrated sustained tolerability in some patients. Clinical benefit was modest, but immune activation was seen suggesting further study of antitumor applications is warranted. Because of cardiac toxicity; 852A should be used cautiously in heavily pretreated patients.
Geller
Melissa A
MA
Department of Obstetrics, Gynecology and Women's Health, University of Minnesota, MMC 395 420 Delaware St. SE., Minneapolis, MN, 55455 USA.
Cooley
Sarah
S
Department of Medicine, MMC 806 420 Delaware St. SE., University of Minnesota, Minneapolis, MN, 55455 USA.
Argenta
Peter A
PA
Department of Obstetrics, Gynecology and Women's Health, University of Minnesota, MMC 395 420 Delaware St. SE., Minneapolis, MN, 55455 USA.
Downs
Levi S
LS
Department of Obstetrics, Gynecology and Women's Health, University of Minnesota, MMC 395 420 Delaware St. SE., Minneapolis, MN, 55455 USA.
Carson
Linda F
LF
Department of Obstetrics, Gynecology and Women's Health, University of Minnesota, MMC 395 420 Delaware St. SE., Minneapolis, MN, 55455 USA.
Judson
Patricia L
PL
Department of Obstetrics, Gynecology and Women's Health, University of Minnesota, MMC 395 420 Delaware St. SE., Minneapolis, MN, 55455 USA.
Ghebre
Rahel
R
Department of Obstetrics, Gynecology and Women's Health, University of Minnesota, MMC 395 420 Delaware St. SE., Minneapolis, MN, 55455 USA.
Weigel
Brenda
B
Department of Pediatrics, University of Minnesota, MMC 391 420 Delaware St. SE., Minneapolis, MN, 55455 USA.
Panoskaltsis-Mortari
Angela
A
Department of Medicine, MMC 806 420 Delaware St. SE., University of Minnesota, Minneapolis, MN, 55455 USA.|Department of Pediatrics, University of Minnesota, MMC 391 420 Delaware St. SE., Minneapolis, MN, 55455 USA.
Curtsinger
Julie
J
Department of Medicine, MMC 806 420 Delaware St. SE., University of Minnesota, Minneapolis, MN, 55455 USA.
Miller
Jeffrey S
JS
Department of Medicine, MMC 806 420 Delaware St. SE., University of Minnesota, Minneapolis, MN, 55455 USA.
D000328:Adult; D000368:Aged; D000634:Aminoquinolines / Q000008:administration & dosage* / Q000009:adverse effects / Q000276:immunology; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000276:immunology; D001943:Breast Neoplasms / Q000188:drug therapy*; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007279:Injections, Subcutaneous; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy*; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D011446:Prospective Studies; D011804:Quinolines; D013449:Sulfonamides / Q000008:administration & dosage* / Q000009:adverse effects / Q000276:immunology; D051199:Toll-Like Receptor 7 / Q000819:agonists*; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy*
D000634:Aminoquinolines; D000970:Antineoplastic Agents; C523097:N-(4-(4-amino-2-ethyl-1H-imidazo(4,5c)quinolin-1-yl)butyl)methanesulfonamide; D011804:Quinolines; D013449:Sulfonamides; C495348:TLR7 protein, human; D051199:Toll-Like Receptor 7
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