In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 14_Supplement ( 2016-07-15), p. 2089-2089
Abstract:
BAY-356 is a novel aglycosylated anti-TWEAK receptor antibody with potent agonistic activity evaluated for cancer therapy. In order to predict an efficacious therapeutic dose of BAY-356 in man, we sought to determine a therapeutic index where the exposure related to therapeutic efficacy was compared with the exposure obtained following doses tested in toxicology studies. BAY-356 (1 mg/kg) was administered intravenously to healthy Cynomolgus monkeys and plasma concentrations measured in order to determine pharmacokinetic (PK) parameters. Using allometric scaling, the PK in humans was predicted. Efficacy data of BAY-356 in WiDr, HN10321, A253 and SCaBER xenograft models representing colorectal, head and neck squamous cell carcinoma and bladder cancer, were used to derive exposure-response models for each tumor model where the plasma exposure of BAY-356 is assumed to have an effect on the tumor size in a tumor growth model. NONMEM 7.3 was used in the estimations. The tolerability of BAY-356 was tested in monkeys at doses of 10, 20 and 40 mg/kg by weekly intravenous injections over 4 weeks. Treatment resulted in slight to moderate toxicity in liver, kidneys and pancreas and 10 mg/kg was set to be an exposure dose well tolerated and not to be exceeded by therapeutic exposure. A dosing strategy in humans predicted to result in the same exposure as 10 mg/kg weekly in monkey is 18 mg/kg every third weeks (Q3W). Using the estimated exposure-response in xenograft models, human tumor doubling times of 8 weeks (A253 and HN10321), 24 weeks (WiDr) and 12 and 24 weeks (SCaBER) in combination with human predicted PK parameters, tumor reduction over time in humans was predicted based on a human dosing strategy of 18 mg/kg BAY-356 Q3W. For the A253 tumor model, stable disease in humans was predicted while the results from HN10321 and SCaBER models predicted a 13-60% decrease in tumor size in humans following 12 weeks treatment. For WiDr, this dosing strategy was predicted to not be efficacious in humans. The results based on modelling of xenograft data indicate that 18 mg/kg BAY-356 dosed Q3W is predicted to be efficacious in humans for certain tumor cells. Citation Format: Anders Viberg, Eva Hanze, Lisa Dietz, Ruprecht Zierz, Sandra Berndt, Sabine Wittemer-Rump. Therapeutic index prediction of the agonistic aglycosylated TWEAK receptor binding antibody BAY-356. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2089.
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2016-2089
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2016
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
