Multi-Chemotherapeutic Schedules Containing the pan-FGFR Inhibitor ARQ 087 are Safe and Show Antitumor Activity in Different Xenograft Models.
ARQ 087 is a multi-tyrosine kinase inhibitor with potent activity against the FGFR receptor family, currently in Phase I clinical studies for the treatment of advanced solid tumors. The compound has a very safe profile and induces tumor regressions in FGFR-driven models. The feasibility of combining ARQ 087 with chemotherapy was investigated in FGFR deregulated human xenografts. Nude mice were transplanted subcutaneously with H1581, and when tumor masses reached 150 mg, were randomized to receive vehicle, ARQ 087, paclitaxel, carboplatin as single agents or in combination. Similar experimental conditions were applied in nude mice bearing SNU16 and MFE296 xenografts, with the inclusion of capecitabine in the former xenograft model. In the different xenograft models, the drugs given as single agents ranged from very active to partially active. The double combinations were more active than the single ones, but the triple combinations were the most active. In particular, the combination of ARQ 087 + paclitaxel + carboplatin in H1581 bearing mice was able to induce tumor regression in all the mice, with 6/8 mice tumor free at day 140 after tumor transplant. Of note, no toxic deaths nor premature stopping or delaying of drug administration were observed. The data herein reported demonstrated the feasibility of using xenografts models for poli-chemotherapeutic trials mimicking the best standard of care in treatment of specific tumor type and that ARQ 087, a new pan-FGFR inhibitor, can be safely combined with standard cytotoxic chemotherapeutic drugs with apparently no sign of cumulative toxicity and an associated increased antitumor effect.
Department of Oncology, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Via La Masa 19, 20156 Milan, Italy.
Rosaria
R
Chilà
ArQule, Inc., Burlington, MA, USA.
Terence
T
Hall G
ArQule, Inc., Burlington, MA, USA.
Giovanni
G
Abbadessa
Department of Oncology, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Via La Masa 19, 20156 Milan, Italy.
Massimo
M
Broggini
Department of Oncology, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Via La Masa 19, 20156 Milan, Italy. Electronic address: giovanna.damia@marionegri.it.
Giovanna
G
Damia