Abstract 2756: Combination therapy of doxorubicin and the acid-sensitive albumin-binding prodrug of doxorubicin INNO-206 induces complete regressions in a xenograft pancreatic carcinoma model demonstrating excellent tolerability

Combination therapy of macromolecular prodrugs with clinically established low-molecular weight anticancer drugs is a field of research that has been insufficiently explored to date. Recently, we investigated the anticancer effect of a combination of doxorubicin with the clinically assessed albumin-binding prodrug INNO-206, the (6-maleimidocaproyl)hydrazone of doxorubicin, in an ovarian carcinoma xenograft model (A2780). The combination achieved complete remissions as did therapy with INNO-206 alone, but was far better tolerated. Due to these encouraging results, we extended our combination trials to a more chemoresistant tumor indication, i.e. pancreatic cancer. Thus, we compared the following weekly schedules against the MiaPaca-2 xenograft model (i.v. administration): 3 x 6 mg doxorubicin (MTD), 3 x 24 mg/kg INNO-206 (doxorubicin equivalents, MTD), 3 x 3 mg/kg doxorubicin followed 6 h later by 3 x 12 mg/kg INNO-206, and 3 x 12 mg/kg INNO-206 followed 6 h later by 3 x 3 mg/kg doxorubicin. Whereas therapy with doxorubicin only produced a moderate tumor inhibition, all other therapy arms induced complete long-term remissions until the end of the experiment on day 44. However, there were significant differences in the tolerability as assessed by the body weight changes: whereas therapy at the MTD of INNO-206 (3 x 24 mg/kg) produced a body weight loss of −16 %, therapy with 3 x 12 mg/kg INNO-206 followed 6 h later by 3 x 3 mg/kg doxorubicin produced −7 % body weight loss, but 3 x 3 mg/kg doxorubicin followed 6 h later by 3 x 12 mg/kg INNO-206 produced a body weight gain of + 2 % as a clear indication of minimal systemic toxicity. This animal study is to best of our knowledge the first investigation demonstrating that a combination of an albumin-binding prodrug with its free parent drug not only has clear therapeutic advantages over the free drug but that the time-dependent schedule has a critical influence on the overall tolerability and results in its best case in a 100 % cure rate without causing any body weight loss. The current working hypothesis to explain this surprising effect is that the combination of doxorubicin with an albumin-binding prodrug of doxorubicin with acid-sensitive properties enables a more homogenous distribution of the drugs in the tumor due to different uptake mechanisms in a heterogeneous solid tumor (EPR effect for INNO-206 and free diffusion into the tumor interstitium for doxorubicin). Citation Format: {Authors}. {Abstract title