Inhibitor of Apoptosis Proteins (IAPs) are cellular proteins that prevent cell death by apoptosis and are frequently overexpressed in cancer cells resulting in elevated levels leading to tumor survival and progression. SMAC mimetics are a new class of apoptosis-inducing agents that relieve the effects of IAPs including XIAP, cIAP1 and cIAP2 resulting in apoptosis of sensitive tumor cells from a broad range of tumor types. TL32711 is a potent SMAC mimetic currently in Phase 1 clinical trials. To date, a weekly IV infusion schedule has proved to be well tolerated in patients, resulting in sustained cIAP1 suppression throughout the dosing interval. Initial pharmacokinetics modeling of TL32711 in mice bearing the MDA-MB-231 tumor indicated a potential efficacy benefit may be possible with a biweekly dosing schedule. The objectives of the current study were to 1) evaluate the efficacy of TL32711 as a single agent in primary human melanoma tumor xenograft models, 2) assess the efficacy and tolerability of TL32711 in combination with carboplatin and paclitaxel and 3) determine if a biweekly dosing schedule is more effective than weekly administration.

Significant tumor growth inhibition was observed in 5 of 6 of the primary melanoma tumor xenografts evaluated following treatment with single agent TL32711 (30 mg/kg, IP). Combining TL32711 with carboplatin and paclitaxel resulted in a further enhancement in anti-tumor efficacy with tumor regressions noted in 4 of the 6 models without any marked changes in tolerability (<14% reduction in bodyweight). Based on the initial PK modeling a follow up study was conducted to assess the activity of TL32711 in a primary melanoma model when the dose was fractionated (15 mg/kg twice/week versus 30 mg/kg once/week). Surprisingly, the biweekly dosing schedule did not result in enhanced anti-tumor activity and demonstrated equivalent suppression of cIAP1 in tumors compared to the weekly dosing schedule. Pharmacokinetic analysis of the TL32711 in tumor tissue at 15, 30 and 60 mg/kg revealed that TL32711 exhibits a greater than dose proportional relationship in that a 4-fold increase in dose, resulted in a 14-fold increase in exposure. This increase in exposure led to a change in the TL32711 tumor half-life from 56 to 166 hrs, possibly due to the saturation of an efflux transporter at higher dose levels. Together, these data show that TL32711 is highly active in primary human melanoma xenografts and that efficacy can be enhanced by combination therapy with carboplatin and paclitaxel without reducing tolerability. These data also demonstrate that biweekly dosing confers no advantage over the current clinical weekly dosing regimen due to the dose dependent changes in TL32711 half-life and exposure observed in tumor tissue.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A225.