In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 71, No. 8_Supplement ( 2011-04-15), p. LB-406-LB-406
Abstract:
Introduction: TL32711 is a small molecule Smac mimetic that potently and specifically antagonizes inhibitor of apoptosis proteins (IAPs), resulting in caspase-dependent apoptosis and inactivation of NF-kB signaling. In preclinical studies, single agent tumor regression was observed for multiple tumor types and potent anti-tumor activity was observed when TL32711 was combined with specific chemotherapies and death receptor ligands. This first-in-human study assesses the safety, pharmacokinetic (PK), and pharmacodynamic (PD) profile and anti-tumor activity of single agent TL32711. Methods: Using a standard 3+3 dose escalation design, subjects with refractory solid tumors and lymphoma received weekly intravenous TL32711 for 3 weeks on/ 1 week off, with disease assessment every 2 cycles. PK analysis was conducted using an intensive sampling approach. PD assays included measurement of cIAP1 and cIAP2 levels in lysates from serially collected PBMC and tumor tissue, serum levels of cleaved cytokeratin-18 (CK-18, requiring activated caspase-3) and activated caspase-3/7. Results: 27 patients were treated at doses 0.18–26 mg/m2 over 9 cohorts. TL32711 was well-tolerated, with no dose-limiting toxicities. Toxicities included reversible grade 2 lymphocytopenia and grade 1 rash at ≥11.5 mg/m2. TL32711 exhibited dose-proportional, uniform, non-accumulating PK, with a mean β-phase half-life of 35 hrs. Doses ≥2.88 mg/m2 achieved an AUC0-∞ exposure sufficient for single agent activity in preclinical tumor models. At doses ≥1.44 mg/m2, cIAP1 levels were suppressed & gt;80% within 24 hrs and after 1 week & gt;50% suppression was maintained. Based on PBMC drug levels, actual and predicted cIAP1 suppression was well-correlated. A dose-dependent increase in serum levels of cleaved CK-18 and activated caspase-3/7 was observed in patients treated at doses ≥2.88 mg/m2. At 11.5 mg/m2, & gt; 90% cIAP1 suppression, increased activated caspase-8, and PARP cleavage in tumor lysates were observed in a tumor biopsy from a melanoma patient with progressive disease prior to TL32711, with stable disease after 2 cycles. One colon cancer subject with progressive disease after prior therapies, at 0.36 mg/m2 demonstrated tumor shrinkage in radiographic lesions, serum CEA decline, and elevated serum caspase-3/7. One colon cancer subject at 17.2 mg/m2 demonstrated serum CEA decline, elevated serum caspase-3/7, and a large photopenic lesion in a metastatic lesion within the first cycle. Conclusions: TL32711 is well-tolerated, has dose-proportional PK, and demonstrates potent and sustained target inhibition and apoptotic pathway activation in tumor and surrogate tissues. Preliminary evidence of antitumor activity was observed in colon cancer and melanoma. Updated results of final dose escalation cohorts will be presented. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-406. doi:10.1158/1538-7445.AM2011-LB-406
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2011-LB-406
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2011
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
Permalink
