In:
Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 30, No. 15_suppl ( 2012-05-20), p. 3098-3098
Abstract:
3098 Background: Histone deacetylase and mTOR inhibition circumvent critical EBV-oncogenic pathways with preclinical studies demonstrating lytic induction in EBV infected cells, as well as immunomodulatory and antiangiogenic effects. Methods: Patients (Pt) with advanced solid tumors enriched for EBV–related cancers were enrolled to determine safety, tolerability, maximum tolerated dose (MTD), pharmacokinetics (PK), pharmacodynamics and preliminary antitumor activity. LBH was instituted 7-days prior to combination treatment. NPC pt received antiviral prophylaxis of either acyclovir (Ac) or valaciclovir (Vc). Serum EBV DNA levels (EBNA-1) were measured weekly and plasma cytokines profiled using a 31-plex Luminex panel. Results: 15 pt have been treated (M:F 13:2, median age 50, R: 38-63) 10 NPC, 5 non-NPC (colon, RCC, breast, gastric, sarcoma) at 3 dose levels – LBH (3x/wk)-EVE (daily):10-2.5, 10-5, 15-5. Two dose limiting toxicities of G4 (grade) thrombocytopenia were observed at LBH15-RAD5. Significant adverse events (AE) (G≥3) were dysphagia (1) and thrombocytopenia (3). Common AEs (G1/2) included fatigue (80%), anorexia (60%), mucositis (53%), xerostomia (26%), dysphagia (26%). Two minor responses were seen (1 NPC, 1 breast) and 2 pt (1 NPC, 1 RCC) had prolonged stable disease ( 〉 16 weeks). Modulation of EBV DNA titres was seen only in NPC pt, with median fold-change from baseline of 10.9 (0.05-174). Pt on Ac prophylaxis (n=5) had significant increases in DNA titres (9-174 fold), while those on Vc (n=4) were less pronounced (0.05-11 fold, p 〈 0.03), with one pt (with minor response) having persistent decline in EBV titres. In a limited pt subset (n=9, 30 timepoints), plasma cytokine profiles were consistent with a T-cell response, specifically, elevated levels of FLT3L, IFN-gamma, IL-13 and IL-17. PK and PBMC target modulation studies are being analysed. Conclusions: LBH-EVE results in induction of EBV DNA titres with an associated host T cell response. MTD is LBH10-EVE5 in Asian pt, majority of whom had NPC. A pre-planned expansion cohort that incorporates multi-parametric functional imaging exploring two schedules of LBH in combination with EVE5 is ongoing.
Type of Medium:
Online Resource
ISSN:
0732-183X
,
1527-7755
DOI:
10.1200/jco.2012.30.15_suppl.3098
Language:
English
Publisher:
American Society of Clinical Oncology (ASCO)
Publication Date:
2012
detail.hit.zdb_id:
2005181-5
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