A Phase I Study of Belinostat in Combination With Cisplatin and Etoposide in Adults With Small Cell Lung Carcinoma and Other Advanced Cancers

Summary

BACKGROUND: * The histone deacetylase (HDAC) inhibitors are a novel class of anticancer agent. These agents lead to the increased acetylation of both histone and non-histone proteins, which leads to rapid cell death in many tumor models. It is thought that the cell death observed with this class of agents may be mediated, in part, through the selective acetylation of histone proteins resulting in increased expression of specific genes. * For solid tumors in general, cell death in preclinical models has not translated to activity in patients. For this reason, studies increasingly have combined chemotherapy with HDAC inhibitors to achieve additive and potentially synergistic effects on cancer cells. * This protocol will study a continuous infusion of the HDAC inhibitor belinostat in combination with cisplatin and etoposide for patients with advanced cancer. OBJECTIVES: * To determine a safe and tolerable phase 2 dose for the combination of belinostat with cisplatin and etoposide. * Evaluate molecular markers of HDAC inhibition. ELIGIBILITY: * The protocol will be open to all patients with recurrent or advanced cancer (small-cell lung cancer and other advanced cancers) for whom standard therapy offers no curative potential. * Age greater than or equal to 18 years * ECOG Performance Status 0-2 DESIGN: * The study will begin with belinostat 400 mg/m (2)/24h administered by continuous IV infusion on days 1 and 2, cisplatin at 80 mg/m (2) IV on day 2, and etoposide at 100 mg/m (2) IV daily times 3 on days 2 - 4. Dose escalation of belinostat will follow according to traditional 3 patient cohorts. * Treatment schedule and dose escalation schemata.

Timeline

Start

2009-07-01

Primary completion

2017-06-16

Completion

2018-04-20

Publications

• Background Akerley W, McCoy J, Hesketh PJ, Goodwin JW, Bearden JD, Atkins JN, Chansky K, Crowley JJ, Gandara DR; SWOG. Gemcitabine and irinotecan for patients with untreated extensive stage small cell lung cancer: SWOG 0119. J Thorac Oncol. 2007 Jun;2(6):526-30. doi: 10.1097/JTO.0b013e318060d2dc.
• Background Bevins RL, Zimmer SG. It's about time: scheduling alters effect of histone deacetylase inhibitors on camptothecin-treated cells. Cancer Res. 2005 Aug 1;65(15):6957-66. doi: 10.1158/0008-5472.CAN-05-0836.
• Background Camphausen K, Scott T, Sproull M, Tofilon PJ. Enhancement of xenograft tumor radiosensitivity by the histone deacetylase inhibitor MS-275 and correlation with histone hyperacetylation. Clin Cancer Res. 2004 Sep 15;10(18 Pt 1):6066-71. doi: 10.1158/1078-0432.CCR-04-0537.
• Peer CJ, Hall OM, Sissung TM, Piekarz R, Balasubramaniam S, Bates SE, Figg WD. A population pharmacokinetic/toxicity model for the reduction of platelets during a 48-h continuous intravenous infusion of the histone deacetylase inhibitor belinostat. Cancer Chemother Pharmacol. 2018 Sep;82(3):565-570. doi: 10.1007/s00280-018-3631-7. Epub 2018 Jun 27.

Drugs

Indications