399P - A phase I dose-escalation trial of bi-daily (BID) weekly oral docetaxel as ModraDoc006 in combination with ritonavir

Date 10 October 2016
Event ESMO 2016 Congress
Session Poster display
Topics Clinical research
Basic Scientific Principles
Presenter Vincent de Weger
Citation Annals of Oncology (2016) 27 (6): 114-135. 10.1093/annonc/mdw368
Authors V.A. de Weger1, F.E. Stuurman1, M. Mergui-Roelvink1, B. Nuijen2, A.D.R. Huitema2, J.H. Beijnen2, J.H.M. Schellens1, S. Marchetti1
  • 1Clinical Pharmacology, The Netherlands Cancer Institute, 1066CX - Amsterdam/NL
  • 2Pharmacy & Pharmacology, The Netherlands Cancer Institute, 1066EC Amsterdam - Amsterdam/NL

Abstract

Background

The development of an oral formulation of the anti-cancer drug docetaxel is hampered by its poor bio-availability. In (pre-)clinical studies, absorption from the gastro-intestinal tract could significantly be improved by the use of a solid dispersion formulation and the co-administration of ritonavir, an inhibitor of CYP3A4 and P-glycoprotein. The primary aim of this trial was to assess the feasibility, determine the maximum tolerated dose (MTD) and the recommended phase two dose (RP2D) of the co-administration of the novel oral docetaxel formulation ModraDoc006 (10 mg tablet) with 100 mg of ritonavir (/r) in a BID weekly schedule.

Methods

Patients with metastatic solid tumors, ≥18 years old, and a WHO performance status ≤2 were included. ModraDoc006/r was administered BID weekly with a 7-12 hour interval. Dose-escalation was performed using a classical 3 + 3 design. Pharmacokinetic sampling was performed during the first two weeks of treatment up to 48 hours after study drug administration. Safety was evaluated using CTCAE v3.0. The dose-limiting toxicity (DLT) period was defined as the first four weeks of treatment. Anti-tumor activity was assessed every 6-8 weeks with a CT or MRI scan.

Results

ModraDoc006/r was administered to 26 patients at three dose-levels. Seven DLTs were observed in three patients. Observed DLTs were grade 3 nausea (2x), mucositis (2x), dehydration (1x), neutropenic fever (1x) and inability to restart treatment within 3 weeks due to treatment related toxicity (1x). The most common adverse events observed were nausea, vomiting, diarrhea and fatigue, most often grade 1-2. No hypersensitivity reactions, peripheral polyneuropathy or grade 4 neutropenia were observed. The MTD and RP2D were determined as 30/20 mg ModraDoc006/r (morning/afternoon dose) per week. The area under the plasma concentration time curve (AUC) of docetaxel at this dose was 1250 ±443 ng*h/ml. Three partial responses and six stable diseases were reported as best response to treatment.

Conclusions

Oral administration of BID weekly ModraDoc006/r is feasible. The MTD and RP2D of ModraDoc006/r are 30/20 mg per week. Anti-tumor activity is promising.

Clinical trial identification

NCT 01173913 (NIH register)

Legal entity responsible for the study

The Netherlands Cancer Institute

Funding

The Netherlands Cancer Institute

Disclosure

B. Nuijen: Is holder of a patent of oral formulations of taxanes. J.H. Beijnen, J.H.M. Schellens: Is holder of a patent of oral formulations of taxanes and shareholder of Modra Pharmaceuticals, a company developing oral taxane formulations. All other authors have declared no conflicts of interest.