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Poster display

1553 - A phase I dose-escalation trial of bi-daily (BID) weekly oral docetaxel as ModraDoc006 in combination with ritonavir

Date

10 Oct 2016

Session

Poster display

Presenters

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

Author affiliations

  • 1 Clinical Pharmacology, The Netherlands Cancer Institute, 1066CX - Amsterdam/NL
  • 2 Pharmacy & Pharmacology, The Netherlands Cancer Institute, 1066EC Amsterdam - Amsterdam/NL
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Abstract 1553

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.

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