3224 - Addition of an oral docetaxel treatment (ModraDoc006/r) to androgen deprivation therapy (ADT) and intensity-modulated radiation therapy (IMRT) in patients with high risk N+M0 prostate cancer

Background

High risk lymph node positive non-metastatic (N+M0) prostate cancer (PCa) patients (pts) are treated with pelvic radiotherapy (RT) and androgen deprivation therapy (ADT), which can lead to significant toxicity. Docetaxel (Doc) has been acknowledged for its radiosensitizing activity. Chemoradiation with RT on the primary tumour could improve local and systemic control, while avoiding toxicity of pelvic RT. This has been investigated in 6 trials with weekly intravenous Doc. Oral chemotherapy is often preferred, improves cost-effectiveness and avoids dexamethasone prophylaxis. However, oral Doc treatment is challenging due to a low systemic uptake. Co-administration of ritonavir (r), a Cyp3A4 and P-glycoprotein inhibitor, and formulation of water soluble tablets (ModraDoc006), increased the bioavailability of orally given Doc (ModraDoc006/r). This phase I study assesses the pharmacokinetics (PK), safety and maximum tolerated dose (MTD) of ModraDoc006/r, given with IMRT and ADT in high risk N+M0 PCa.

Trial design

High risk PCa is defined as newly diagnosed N+M0 disease (>4 radiologic pathologic pelvic lymph nodes), Gleason score ≥4 + 3=7, ≥cT2c and any PSA, with an indication for (pelvic) RT and ADT. Pts are treated with ADT (28 mo), Image-guided Arc Therapy on the primary tumour (77 Gy in 35 fractions) and weekly ModraDoc006/r for 7 (Part 1A) or 18 weeks (Part 1B). Sampling for PK of ModraDoc006/r, measured by a validated liquid chromatography with tandem mass spectrometry assay, is done up to 48h after intake. Adverse events (AEs) are evaluated with the National Cancer Institute’s Common Terminology Criteria for AEs and RT Oncology Group/European Organization for Research and Treatment of Cancer scale. Efficacy is assessed by Prostate Specific Antigen and Magnetic Resonance Imaging. In Part 1A, three dose levels are investigated. Dose-escalation is based on acute (within 3 mo) and late (within 12 mo) dose limiting toxicities (DLTs), evaluated in a Time-to-Event Continual Reassessment Method model. The MTD is the highest dose at which ≤15% of ≥ 6 pts experience DLTs. The number of pts is currently 19 in Part 1A and will be ≥ 9 in Part 1B.

Clinical trial identification

NCT03066154.

Editorial acknowledgement

Legal entity responsible for the study

Netherlands Cancer Institute - Antoni van Leeuwenhoek (NKI-AVL).

Funding

Netherlands Cancer Institute - Antoni van Leeuwenhoek (NKI-AVL).

Disclosure

J.H. Beijnen: Shareholder / Stockholder / Stock options, Full / Part-time employment: Modra Pharmaceuticals B.V. All other authors have declared no conflicts of interest.