Phase I feasibility study of Olaparib in combination with loco-regional radiotherapy in head and neck squamous cell carcinoma.

Purpose: PARP-inhibitors have potent radiosensitizing properties in pre-clinical models. To identify the maximum tolerated dose (MTD) of the PARP-inhibitor Olaparib in combination with radiotherapy in patients with head and neck cancer, a single institutional phase-I dose escalation trial was initiated.

Patients And Methods: The starting dose of Olaparib was 25 mg BID, combined with radiotherapy (70 Gy in 35 fractions).

Phase I and Pharmacologic Study of Olaparib in Combination with High-dose Radiotherapy with and without Concurrent Cisplatin for Non-Small Cell Lung Cancer.

Purpose: To identify an MTD of olaparib, a PARP inhibitor, in combination with loco-regional radiotherapy with/without cisplatin for the treatment of non-small cell lung cancer (NSCLC).

Patients And Methods: Olaparib dose was escalated in two groups: radiotherapy (66 Gy/24 fractions in 2.75 Gy/fraction) with and without daily cisplatin (6 mg/m), using time-to-event continual reassessment method with a 1-year dose-limiting toxicity (DLT) period.

Practicalities in running early-phase trials using the time-to-event continual reassessment method (TiTE-CRM) for interventions with long toxicity periods using two radiotherapy oncology trials as examples.

Background: Awareness of model-based designs for dose-finding studies such as the Continual Reassessment Method (CRM) is now becoming more commonplace amongst clinicians, statisticians and trial management staff. In some settings toxicities can occur a long time after treatment has finished, resulting in extremely long, interrupted, CRM design trials. The Time-to-Event CRM (TiTE-CRM), a modification to the original CRM, accounts for the timing of late-onset toxicities and results in shorter trial duration.

Improved pharmacodynamic (PD) assessment of low dose PARP inhibitor PD activity for radiotherapy and chemotherapy combination trials.

Background: PARP inhibitors are currently evaluated in combination with radiotherapy and/or chemotherapy. As sensitizers, PARP inhibitors are active at very low concentrations therefore requiring highly sensitive pharmacodynamic (PD) assays. Current clinical PD-assays partly fail to provide such sensitivities.

Extent of radiosensitization by the PARP inhibitor olaparib depends on its dose, the radiation dose and the integrity of the homologous recombination pathway of tumor cells.

Background And Purpose: The PARP inhibitor olaparib is currently tested in clinical phase 1 trials to define safe dose levels in combination with RT. However, certain clinically relevant insights are still lacking. Here we test, while comparing to single agent activity, the olaparib dose and genetic background dependence of olaparib-mediated radiosensitization.

Retinal arteriolar geometry is associated with cerebral white matter hyperintensities on magnetic resonance imaging.

Background: Cerebral small vessel disease (lacunar stroke and cerebral white matter hyperintensities) is caused by vessel abnormalities of unknown aetiology. Retinal vessels show developmental and pathophysiological similarities to cerebral small vessels and microvessel geometry may influence vascular efficiency.

Hypothesis: Retinal arteriolar branching angles or coefficients (the ratio of the sum of the cross-sectional areas of the two daughter vessels to the cross-sectional area of the parent vessel at an arteriolar bifurcation) may be associated with cerebral small vessel disease.