The primary objective of this study is to identify, in human tumour samples, biomarker changes associated to short exposure to AZD2281 as potential predictors of activity in Endometrial Carcinoma (EC). This is an exploratory study with a biological primary endpoint. Clinical efficacy or safety are not a primary objective of the study.
The main objective of the present proposal study is to assess the biological consequences of PARP inhibition in type I primary EC, in patients who receive therapy with AZD2281 during the period of time between diagnosis and surgery. This is a phase 0 trial or "Exploratory Investigational New Drug" study, a type of trial that involves limited number of patient under drug therapy and has no therapeutic or diagnostic intent because the drug exposure has a limited duration and the dosage is lower than 100% of the dose required to yield a pharmacologic effect. The purpose of the phase 0 studies is to assist in the go versus no-go decision-making process of a drug's fate earlier in the development process, using relevant human models instead of relying on sometimes inconsistent animal data, thus helping to confirm endpoints such as mechanism of action, pharmacology, bioavailability and pharmacodynamics.
Study Type
OBSERVATIONAL
Enrollment
36
Drug exposure has a limited duration 28 (+/- 5) days and at lower dose (600mg/day) than therapeutical accepted (800mg/day).
MedSIR investigative site
A Coruña, Spain
MedSIR investigative site
Barcelona, Spain
MedSIR investigative site
Barcelona, Spain
MedSIR investigative site
Córdoba, Spain
Expression of Cell Cycle-related Proteins
We assessed the change from baseline in the histological score (H-score) of the cell cycle-related proteins on endometrial tumor tissues after 28 (+/- 5) days of olaparib-based therapy. In detail, expression of the cyclin D1, Ki67, and caspase-3 active proteins evaluated by an H-score according to the following formula: H-score= 1x(%light staining) + 2x(%moderate staining) + 3x(%strong staining). The final score ranges from 0 to 300, where 0 indicates absence of staining (corresponding to the lowest tumor proliferation rate and better outcome) and 300 the maximum staining (corresponding to the highest tumor proliferation score and worse outcome).
Time frame: Baseline and Day 28 (+/- 5)
Protein Expression of Biomarkers Related to PARP-inhibition
We assessed the change from baseline in the H-score of several biomarkers targeted by olaparib-based therapy on endometrial tumor tissues after 28 (+/- 5) days of treatment. In detail, expression of protein involved in the DNA repair (PARP1, ɣH2AX), angiogenesis (VEG, HIF-1α, PTEN), apoptosis (p65, p50, p53), glucose metabolism (GLUT1), proliferation (PH3), and regulation of gene transcription (ARID1A) were evaluated by an H-score according to the following formula: H-score= 1x(%light staining) + 2x(%moderate staining) + 3x(%strong staining). The final score ranges from 0 to 300, where 0 indicates absence of staining and 300 the maximum staining.
Time frame: Baseline and Day 28 (+/- 5)
Plasma Levels of Olaparib
Plasma concentration of olaparib administered at dosis of 300mg twice in a day (600mg/day). Values of plasma level of olaparib on days 7,14,21 and 28 were collected at time when maximum of drug concentration is reached. Data are reported as µg/mL.
Time frame: Days 7,14,21 and 28
Number of Participants With Olaparib-Associated Toxicities
To assess the tolerability for all treated patients (N=36) according to NCI-CTCAE v.4.03.
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MedSIR investigative site
Granollers, Spain
MedSIR
Madrid, Spain
MedSIR investigative site
Madrid, Spain
MedSIR investigative site
Santiago de Compostela, Spain
MedSIR investigative site
Valencia, Spain
MedSIR investigative site
Vigo, Spain
Time frame: Up to 28 days (+/- 5)