Preoperative Olaparib Endometrial Carcinoma Study (POLEN)

Study Overview
=================
Brief Summary
-----------------
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.

Detailed Description
-----------------
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.

Official Title
-----------------
A Preoperative Window-opportunity, Multicenter, Pharmacokinetic-pharmacodynamic Study to Evaluate the Inhibitory Effects of Single Agent AZD2281 (Olaparib), in Patients With Early-stage Endometrial Carcinoma

Conditions
-----------------
Endometrial Carcinoma

Intervention / Treatment
-----------------
* Drug: Olaparib


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients must have histologically-confirmed type I primary endometrial carcinoma (EC). Diagnosis biopsy must contain 3-12 mg of tumour cellularity/stroma (Tumour: 5-20 mm) and this will be checked in the central laboratory for this trial. If tumour cellularity/stroma is inadequate, one re-biopsy with adequate tumour cellularity/stroma will be mandatory before study entry. WHO performance status ≤ 2. Adequate bone marrow function as shown by: ANC ≥ 1.5 x 109/L, Platelets ≥ 100 x 109/L, Hb >10g/dL. Adequate liver function as shown by: serum bilirubin ≤ 1.5 x ULN INR < 1.3 (or < 3 on anticoagulants) ALT and AST ≤ 2.5x ULN Adequate renal function: serum creatinine ≤ 1.5 x mg/dL. Fasting serum cholesterol ≤300 mg/dL or ≤7.75 mmol/L and fasting triglycerides ≤ 2.5 x ULN. Signed informed consent, including consent to tissue collection and blood samples as specified by the protocol. Exclusion Criteria: Subjects who have received prior anticancer therapies for the current endometrial cancer (including chemotherapy, radiotherapy, antibody based therapy, hormonotherapy or surgery). Patients, who have had a major surgery or significant traumatic injury within 4 weeks of start of study drug, patients who have not recovered from the side effects of any major surgery (defined as requiring general anesthesia) or patients that may require major surgery during the course of the study. Prior treatment with any investigational drug within the preceding 4 weeks. Patients receiving chronic, systemic treatment with corticosteroids or another immunosuppressive agent, except corticosteroids with a daily dosage equivalent to prednisone ≤ 20 mg. However, patients receiving corticosteroids must have been on a stable dosage regimen for a minimum of 4 weeks prior the study entry. Topical or inhaled corticosteroids are allowed. Patients who have received immunization with attenuated live vaccines within one week of study entry (note: during study period these kind of vaccines are also not allowed). Patients who have any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study such as: Symptomatic congestive heart failure of New York heart Association Class III or IV Unstable angina pectoris, myocardial infarction within 6 months of start of study drug, Serious uncontrolled cardiac arrhythmia or any other clinically significant cardiac disease Severely impaired lung function Uncontrolled diabetes as defined by fasting serum glucose >1.5 x ULN Active (acute or chronic) or uncontrolled severe infections Liver disease such as cirrhosis, chronic active hepatitis or chronic persistent hepatitis A known history of HIV seropositivity. Patients with an active, bleeding diathesis. Female patients who are pregnant or breast feeding, or adults of reproductive potential who are not using effective birth control methods. If barrier contraceptives are being used, these must be continued throughout the trial by both sexes. Hormonal contraceptives are acceptable as a sole method of contraception. (Women of childbearing potential must have a negative urine or serum pregnancy test within 7 days prior to administration of AZD2281). History of noncompliance to medical regimens. Patients unwilling to or unable to comply with the protocol.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 90 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Olaparib<br>Drug exposure has a limited duration 28 (+/- 5) days. | Drug: Olaparib<br>* Drug exposure has a limited duration 28 (+/- 5) days and at lower dose (600mg/day) than therapeutical accepted (800mg/day).<br>* Other names: Lynparza;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | Baseline and Day 28 (+/- 5) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 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. | Up to 28 days (+/- 5) |