Neoplasms

All Conditions

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Gland and Hormone Related Diseases

Immune System Diseases

Rare Diseases

Carcinoma

Ovarian Neoplasms

Carcinoma, Ovarian Epithelial

Hypersensitivity

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Endocrine Gland Neoplasms

Ovarian Diseases

Adnexal Diseases

Genital Diseases, Female

Genital Diseases

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Genital Neoplasms, Female

Urogenital Neoplasms

Endocrine System Diseases

Gonadal Disorders

Ovarian Cancer

Ovarian Epithelial Cancer

Herbal and Botanical

All Drugs and Chemicals

Kava

Lavage of the Cavum uteri and proximal fallopian tubes

Paul Speiser, Prof.,Dr.,MD

The ovarian surface, the Fallopian tubes, the uterine cavity and the peritoneal cavity all together form a communicating compartment. The physiologic function of the ciliated lining of the tubes is to transport the egg, after ovulation, into the uterine cavity. Thus, making it very likely that exfoliated cells from pathologic changes of the ovarian surface and Fallopian tube lining will be present in a lavage from the uterine cavity.

The proof of concept that malignant cells from the upper genital tract get transported even into the lower genital tract was recently published by Kind I. et al. Liquid-based cervical cytology allows not only cytological evaluation but also collection of DNA. A panel of genes that are commonly mutated in endometrial and ovarian cancers was assembled with new whole-exome sequencing data from 22 endometrial cancers and previously published data on other tumour types, including mutations in the TP53 gene. This panel was used to search for mutations in 24 endometrial and 22 ovarian cancers and identified mutations in all 46 samples. With a sensitive massively parallel sequencing method, it was possible to identify the same mutations in the DNA from liquid Pap smear specimens in 100% of endometrial cancers (24 of 24) and in 41% of ovarian cancers (9 of 22).

In the current project the investigators will study the specificity and sensitivity of the lavage of uterine cavity and proximal tubes as a test to differentiate between malign and benign ovarian tumours. The investigators aim to detect cells from EOCs or genetic material from those cells in the lavage.

Epithelial ovarian cancer (EOC) is the leading cause of death among gynaecologic malignancies in western civilized countries, with an estimated prevalence in Europe and the US of 752,600 in 2007 and 59,828 deaths annually. Treatment and survival of the patients depend primarily on the stage of the disease. Of all EOC patients only 25% are diagnosed at an early stage while the tumour is confined to the pelvis. In these cases the five-year survival rate is 80% to 90% and the disease can often be cured by the combination of surgery and chemotherapy. Unfortunately, almost 75% of women affected have advanced stage disease with metastatic spread throughout the abdominal cavity or to retroperitoneal lymph nodes at the time of diagnosis; five-year survival rates drop to 10%-30% for advanced disease, despite maximum surgical effort and combination chemotherapy.

Currently, state of the art differential diagnosis between malignant and benign ovarian pathologies suspicious for EOC relies predominantly on transvaginal ultrasonography and serum cancer antigen (CA-125) measurements. The specificity of these diagnostic tools however is low, and both tests are not effective enough to reliably differentiate between benign and malignant conditions. Even in highly specialised units, of all patients receiving surgery for suspected ovarian cancer only about 20% will have a malignant disease. These findings underline the need for new diagnostic tests, able to better differentiate between benign and malignant ovarian changes. This would possibly spear many patients from unnecessary surgery completely and improve the triage of patients with malignant ovarian tumours to highly specialised gynaecologic oncology units.

A promising approach for improvement of differential diagnosis of suspicious ovarian changes has been established by Paul Speiser and Robert Zeillinger (Molecular Oncology Group, Department of General Gynaecology and Gynaecologic Oncology, Medical University of Vienna, Austria) (EK 1148/2011). This approach is called the ALPINE technique (Austrian Lavage Procedure for the Detection of tubal Intraepithelial Neoplasms) (manuscript under preparation). It includes a lavage of the uterine cavity and proximal fallopian tubes and subsequent analysis of this lavage fluid for the presence of pre-malignant and malignant cells.

For the proof of principle that tumour cells are shed from ovarian cancer and can be found in the lavages of the uterine cavity, uterine lavages were collected before a surgical intervention for suspected ovarian malignancy at the investigators' institution and at the Catholic University Leuven, Department of Obstetrics and Gynaecology. After malignancy was confirmed, genetic changes in the TP53 and KRAS gene were determined in tumour tissue. In a set of 9 epithelial ovarian cancer patients (EOC) and 1 ovarian metastases of a signet ring carcinoma, the presence of these genetic changes was examined in lavage samples, using digital droplet PCR (ddPCR). Ten genetic changes were identified in tumour tissue of these patients and 9/10 (90%) of these changes were detected in the corresponding lavage specimen too. Mutation rates were in the range between 0.01% and 39.65% in EOC patients. Furthermore, a filter approach, followed by p53 immunofluorescence staining was established, confirming the presence of tumour cells in the lavage sample of one additional patient.

In a next step, lavage samples of 22 ovarian carcinoma patients, and if applicable corresponding tumour tissue, were analysed through deep sequencing by the group of Bert Vogelstein (Johns Hopkins University, Baltimore, USA). The presence of genetic changes, indicative for ovarian cancer, could be confirmed in 16/22 (72.7%) lavage specimen. Of 18 patients, corresponding tumor tissues were available, showing the same mutation.

These results are proof that ovarian cancer cells are shed into the fallopian tubes and uterine cavity, and can be collected through our ALPINE technique. The fact that ovarian cancer cells were detected with high sensitivity in the lavage of the uterine cavity and proximal tubes shows that this approach has a great potential in differential diagnosis of ovarian masses.

Lavage of the Uterine Cavity for the Diagnosis of Ovarian and Tubal Carcinoma - Study of Sensitivity and Specificity

In the current project the investigators will study the specificity and sensitivity of the lavage of uterine cavity and proximal tubes as a test to differentiate between malign and benign ovarian tumours. The investigators aim to detect cells from EOCs by somatic mutation analysis of the genetic material from those cells in the lavage.

To detect cells from EOCs, analysis of lavage fluid will be carried out applying the sensitive massively parallel sequencing method published by Kinde et al. Mutations in the following genes will be analysed: AKT1, APC, ARID1A, BRAF, CTNNB1, CSMD3, CDKN2A, EGFR, FBXW7, FAT3, FGFR2, KRAS, MLL2, NRAS, PTEN, PIK3CA, PIK3R1, PPP2R1A, PIK3R, RNF43, and TP53.

Medical University of Vienna

Prof. Dr.

Symptoms and General Pathology

Nervous System Diseases

Recurrence

Glioblastoma

Glioma

Brain Neoplasms

Central Nervous System Neoplasms

Nervous System Neoplasms

Astrocytoma

Gliosarcoma

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Neuroepithelial

Neoplasms, Germ Cell and Embryonal

Neoplasms, Nerve Tissue

Brain Tumor, Adult

Neuroepithelioma

Antineoplastic Agents

Temozolomide

Pamiparib

Enzyme Inhibitors

Poly(ADP-ribose) Polymerase Inhibitors

Alkylating Agents

Participants with newly diagnosed unmethylated GBM will receive Pamiparib and radiation therapy.

Participants with newly diagnosed unmethylated GBM will receive Pamiparib, radiation therapy (RT) and temozolomide (TMZ).

Participants with recurrent/refractory methylated or unmethylated GBM will receive Pamiparib and TMZ.

Administered as specified in the treatment arm

Radiation

Study Director

The primary objective of this study is to evaluate the safety, efficacy and clinical activity of Pamiparib in combination with radiation therapy (RT) and/or temozolomide (TMZ) in participants with newly diagnosed or recurrent/refractory glioblastoma.

An open-label, multiple-dose, dose-escalation study to determine the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of Pamiparib in combination with radiation therapy (RT) and/or TMZ.

In dose escalation/Phase 1b, Pamiparib will be combined with RT (Arm A) or RT and TMZ (Arm B) in participants with newly diagnosed unmethylated glioblastoma (GBM) and in Arm C of the study Pamiparib will be combined with TMZ in participants with methylated or unmethylated recurrent/refractory GBM.

The dose expansion/Phase 2 phase will enroll up to 4 cohorts: participants with newly diagnosed unmethylated GBM in Arms A and B, and 2 cohorts of participants with recurrent/refractory GBM grouped by O-6-methylguanine-DNA methyltransferase (MGMT) status - unmethylated or methylated - in Arm C.

Participants in Arms A and B are treated until completion of RT and participants in Arm C may continue treatment in the absence of safety concerns and disease progression.

A Study Assessing Pamiparib With Radiation and/or Temozolomide (TMZ) in Participants With Newly Diagnosed or Recurrent Glioblastoma

A Phase 1b/2 Study to Assess the Safety, Tolerability and Efficacy of BGB-290 in Combination With Radiation Therapy (RT) and/or Temozolomide (TMZ) in Subjects With First-line or Recurrent/Refractory Glioblastoma

A DLT is defined as one of the following toxicities occurring during the DLT assessment window:

Grade ≥3 non-hematologic, non-hepatic major organ adverse event (AE) Grade 4 neutropenia lasting \>7 days Grade ≥3 febrile neutropenia Grade 3 thrombocytopenia with clinically significant bleeding Grade 4 thrombocytopenia lasting \> 3 days and requiring transfusion, or any decreased platelet count \<15,000/mm3/ \<15.0 x 109/L Grade ≥4 anemia Grade ≥3 total bilirubin or hepatic transaminases (ALT or AST)

A treatment-emergent adverse event (TEAE) is defined as an AE that had an onset date on or after first dose of study treatment or was worsening in severity from baseline (pretreatment) up to 30 days following permanent study treatment discontinuation or initiation of new anti-cancer therapy, whichever occurs first.

An SAE is any untoward medical occurrence that, at any dose meets at least one of the following criteria: results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, is considered a significant medical AE based on medical judgment.

Modified DCR is defined as the percentage of participants with complete response (CR), partial response (PR) or stable disease (SD) per RANO criteria as the response assessment at the end-of-treatment (EOT) visit.

ORR (objective response rate) is defined as percentage of participants with best overall response of CR or PR per RANO criteria (confirmed by a subsequent tumor assessment at least four weeks apart).

Data shows the number of participants who received treatment for the given number of cycles.

The average dose intensity per participant = total dose (mg) per participant / duration of treatment (days).

DCR is defined as the percentage of participants with best overall response of CR, PR or SD per RANO criteria. CR or PR will be confirmed by a subsequent tumor assessment at least four weeks apart

ORR is defined as percentage of participants with best overall response of CR or PR per RANO criteria (confirmed by a subsequent tumor assessment at least four weeks apart).

Clinical benefit rate (CBR) is defined as the percentage of participants with best overall response of CR, PR or SD ≥ 24 weeks per RANO criteria (confirmed by a subsequent tumor assessment at least four weeks apart).

DOR is defined as the time from the date of the earliest documented response to disease progression or death for any cause whichever occurs earlier (confirmed by a subsequent tumor assessment at least four weeks apart).

PFS is defined as the time from the first dose date to disease progression per RANO criteria or death, whichever occurs first.

OS is defined as the time from the first dose date to date of death for any cause.

A treatment-emergent adverse event (TEAE) is defined as an AE that had an onset date on or after first dose of study treatment or was worsening in severity from baseline (pretreatment) up to 30 days following permanent study treatment discontinuation or initiation of new anti-cancer therapy, whichever occurs first. An SAE is any untoward medical occurrence that, at any dose meets at least one of the following criteria: results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, is considered a significant medical AE based on medical judgment.

BeiGene USA, Inc.

A treatment-emergent adverse event (TEAE) is defined as an AE that had an onset date on or after first dose of study treatment or was worsening in severity from baseline (pretreatment) up to 30 days following permanent study treatment discontinuation or initiation of new anti-cancer therapy, whichever occurs first.

Participants with newly diagnosed unmethylated glioblastoma (GBM) received 60 mg pamiparib orally BID for 2 weeks in combination with up to 60 Gy radiation for 6 weeks

Arm 1Arm A: DE - Pamiparib 2 Wks + Radiation Therapy (RT) 6 Wks

Participants with newly diagnosed unmethylated GBM received 60 mg pamiparib orally for 4 weeks in combination with up to 60 Gy radiation for 6 weeks

Arm A: DE-Pamiparib 4 Wks + RT 6 Wks

Participants with newly diagnosed unmethylated GBM received 60 mg pamiparib orally for 6 weeks in combination with up to 60 Gy radiation for 6 weeks

Arm A: DE- Pamiparib 6Wks + RT 6 Wks

Arm A: Dose Expansion (E) - Pamiparib 6 Wks + RT 6 Wks

Participants with newly diagnosed unmethylated GBM received 60 mg pamiparib orally for 6 weeks in combination with up to 60 Gy radiation for 6 weeks and 60 mg temozolomide Wks 1 and 5

Arm B: DE-Pamiparib 6 Wks + RT 6 Wks + Temozolomide

Participants with both methylated and unmethylated recurrent/refractory GBM received 60 mg pamiparib BID and 20 mg temozolomide once daily orally from Day 1 to Day 21

Arm C: DE - Pamiparib + Temozolomide 20 mg

Participants with both methylated and unmethylated recurrent/refractory GBM received 60 mg pamiparib BID and 40 mg temozolomide once daily orally from Day 1 to Day 21

Arm C: DE - Pamiparib + Temozolomide 40 mg

Participants with both methylated and unmethylated recurrent/refractory GBM received 60 mg pamiparib BID and 60 mg temozolomide once daily orally from Day 1 to Day 7

Arm C: E- Pamiparib + Temozolomide 60 mg

Arm A: DE - Pamiparib 2 Wks + Radiation Therapy (RT) 6 Wks

Total

Age, Continuous

Sex: Female, Male

Asian

Black or African American

White

Unknown/Not Reported

Race/Ethnicity, Customized

The Safety Analysis Set includes all participants who received any study treatment (pamiparib, RT, and/or TMZ). The Safety Analysis Set was used for all efficacy and safety analyses.

Phase 1b Escalation Phase: Number of Participants With Dose-Limiting Toxicities (DLTs) as Assessed by CTCAE

Participants with At Least 1 TEAE

TEAE with Grade 3 or Higher

Treatment Emergent SAEs

TEAE Leading to Death

Phase 1b Escalation Phase: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) as Assessed by CTCAE

Phase 1b Escalation Phase Arm C: Number of Participants With Clinically Relevant Changes in Vital Signs and Clinical Laboratory Measurements

The Efficacy Analysis Set (Arm A) includes participants in the Safety Analysis Set who had a tumor assessment at baseline and at End of Treatment unless discontinued treatment or study early due to disease progression or death prior to tumor assessment. Participants with available data were included in the analysis.

Phase 2 Arm A: Modified Disease Control Rate (DCR) as Assessed by Response Assessment in Neuro-Oncology (RANO) Criteria

The Efficacy Analysis Set (Arm C) includes participants in the Safety Analysis Set who had measurable disease at baseline and at least one postbaseline tumor assessment unless discontinued treatment or study early due to disease progression or death prior to tumor assessment. Participants with available data were included in the analysis.

Phase 2 Arm C: Objective Response Rate (ORR) as Assessed Using RANO Criteria

<1 cycle

1 cycle

2 cycles

3 cycles

4 cycles

5 cycles

6 cycles

7 cycles

>7 cycles

Phase 1b Arm C: Number of Cycles of Treatment Received by Participants

Phase 1b Arm C: Average Dose Intensity of Pamiparib And TMZ Received Per Participant

The Pharmacokinetic (PK) Analysis Set includes all participants for whom valid pamiparib PK parameters can be estimated. Participants with available data were included in the analysis.

Phase 1B and Phase 2: Pharmacokinetics: Ctrough of Pamiparib

Efficacy Analysis Set; Participants with available data were included in the analysis

Phase 1b Arm A and Arm B Escalation Phase: Modified Disease Control Rate as Assessed by RANO Criteria

Arm C: DE- Pamiparib + Temozolomide 20 mg

Efficacy Analysis Set; Participants with available data were included in the analysis.

Phase 1b Escalation Phase Arm C: Disease Control Rate as Assessed by RANO Criteria

Efficacy Evaluable Analysis Set; Participants with available data were included in the analysis.

Phase 1b and Phase 2 Arms A and B: ORR as Assessed Using RANO Criteria

Efficacy Analysis Set; participants with available data were included in the analysis

Phase 1b and Phase 2 Arms A, B and C: Clinical Benefit Rate as Assessed Using RANO Criteria

Efficacy Analysis Set; Only the participants with objective responses were included in DOR analysis.

Phase 1b and Phase 2 Arms A, B and C: Duration of Response (DOR) as Assessed Using RANO Criteria

Phase 1b and Phase 2 Arms A, B and C: Progression Free Survival (PFS) as Assessed Using RANO Criteria

Phase 1b and Phase 2 Arms A, B and C: Overall Survival (OS)

Participants with at Lease 1 TEAE

Phase 2 Arms A and C Expansion Phase: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)

Phase 2 Expansion Phase Arm A and C: Number of Participants With Clinically Relevant Changes in Vital Signs and Clinical Laboratory Measurements

Safety Analysis Set; For Arm A Only participants who entered the maintenance phase were included in the analysis as per protocol.

Phase 2 Arms A and C Expansion Phase: Number of Cycles of Treatment Received by Participants

Phase 2 Arms A and C Expansion Phase: Average Dose Intensity of Pamiparib and TMZ Received Per Participant

Participants with newly diagnosed unmethylated glioblastoma (GBM) received 60 milligrams (mg) pamiparib orally twice daily (BID) for 2 weeks in combination with up to 60 Gy radiation for 6 weeks

Arm A: Dose Escalation (DE) - Pamiparib 2 Weeks (Wks) + Radiation Therapy (RT) 6 Wks

Overall Study

Precancerous Conditions

* Lavage of the Cavum uteri and proximal fallopian tubes
* Liquid-PAP (Papanicolaou) smear

Liquid-PAP smear

Paul Speiser, Univ.Prof.Dr.

Epithelial Ovarian cancer (EOC) is the leading cause of death among gynaecologic malignancies in western civilized countries, with an estimated prevalence in Europe and the US of 752,600 in 2007 and 59,828 deaths annually.

State-of-the-art diagnostic tests for EOC include transvaginal ultrasonography and serum cancer antigen (CA-125) measurements; the specificity of these diagnostic tools however is low, and both tests are not effective enough at detecting EOC early enough to improve clinical outcomes. Definitive diagnosis of EOC still relies on histological or cytological confirmation. These findings underline the importance for an effective test for early detection of EOC.

In the current project we will obtain a lavage of the uterine cavity. It will be investigated whether cells from EOCs or genetic material from those cells can be detected in the lavage fluid.

Aim of this study:

There is a clear clinical need for a diagnosis test to detect EOC at an earlier stage.

Epithelial Ovarian cancer is the leading cause of death among gynaecologic malignancies in western civilized countries, with an estimated prevalence in Europe and the US of 752,600 in 2007 and 59,828 deaths annually. Treatment and survival of the patients depend primarily on the stage of the disease. Of all EOC patients only 25% are diagnosed at an early stage while the tumour is confined to the pelvis. In these cases the five-year survival rate is 80% to 90% and the disease can often be cured by the combination of surgery and chemotherapy. Unfortunately, almost 75% of women affected have advanced stage disease with metastatic spread throughout the abdominal cavity or to retroperitoneal lymph nodes at the time of diagnosis; five-year survival rates drop to 10%-30% for advanced disease, despite maximum surgical effort and combination chemotherapy.

State-of-the-art diagnostic tests for EOC include transvaginal ultrasonography and serum cancer antigen (CA-125) measurements; the specificity of these diagnostic tools however is low, and both tests are not effective enough at detecting EOC early enough to improve clinical outcomes. Definitive diagnosis of EOC still relies on histological or cytological confirmation. These findings underline the importance for an effective test for early detection of EOC.

In the current project we will obtain a lavage of the uterine cavity. It will be investigated whether cells from EOCs or genetic material from those cells can be detected in the lavage fluid.

Aim of this study:

There is a clear clinical need for a diagnosis test to detect EOC at an earlier stage.

Lavage of the Uterine Cavity for the Diagnosis of Ovarian and Tubal Carcinoma and Their Premalignant Changes.

Pilot Study of the Lavage of the Uterine Cavity for the Diagnosis of Ovarian and Tubal Carcinoma and Their Premalignant Changes - LUDOC Study

If the adnexal tumor removed turns out to be an EOC, mutation analysis will be carried out applying the sensitive massively parallel sequencing method published by Kinde et al. Mutations in the following genes will be analysed: AKT1, APC, ARID1A, BRAF, CTNNB1, CSMD3, CDKN2A, EGFR, FBXW7, FAT3, FGFR2, KRAS, MLL2, NRAS, PTEN, PIK3CA, PIK3R1, PPP2R1A, PIK3R, RNF43, and TP53.

Obtaining material from the uterine cervix by applying a liquid-based Pap smear technique to directly compare the two sampling techniques - Lavage and liquid-based Pap.

Univ.Prof.MD.

Skin and Connective Tissue Diseases

Breast Neoplasms

Carcinoma in Situ

Procedure/Surgery: Lavage of the Cavum uteri and proximal Fallopian tubes, performed in the luteal phase of the female cycle

Speiser-catheter for uterine and tubal lavage

In Phase I the sponsor will systematically test conditions for lavage filtration that increase tumor cell fraction without reducing tumor mutation yield. The Sponsor will also transition all lavages to luteal phase timing, when endometrial shedding is least. In Phase II the Sponsor will examine our data in context of clinical characteristics, particularly age, to develop a multivariate model that determines optimal mutant allele frequency (MAF) diagnostic threshold by patient. Furthermore, the sponsor will explore a highly innovative idea, entailing empirically determining each individual's background mutation load, agnostic of the aging or mutagenic exposures responsible, and using this as a personalized calibrator to determine optimal MAF diagnostic threshold.

Case control study in two patient population (AIM 1 in average risk population, AIM 2 in high risk population)

Early Detection of High Grade Ovarian Cancer Using Uterine Lavage EHUD Study and Duplex Sequencing

Pilot Study of Early Detection of High Grade Ovarian Cancer Using Uterine Lavage and Duplex Sequencing

Preliminary testing with two samples indicated that filtration of UtLs to remove clusters of endometrial cells could increase sensitivity for tumor mutations several fold. This dataset will be expanded by analyzing the filtration effect in 10 ULs from patients with HGSC with known TP53 mutations. Each UtL will be divided in half: the first half will be filtered and the second will remain unfiltered. DNA will be extracted from the filtered, filtrate, and unfiltered fractions and analyzed by TP53KDS (total of 30 samples). For each UL, the DNA yield will be compared in each of the fractions and the MAF of the tumor mutation. It is anticipated that the filtered fraction will contain less DNA then the unfiltered fraction but the tumor mutation will be present at a higher frequency (i.e. more is gained by enrichment than is lost by reduction from less available DNA).

SNP allele fraction (AF) will be compared at different dilutions to determine accuracy (expected AF vs. observed AF), precision (AF variation among replicates), and lowest limit of detection achievable.

To asses the reproducibility in clinical use total mutation frequency will be assayed. The coefficient of variation among replicates will be calculated. Overall mutation frequency across TP53 in UtLs samples will be measured for both replicates of each patient. VAF will be approximated by number of non-reference duplex bases/total duplex bases sequenced. Confidence intervals will be computed using a binomial normal approximation.

A detailed mutation profile will be generated from the DS output files: mutant allele frequency (MAF) for all mutated positions, mutation spectrum, predicted pathogenicity to protein function, relationship to known hotspots, and overall mutation load (number of mutant nucleotides divided by the total number of nucleotides sequenced). Following this, samples will be unblinded for cases-controls status.

TP53 MAF from DNA collected by UtLs will be used as predictor for differentiating between average risk patients (AIM I) with and without HGSC by logistic regression modelling. An analogous analysis will be applied to the group of high risk patients (AIM II) where presence and absence of STIC is defining the outcome variable. Cut off values for mutant allele frequency will be suggested in both cases and specificity and sensitivity will be estimated including appropriate confidence intervals.

The association between TP53 mutation frequencies in uterine lavage and leukocytes will be examined and will determine whether false negatives in Aim 1A correspond to cases with increased BB in leukocytes. In addition, TP53 mutation frequencies in leukocytes will be analyzed as a predictor of case control status, again using the leave out 10% procedure. This innovative calibration method will be compared with the simple ROC metrics achieved with the univariate model using a fixed mutation fraction as well as the adjusted multivariate model developed based on other patient characteristics such as age. As a scientific question unrelated to the present aims, it is worth investigating whether leukocyte TP53 mutation load will serve as an independent predictor of patient age, overall health or history of mutagenic exposures.

Comparison of performance of UtL collection with that of Pap smear collection. It will be investigated if any additional power to discriminate cases from controls can be gained by combining information from Pap smears and ULs.

Aiming to evaluate the potential for defining a DNA-Methylation signature for simple PCR testing, dCT-PCR values from 96-plexed high-throughput MSREqPCR analysis will be analysed by bioinformatics \& biostatistics. See Detailed description og the Aim III above for more details.

Paul Speiser, Prof.MD,

Clinical Professor

Lavage of the Cavum uteri and proximal Fallopian tubes, performed in the luteal phase of the female cycle

Paul Speiser, Univ.Prof.Dr.med.

The current study aims at answering the scientific question, whether exfoliated cells from STICs get transported into the uterine cavity via the fallopian tube, and whether it is possible to detect those cells in the lavage fluid from the uterine cavity and proximal fallopian tubes.

To address this question, the investigators will study 20 lavage samples and their 20 corresponding STIC-positive tissue samples in women who opt for risk-reducing bilateral salpingo-oophorectomy (rrBSO) because of increased risk of high grade serous carcinoma of the pelvis (HGSC) (mostly carrying a BRCA mutation), without a history of tubal occlusion for sterilization. Women who opt to have the fallopian tubes removed but the ovaries preserved are eligible for the study too, as are women who opt for rrBSO plus hysterectomy.

The term "high grade serous carcinoma" (HGSC) describes a group of ovarian, tubal and peritoneal cancers with an aggressive biological behavior. HGSC is the leading cause of death from gynecologic malignancy in western civilized countries. Women affected, usually have advanced stage disease with metastatic spread throughout the abdominal cavity at time of diagnosis. Five-year survival rates are in the range of 10 to 30 percent. The specificity of current diagnostic tools (CA-125 and transvaginal ultrasonography) is low and ineffective at detecting HGSC early enough to improve clinical outcomes. Definitive diagnosis of HGSC mostly relies on surgical confirmation. These findings underline the need for an effective test for early detection of HGSC. In the general population, the lifetime risk is 1.5 percent.

Women with germ line mutations in the BRCA1 and BRCA2 gene or a strong family history of epithelial ovarian cancer carry a high risk for breast cancer and/or HGSC development. Familial or inherited syndromes account for approximately 13 percent of cases of invasive epithelial ovarian and fallopian tube cancer. The lifetime risk of ovarian cancer is 35 to 46 percent in women with BRCA1 gene mutations and 13 to 23 percent in those with BRCA2 mutations. Again, even in this population with high-risk for HGSC, the specificity of CA-125 and transvaginal ultrasonography is still too low and ineffective to improve clinical outcomes.

Over the last years, increasing scientific evidence conglomerated that a large proportion of not only familial HGSC develop primarily in the lining of the fallopian tube, that resembles Müllerian epithelium. These precursor lesions are called "serous tubal intraepithelial carcinomas" (STICs) and are characterized by p53 overexpression on immunohistochemistry and high Ki-67 labelling index indicating a high proliferation index. In over 90 percent, STICs carry mutations in the TP53 tumor suppressor gene.

As for today, risk reducing bilateral salpingo-oophorectomy (rrBSO) is the most effective approach to reducing the risk of HGSC in high risk women. Among women with an increased risk of HGSC (most with BRCA mutations) who underwent rrBSO, 4 to 17 percent are found to have a STIC or even invasive neoplasm, and approximately 80 percent of these neoplasms are in the ampullar part of the fallopian tube.

Recent findings highlighted the malignant potential of STICs. On histopathological specimen, intraluminal shedding of tumor cells from STICs can be frequently demonstrated in the fallopian tube. This shedding of tumor cells from STICs appears to be a risk factor for early transperitoneal metastasis frequently found in HGSC. There is a strong clinical need for screening for STICs, since they are the precursor lesion of HGSC. These facts underline the importance of an effective - non-invasive - test for early detection of STICs.

The ovarian surface, the fallopian tubes, the uterine cavity and the peritoneal cavity all together form a communicating compartment. The physiological function of the ciliated lining of the tubes is to transport the egg into the uterine cavity after ovulation thus making it likely that exfoliated cells from STICs can be found in the uterine cavity.

A promising approach for the detection of STICs has been established by Paul Speiser and Robert Zeillinger (Molecular Oncology Group, Department of General Gynaecology and Gynaecologic Oncology, Medical University of Vienna, Austria). This approach is called the ALPINE technique (Austrian Lavage Procedure for the Detection of tubal Intraepithelial Neoplasms) (manuscript under preparation). To facilitate an quick and easy lavage of the uterine cavity and proximal tubes, a special catheter was developed (MEDICOPLAST, MF 13005, catheter for uterine and tubal lavage). The ALPINE technique includes a lavage of the uterine cavity and proximal fallopian tubes and subsequent analysis of this lavage fluid for the presence of pre-malignant and malignant cells.

For the proof of principle that tumor cells from ovarian cancer are shed and can be found in the lavages of the uterine cavity, uterine lavages were collected before a surgical intervention for suspected ovarian malignancy at our institution and at the Catholic University Leuven, Division Gynaecological Oncology, Belgium. After malignancy was confirmed, genetic changes in the TP53 and KRAS genes were determined in tumor tissue. In a set of 9 epithelial ovarian cancer patients (EOC) and 1 ovarian metastases of a signet ring carcinoma, the presence of these genetic changes was examined in lavage samples, using digital droplet PCR (ddPCR). 10 genetic changes were identified in tumor tissue of these patients and 9/10 (90%) of these changes were detected in the corresponding lavage specimen too.

Furthermore, a filter approach, followed by p53 immunofluorescence staining was established, confirming the presence of tumor cells in the lavage sample of one additional patient.

In a next step, lavage samples of 23 ovarian carcinoma patients, and if applicable corresponding tumor tissue, were analysed through deep sequencing by the group of Bert Vogelstein (Johns Hopkins University, Baltimore, USA). The presence of genetic changes, indicative for ovarian cancer, could be confirmed in 18/23 (78.3%) lavage specimen including both, early and advanced stages.

These results are proof that ovarian cancer cells are shed into the fallopian tubes and uterine cavity, and can be collected through our ALPINE technique. The fact that ovarian cancer cells were detected with high sensitivity in the lavage of the uterine cavity and proximal tubes shows that this approach has potential in early diagnosis. Therefore, the investigators are confident that this method could be applied in detection of premalignant changes in high risk patients, as well.

Aim of the study:

The current study aims at answering the scientific question, whether exfoliated cells from STICs get transported into the uterine cavity via the fallopian tube, and whether it is possible to detect those cells in the lavage fluid from the uterine cavity and proximal fallopian tubes.

Methods:

To address this question, the investigators will study 20 lavage samples and their 20 corresponding STIC-positive tissue samples in women who opt for rrBSO because of increased risk of HGSC (mostly carrying a BRCA mutation), without a history of tubal occlusion for sterilization. Women who opt to have the fallopian tubes removed but the ovaries preserved are eligible for the study too, as are women who opt for rrBSO plus hysterectomy.

Lavage of the Uterine Cavity for the Diagnosis of Serous Tubal Intraepithelial Carcinoma

Pilot Study of the Lavage of the Uterine Cavity for the Diagnosis of Serous Tubal Intraepithelial Carcinoma

Women who opt for rrBSO or opt to have the fallopian tubes removed but the ovaries preserved, and women who opt for rrBSO plus hysterectomy. The lavage can be done either in an outpatient setting or in the operating theatre under general anaesthesia.

Univ.Prof.Dr.med.

Carcinoma, Transitional Cell

Transitional Cell Carcinoma

Administration of 89Zr-Girentuximab as per protocol

Administration of 89Zr-girentuximab as per protocol.

89Zr-Girentuximab

The aim of this study is to determine if it is practical to use 89Zr-TLX250 PET/CT in the staging and detection of localized and metastatic urothelial carcinoma or bladder cancer.

The primary objective is to evaluate the feasibility of using 89Zr-TLX250 PET/CTas a new diagnostic and staging modality to detect urothelial carcinoma or bladder cancer.

This will be a non-randomised, non-blinded, single centre, phase 1 feasibility study comparing 89Zr-girentuximab PET with FDG PET in patients with urothelial carcinoma or bladder cancer. This study would include 2 cohorts of adult patients; those with known metastatic urothelial carcinoma and bladder cancer and those undergoing primary staging for recently diagnosed urothelial carcinoma or bladder cancer.

This study is open-label, single centre and eligible patients will receive a single administration of study drug prior to imaging on day 5 (+/- 2 days). PET scans will be independently interpreted by nuclear medicine physicians blinded to the FDG PET findings. For patients proceeding to radical cystectomy, subsequent histological confirmation of areas of increased uptake will be retrospectively correlated with both PET scans.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Lavage of the Uterine Cavity for the Diagnosis of Ovarian and Tubal Carcinoma - Study of Sensitivity and Specificity	NCT02518256	Ovarian Epithel...	Lavage of the C...	18 Years - 85 Years	Medical University of Vienna
A Study Assessing Pamiparib With Radiation and/or Temozolomide (TMZ) in Participants With Newly Diagnosed or Recurrent Glioblastoma	NCT03150862	Brain and Centr...	Pamiparib TMZ Radiation	18 Years -	BeiGene
Lavage of the Uterine Cavity for the Diagnosis of Ovarian and Tubal Carcinoma and Their Premalignant Changes.	NCT02062697	Ovarian Epithel...	Lavage of the C... Liquid-PAP smea...	18 Years - 80 Years	Medical University of Vienna
Early Detection of High Grade Ovarian Cancer Using Uterine Lavage EHUD Study and Duplex Sequencing	NCT04823871	Ovarian Epithel... Carcinoma in Si... Ovarian Cancer	Speiser-cathete...	18 Years - 80 Years	Medical University of Vienna
Lavage of the Uterine Cavity for the Diagnosis of Serous Tubal Intraepithelial Carcinoma	NCT02039388	Ovarian Epithel... Carcinoma in Si... Ovarian Cancer	Lavage of the C...	18 Years - 80 Years	Medical University of Vienna
Lavage of the Uterine Cavity for the Diagnosis of Ovarian and Tubal Carcinoma and Their Premalignant Changes.	NCT02062697	Ovarian Epithel...	Lavage of the C... Liquid-PAP smea...	18 Years - 80 Years	Medical University of Vienna
Phase I Study to Evaluate the Diagnostic Performance of 89Zirconium Girentuximab PET in Urothelial Cancer Patients	NCT05046665	Urothelial Carc...	89Zr-Girentuxim...	18 Years -	South Metropolitan Health Service

Spots Global Cancer Trial Database for glandular and epithelial