Neoplasms

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Gland and Hormone Related Diseases

All Conditions

Symptoms and General Pathology

Rare Diseases

Ovarian Neoplasms

Carcinoma, Ovarian Epithelial

Cysts

Ovarian Cysts

Carcinoma

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

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Pathological Conditions, Anatomical

Ovarian Cancer

Ovarian Epithelial Cancer

Information on symptoms, specialized ultrasound in accordance to IOTA, and HE4 is registered in women with ovarian cysts. Participation in the study including symptom registration, description of the cyst using IOTA terminology, and HE4 determination will not affect further diagnostics or treatment. HE4 will not be informed to the patient or clinician.

Detailed symptomregistration

Claus Høgdall, Professor

Nikoline Schou Karlsen, MD

Claus K Høgdall, MD, professor, DSc

Nikoline F Karlsen, MD, ph.d.fellow

Background:

Ovarian cysts are common in women. The vast majority is benign; yet, ovarian cancer (OC) is seen in 500 women every year in Denmark. OC is often diagnosed in advanced stages, and OC is the fifth most deadly cancer in women in more developed countries. It can be a clinical challenge to distinguish benign ovarian cysts from OC. Currently, the Risk of Malignancy Index (RMI) is used to detect women at high risk of OC in Denmark, however, new methods to correctly differentiate benign ovarian cysts from OC at an early stage is needed. New promising studies suggest an improved diagnostic accuracy by adding the biomarker Human Epididymis Protein 4 (HE4) and systemized ultrasound imaging International Ovarian Tumor Analysis (IOTA).

Purpose:

The purpose is to evaluate the diagnostic performance of HE4 and IOTA in a Danish clinical setting. Furthermore, to develop an optimized diagnostic algorithm to differentiate ovarian cysts based on a combination of symptoms, biomarkers and IOTA.

Methods:

The study is a prospective, observational study. Women with ovarian cysts are included from gynecological practitioners and departments in the Capital Region of Denmark. Detailed information on health and symptoms are registered, and the cysts are systematically described by the gynecologist in accordance to the IOTA terminology. HE4 will be analyzed in those women who routinely needs a diagnostic blood test for CA125. Data will be coupled with data from the patient file and Danish Gynecological Cancer Database (DGCD). The diagnostic utility of HE4 and IOTA will be evaluated both alone and in combinations with health information, symptoms, and CA125. The study has been approved by the Regional Committee on Health Research Ethics (H-19021342) and the Data Protection Agency (P-2019-340).

Significance:

This study establishes a unique database which will form the basis for developing an optimized method for differentiating ovarian cysts, and thus optimize referral and diagnosis.

Background:

Ovarian cysts are commonly found in women with an estimated prevalence up to 35 % in premenopausal women and 17 % in postmenopausal women. The majority are of benign character and sometimes self-limiting; however, malignancy occurs as ovarian cancer (OC). More than 500 women are diagnosed with OC every year in Denmark, and Denmark has the highest OC incidence rate in the Nordic countries. Today, more than 70% of women with OC are diagnosed with advanced stage disease, where the five-year overall survival rate is 16-29% compared to 70-88% in early stages. Symptoms are often present months prior to diagnosis, however, they are vague and un-specific of character leading to delay of diagnosis. Attempts to improve patient awareness and correct symptom interpretation are encouraged. OC rates the fifth most deadly cancer among women and causes more deaths than any other cancer of the female reproductive system in more developed countries. Centralized treatment of OC9, OC guidelines10, fast-track OC programs, and a gynecologic cancer database (Danish Gynecological Cancer Database (DCGD)) are all national approaches that has contributed to a decreased mortality rate in Denmark during the past decades.

Yet further approaches to improve OC survival are highly needed. Given that OC survival is considerably better in early stage disease, methods to correctly differentiate benign ovarian tumors from OC at an early stage is a high research priority. In Denmark, gynecologists currently use the Risk of Malignancy Index (RMI) to detect women at high risk of OC. RMI calculation is based on transvaginal ultrasound findings, serum Cancer Antigen 125 (CA125) level, and menopausal status. Women in high risk of OC (RMI ≥ 200) are referred in the national fast-track cancer program for further diagnostics at a tertiary center specialized in gynecologic malignancies, whereas women in low risk of OC (RMI \< 200) can be observed or treated at a local department of gynecology or in a gynecology practice. However, RMI is not optimal to distinguish between benign and malignant tumors with a sensitivity of 92 %, specificity of 82 %, negative predictive value of 97 %, and a positive predictive value of 62 % in a Danish population.

Considering the high prevalence of benign ovarian cysts in comparison to OC, it is of utmost importance, that efforts to detect OC at an early stage is not accompanied by an unintended increase of false positive tests, resulting in overdiagnosis and overtreatment. New promising studies suggest an improvement in the diagnostics and risk assessment models by adding the serum biomarker Human Epididymis protein 4 (HE4) and systemized ultrasound imaging in accordance to the International Ovarian Tumor Analysis (IOTA).

The biomarker HE4 is a secretory gluco-protein that is highly elevated especially in serum from women with OC. The diagnostic performance of HE4 is equal to CA125 and improves further when HE4 and CA125 is combined In the newly developed diagnostic Copenhagen Index (CPH-I), HE4 is combined with age and CA125. On tertiary center data, CPH-I has shown to distinguish benign gynecologic disease from OC significantly better than RMI in the international, multicenter, validating cohort demonstrating an area-under-curve (AUC) at 0.951 and 0.935, respectively.

IOTA is an internationally accepted classification system for describing a pelvic mass; and was developed by the IOTA group and published by Timmerman et al. in 2001. The classification system is based on standardized definitions and terms regarding ultrasound morphological features, doppler analysis, and presence/absence of ascites. Several promising models for risk analysis of a pelvic mass (e.g. Logistic Regression 2 model, Simple Rules, ADNEX model) have been developed based on the IOTA classification system. An increasing number of gynecologists in Denmark are IOTA certified; however, IOTA has never been validated in a Danish cohort and is not yet implemented . HE4, CPH-I, and the IOTA classification appear to be more accurate in differentiating ovarian cysts. However, these methods all need further prospective evaluations in the primary- and secondary sector before clinical implementation in Denmark.

Purpose:

The purpose is to evaluate symptoms and the diagnostic performance of HE4, CPH-I and the IOTA classification in Danish women diagnosed with an ovarian cyst. Furthermore, the aim is to develop and validate an optimized diagnostic algorithm to differentiate benign ovarian cysts from OC, based on symptoms, biomarkers, and IOTA.

Methods:

Study design and population: The study is a prospective, observational study. After oral and written project information and consent is given, women are included by gynecologist from a gynecology practice or a department of gynecology in the Capital Region of Denmark. Women with ovarian cysts are eligible for study inclusion. Exclusion criteria are age \< 18 years and unable to provide consent. We expect to include around 2.500 women in a period from ultimo 2019 to May 2022.

Power calculation: A preliminary power calculation was performed based on specificities of RMI and CPH at 0.78 and 0.81, respectively. Sample size was estimated to 665 cases using a 2 sample non-inferiority or superiority calculation with type I error set at 1 %, power at 0.80, a non-inferiority or superiority margin of -0.1, and a sampling ratio of 1.

Baseline data: Included women will be asked to answer a questionnaire with detailed information on health data and symptoms, that previously have been shown to be correlated to a pelvic mass.

Ultrasound: The ultrasound examination will be performed as part of the routine examination. It is performed in lithotomy position, with an empty bladder, using a transvaginal probe and high-end equipment. Ultrasound beam frequencies are set between 5.0 and 9.0 MHz, and the internal female reproductive organs are systematically examined with transvaginal gray scale. Doppler settings regarding pulse repetition frequency are fixed at 0.3 to 0.9 MHz, and color gain is gradually increased until appearance of flash artifacts; followed by a frequency decrease to a level, where slow flow in blood vessels is still visible when examining for tumor vascularity. A transabdominal probe is also used when necessary. The ovarian cyst is described by the gynecologist in accordance to IOTA terminology in the patient's medical record. The definition of a lesion and how to classify, distinguish, and measure the morphological features, including septae, solid tissue, papillary projections, regularity of internal walls, cystic content, acoustic shadows, and ascites, are specifically defined by the IOTA group.25 Furthermore, five specific ultrasound images per patient will be stored for later validation.

Blood sampling, biomarkers, and analyses: Blood sampling for HE4 analysis will be performed as part of the routine examination in women tested for CA125. Blood sampling takes place at the gynecology practice or at in- or out-hospital laboratories in the Capital Region. Blood samples will be collected in 4-milliliter blood collection tubes. After sampling, the blood is centrifuged and fractionated; and serum is extracted before analysis. After routine CA125 examination is made, serum will be safely stored in the Danish CancerBiobank (DCB), a part of the Bio- and GenomeBank, Denmark (RBGB).26 Samples will be stored at -80 degrees Celsius until batch analysis. Levels of HE4 will be quantitatively measured using Elecsys HE4 fully automated chemiluminescent immuno-assays.

Data collection and storage: Information on symptoms and health care information will be obtained from questionnaires answered by the patient. Information about routine diagnostics and follow-up are is retrieved from the electronical patient files used in the gynecology practice and departments of gynecology and Labka. Information on diagnosis is retrieved from Patobank and Danish Gynecological Cancer Database (DGCD). Together with ultrasound images and results from HE4 analyses, all data will be continuously transferred to an electronic database as prescribed by the Capitol Region in Denmark.

Statistical considerations:

Descriptive statistics of the study will be listed and compared between groups using the Chi square test or the Fisher's exact test for categorical variables and the Mann-Whitney test for continuous variables. Categorical variables will be listed as numbers (n) and percentages (%), whereas continuous variables will be listed in medians and ranges. P-values for the differences will be calculated, and a p-value ≤ 0.05 will be considered statistically significant.

CPH-I is calculated using the formula defined by Karlsen et al.:

CPH-I = - 14.0647 + 1.0649 x log 2 (HE4) + 0.6050 x log 2 (CA125) + 0.2672 x age / 10.

RMI is calculated by the formula by Jacobs et al.:

RMI = Menopause (yes=3 points; no=1 points) x ultrasonic findings (unilocular=0; bi- or multilocular=1, solid areas=1, excrescences=1, bilateral=1, ascites=1, other ovarian disease=1 --\> 0-1=1 points and 2-6=3 points) x CA125 (U/mL).

The ability to differentiate between healthy women, women with non-gynecologic disease, benign gynecologic disease, and OC will be examined using univariate and multivariate logistic regression analyses.

Dissemination of study results:

All projects with positive, inconclusive, as well as negative results will be published in international peer-reviewed scientific journals. The study group and other relevant collaborators will be co-authors, if they meet the Vancouver criteria. Intellectual property of the study belongs to the study group and can be shared after consent.

Significance of the project:

Most ovarian cysts are benign and can be followed or surgically treated at the local gynecology practice or department of gynecology. Sometimes, however, it can be challenging to differentiate from OC with the diagnostic tools available. We expect to develop an optimized diagnostic tool used to detect women in low risk of OC from women in high risk of OC with a higher precision than existing risk models. Furthermore, the implementation of the DOC study will contribute to a quality improvement in the daily clinical practice applying consistent use of systematic ultrasound and standardized terminology in patient file templates.

Diagnosing Ovarian Cysts - the DOC Study

The diagnostic accuracy (SN, SP, PPV, NPV, AUC) of HE4, CPH-I, and IOTA to determinie ability to differentiate healthy women, women with non-gynecologic disease, benign gynecologic disease, borderline ovarian tumors, and OC will be examined using univariate and multivariate logistic regression analyses. Diagnostic utility of HE4, CPH-I and IOTA will be compared to CA125, ROMA and RMI.

Rigshospitalet, Denmark

Professor, DMSc

Adenocarcinoma

Neoplasm Metastasis

Recurrence

Endometrial Neoplasms

Cystadenocarcinoma, Serous

Carcinosarcoma

Mixed Tumor, Mullerian

Adenocarcinoma, Clear Cell

Fallopian Tube Neoplasms

Cystadenocarcinoma

Carcinoma, Endometrioid

Uterine Diseases

Disease Attributes

Uterine Neoplasms

Fallopian Tube Diseases

Neoplasms, Cystic, Mucinous, and Serous

Sarcoma

Neoplasms, Connective and Soft Tissue

Fallopian Tube Cancer

Malignant Mixed Mullerian Tumor

Adenocarcinoma of the Appendix

Soft Tissue Sarcoma

Micronutrients

Hematinics

All Drugs and Chemicals

Antineoplastic Agents

Vitamins

Folic Acid

Vitamin B Complex

Exatecan

Folinic Acid

Folate

Vitamin B9

Dose Escalation: Escalating doses of ELU001 Dose Expansion: Recommended Dose for Expansion (or RP2D)

Folic-acid functionalized C'Dot-Drug-Conjugate (FA-CDC)

ELU001

Clinical Trial Operations

David J Park, MD

Gerardo Colon-Otero, MD

Colon-Otero Gerardo, M

David J Kahn, MD

Cesar A Perez Batista, MD

Srilata Gundala, MD

Michelle R Rowland, MD, Phd, MPH

Andrea Wahner-Hendrickson, MD

Clinical Trials Information

Yonina R Murciano-Goroff, MD, MsC

Carey Anders, MD

Wen Wee Ma, MBBS

Babar Bashir, MD

Babir Bashir, MD

Cara Mathews, MD

Luis Rojas-Espaillat, MD

Erika P Hamilton, MD

Karina Amaro, Study Coord

Teresa Marquez, ClinTrialMg

Douglas Orr, MD

NEXT Coordinators

Anthony W Tolcher, MD, FRCPC

Elizabeth Swisher, MD

Eliel Bayever, MBBCh, MRCP

This study, ELU- FRα-1, is focused on adult subjects who have advanced, recurrent or refractory folate receptor alpha (FRα) overexpressing tumors considered to be topoisomerase 1 inhibitor-sensitive based on scientific literature, and, in the opinion of the Investigator, have no other meaningful life-prolonging therapy options available.

ELU001 is a new chemical entity described as a C'Dot drug conjugate (CDC), consisting of payloads (exatecans) and targeting moieties (folic acid analogs) covalently bound by linkers to the C'Dot particle carrier. ELU001 will be the first drug-conjugate of its kind to be introduced into the clinic, a first in class, and a novel molecular entity.

The study has two parts: Part 1 Dose Escalation Safety Study to identify the maximum tolerated dose (MTD) and/or the recommended phase 2 dose (RP2D), and Part 2 Tumor Group Expansion Cohort(s) where specific cancer types will be evaluated for efficacy and safety at the RP2D.

Part 1, subjects with cancer types with a high likelihood of having FRα overexpressing tumors based on historical data, specifically, ovarian, endometrial, colorectal, gastric, gastroesophageal junction, triple negative breast, or non-small cell lung cancers, or cholangiocarcinoma, will be enrolled in a basket clinical study. Retrospective analysis of folate receptor alpha (FRα) expression status will be determined. Part 1 is currently closed for further recruitment.

Part 2 Stage 1 of a Simon's Two-Stage design, tumor group expansion cohorts, each consisting of subjects with cancer types studied as part of the basket in Part 1. Part 2 is open for recruitment.

Dose Escalation Dose Expansion, Simon's 2-stage

A Study to Evaluate ELU001 in Patients With Solid Tumors That Overexpress Folate Receptor Alpha (FRα)

Dose Escalation and Expansion Clinical Study to Evaluate the Safety and Efficacy of ELU001 in Subjects Who Have Advanced, Recurrent or Refractory FRα Overexpressing Tumors

To determine the MTD and/or RP2D of ELU001 in patients with over-expressing Folate Receptor Alpha tumors. When at least 2 out of 6 patients in a given dose-level experience a dose-limiting toxicity (DLT), the dose is considered to have exceeded the MTD. The MTD, therefore, is defined as the previous highest tested dose of ELU001 that did not cause a DLT in the first cycle of treatment. In the event of emerging data during Part 1, the Sponsor may, in consultation with a dose-level safety review group, decide to define a recommended dose for expansion (in for Part 2) (RP2D) instead of the MTD. DLTs are defined as a treatment-emergent adverse event (TEAE) or abnormal laboratory value related to ELU001 treatment that result in a failure to meet the criteria for re-treatment.

Percentage of Participants with confirmed objective response as assessed by the investigator and per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 CR is defined as the disappearance of all target or non-target lesions. PR is defined as at least 30 percent (%) decrease in the sum of the longest diameters (SoD) of target lesions, taking as reference the baseline SoD.

Time Measurement: DOR will begin at the date that a response has been identified (stable disease, partial response, or complete response) until the date of progressive disease (PD). PD is defined of at least a 20% increase in the sum of the longest diameters of the target lesions from data of initial response.

The number of participants Frequency/severity of abnormalities in vital signs measurements, physical examination findings, changes in clinical laboratory parameters, and incidence of adverse events after taking ELU001.

Elucida Oncology

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Diagnosing Ovarian Cysts - the DOC Study	NCT04188652	Ovarian Cysts Ovarian Cancer Ovarian Neoplas... Ovarian Cancer ...	Detailed sympto...	18 Years -	Rigshospitalet, Denmark
A Study to Evaluate ELU001 in Patients With Solid Tumors That Overexpress Folate Receptor Alpha (FRα)	NCT05001282	Ovarian Cancer Ovarian Neoplas... Ovarian Carcino... Endometrial Can... Ovary Cancer Ovary Neoplasm Ovary Disease Ovary Metastasi... Ovarian Disease... Ovarian Cancer ... Ovarian Epithel... Ovarian Adenoca... Ovarian Serous ... Ovarian Neoplas... Ovarian Cancer ... Endometrial Dis... Endometrial Ade... Endometrial Car... Endometrial Cle... Endometrioid Ad... Endometrial Neo... Endometrial Can... Endometrioid Tu... Fallopian Tube ... Peritoneal Canc...	ELU001	18 Years -	Elucida Oncology

Spots Global Cancer Trial Database for ovarian cancer stage