We're building a better ClinicalTrials.gov. Check it out and tell us what you think!
Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

Translational Analysis In Longitudinal Series of Ovarian Cancer ORganoids (TAILOR)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04555473
Recruitment Status : Recruiting
First Posted : September 18, 2020
Last Update Posted : September 18, 2020
Sponsor:
Information provided by (Responsible Party):
Fondazione Policlinico Universitario Agostino Gemelli IRCCS

Brief Summary:
This is a longitudinal observational phase II, single center, single arm study on the reliability of high grade serous ovarian carcinoma organoids obtained from primary debulking surgery (PDS)+adjuvant chemotherapy and neoadjuvant chemotherapy + interval debulking surgery (NACT+IDS) cases as model for the patients' response to treatments. Since organoids represent a model system comparable to patient-derived xenografts, the investigators tested the null hypothesis that the possibility of correctly identifying the drug-sensitivity could improve from 80%, as assessed by xenografts to at least 95%. The first step was planned to include 7 patients; if 5 or more patients do not respond, the trial will be terminated. If the trial goes on to the second stage, a total of 43 patients will be studied. Considering a patient dropout of approximately 10%, the study was planned to enroll at least 48 patients.

Condition or disease Intervention/treatment
Organoids Epithelial Ovarian Cancer Procedure: Tumor biopsy

Detailed Description:
In this project, the investigators propose to employ the patients-derived organoid technology to test HGSOC organoids obtained from PDS+adjuvant chemotherapy and NACT+IDS cases to predict patients' response to treatments; moreover, the investigators aim to study genomic and phenotypic evolution of HGSOC organoids from PDS+adjuvant chemotherapy and NACT+IDS patients undergoing relapse. Finally, the investigators intend to investigate splicing-targeting technologies as new potential therapeutic treatments to increase vulnerability of HGSOCs. FIGO stage IIIC or IV ovarian, fallopian tube, or primary peritoneal cancer patients will be included if disease at metastatic sites is supposed to be completely resectable and they will be triaged for staging laparoscopy to obtain histologic diagnosis and to provide the tumor load assessment through the laparoscopic score. If PDS is chosen, open cytoreduction will be performed at the same time and bioptic tissue will be collected for organoids; otherwise, women will be submitted to NACT followed by IDS and tissue for organoids will be collected from both staging LPS biopsy (pre-) and subsequent surgery (post-NACT). Part of each surgical specimen will be used to obtain organoids, whereas part will be frozen for direct comparative analysis of the original tumor. 1-6 organoids from each patient will be prepared from PDS or NACT-IDS patients (pre- and post-NACT) and blood samples will also be collected to purify extracellular circulating RNA (cRNAs).

Layout table for study information
Study Type : Observational [Patient Registry]
Estimated Enrollment : 48 participants
Observational Model: Cohort
Time Perspective: Prospective
Target Follow-Up Duration: 36 Months
Official Title: Translational Analysis In Longitudinal Series of Ovarian Cancer ORganoids
Actual Study Start Date : May 12, 2020
Estimated Primary Completion Date : November 4, 2021
Estimated Study Completion Date : May 4, 2023

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Ovarian Cancer


Intervention Details:
  • Procedure: Tumor biopsy

    Both interventions performed at baseline upon study enrolment (pre- and post-NACT for NACT+IDS patients) and at the time of recurrence.

    1. Part of each surgical specimen will be used to obtain organoids, whereas part will be frozen for direct comparative analysis of the original tumor (1-6 organoids from each patient).
    2. Blood samples will be collected to purify extracellular circulating RNA (cRNAs).
    Other Name: Blood sampling


Primary Outcome Measures :
  1. Reliability (yes/no) of HGSOC organoids obtained from PDS+adjuvant chemotherapy and NACT+IDS cases as a model for the patient's response to treatments [ Time Frame: Up to 36 months ]
    Part of each surgical specimen of eligible women will be used to obtain PDOs according to established protocols (Tuveson et al.), whereas part will be frozen for direct comparative analysis of the original tumor. At first passages, organoids will be characterized for histologic and cytologic features. PDOs maintaining HGSOC features will be analysed for genomic features and splicing-sensitive transcriptomic signatures by next generation sequencing (NGS). The identified transcriptomic signatures of PDOs will be compared to those of the original tumor by quantitative real time PCR (qPCR) analysis. PDOs will then be characterized for their response to specific drugs and the response will be compared to that of the patient undergoing chemotherapy. Dichotomic variable: Yes/No


Secondary Outcome Measures :
  1. The genomic and phenotypic evolution of tumor cells in HGSOC organoids from PDS+ adjuvant chemotherapy and NACT+IDS patients undergoing relapse [ Time Frame: Up to 36 months ]
    At time of relapse (if any), we will repeat NGS genomic and transcriptomic analysis of chemoresistant PDOs derived from selected patients who experienced relapse and underwent secondary surgery. Bioinformatics analyses will be applied to capture changes in the mutational status and in the transcriptional/splicing signature that accompany acquisition of chemoresistance in vitro. These features will then be compared to evolution of the tumor in vivo by sequencing (mutations) and qPCR (transcriptomics) of tissue obtained during surgery. Dichotomic variable: Yes/No

  2. Splicing dysregulation and splicing-targeting technologies as new potential therapeutic treatments to increase vulnerability of MYC-overexpressing HGSOCs [ Time Frame: Up to 36 months ]
    HGSOCs often display amplification of MYC, an oncogene that dysregulates the splicing program. We will test if HGSOC PDOs are sensitive to splicing-targeting drugs (E7107, THZ531, PRMT5 inhibitor) administered either alone or in combination with chemotherapy. THZ531 renders BRCA1/2 proficient HGSOC cell lines sensitive to PARPi. We will extend this study to PDOs and analyze their sensitivity to splicing-targeting drugs during their evolution in vitro. Changes in splicing signatures will be evaluated and correlated with the response to combined treatments, to determine their potential as biomarkers. We will also silence splicing factors deregulated in HGSOCs by RNA interference to determine their impact on PDO response to chemotherapy in terms of survival, expansion potential and transcriptomic signatures. Dichotomic variable: Yes/No


Biospecimen Retention:   Samples With DNA
Bioptic tissue from the tumor will be collected from PDS and NACT+IDS patients at the time of surgery. Part of the bioptic tissue will be used to obtain organoids, whereas part will be frozen for direct comparative analysis of the original tumor. Blood samples will also be collected to purify extracellular circulating RNA (cRNAs).


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Gender Based Eligibility:   Yes
Gender Eligibility Description:   Female patients
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
Eligible population included women with preoperative clinical, serological and radiologic suspicion of International Federation of Gynecology and Obstetrics (FIGO) stage IIIC or IV ovarian, fallopian tube, or primary peritoneal cancer, and histological confirmation of diagnosis for HGSOC. Stage IV patients were included only in case of positive pleural effusion, or any resectable disease. All women were required to sign written informed consent to enter the study.
Criteria

Inclusion Criteria:

  1. age between 18 and 75 years
  2. estimated life expectancy of at least 4 weeks
  3. performance status (PS) according to Eastern Cooperative Oncology Group (ECOG) < 2
  4. adequate bone marrow, respiratory, hepatic, cardiologic medullary and renal function (creatinine clearance < 60 ml/min according to Cockroft formula)
  5. histologic diagnose of epithelial ovarian cancer at frozen section and laparoscopic score ≥ 8 or ≤ 12 (considered HTL) with no evidence of mesenteric retraction

Exclusion Criteria:

  1. Pregnancy or breast-feeding
  2. History of concomitant or previous malignancy in the last 5 years

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04555473


Contacts
Layout table for location contacts
Contact: Giuseppe Vizzielli, PhD 3403990822 ext 0039 giuseppe.vizzielli@policlinicogemelli.it
Contact: Giuseppe Vizzielli, PhD 3403990822 ext 0039 giuseppevizzielli@yahoo.it

Locations
Layout table for location information
Italy
Fondazione Policlinico Universitario "A. Gemelli" IRCCS Recruiting
Rome, Italy, 00168
Contact: Giuseppe Vizzielli, PhD       giuseppevizzielli@yahoo.it   
Sponsors and Collaborators
Fondazione Policlinico Universitario Agostino Gemelli IRCCS
Investigators
Layout table for investigator information
Principal Investigator: Giuseppe Vizzielli, PhD Fondazione Policlinico "A. Gemelli" IRCCS
Study Director: Giovanni Scambia, Professor Fondazione Policlinico "A. Gemelli" IRCCS - Università Cattolica del Sacro cuore
Study Director: Claudio Sette, Professor Catholic University of the Sacred Heart
Study Chair: Camilla Nero, PhD Fondazione Policlinico "A. Gemelli" IRCCS
Study Chair: Eleonari Cesari, PhD Catholic University of the Sacred Heart
Study Chair: Salvatore Gueli Alletti, MD Fondazione Policlinico "A. Gemelli" IRCCS
Study Chair: Marco Pieraccioli, PhD Catholic University of the Sacred Heart
Study Chair: Carolina Bottoni, MD Fondazione Policlinico "A. Gemelli" IRCCS
Study Chair: Carmine Conte, MD Fondazione Policlinico "A. Gemelli" IRCCS
Study Chair: Matteo Loverro, MD Catholic University of the Sacred Heart
Study Chair: Anna Fagotti, Professor Catholic University of the Sacred Heart
Publications of Results:

Layout table for additonal information
Responsible Party: Fondazione Policlinico Universitario Agostino Gemelli IRCCS
ClinicalTrials.gov Identifier: NCT04555473    
Other Study ID Numbers: TAILOR
First Posted: September 18, 2020    Key Record Dates
Last Update Posted: September 18, 2020
Last Verified: April 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
Layout table for MeSH terms
Ovarian Neoplasms
Carcinoma, Ovarian Epithelial
Endocrine Gland Neoplasms
Neoplasms by Site
Neoplasms
Ovarian Diseases
Adnexal Diseases
Genital Neoplasms, Female
Urogenital Neoplasms
Endocrine System Diseases
Gonadal Disorders
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type