Niraparib in High-grade Endometrial Cancer Trial

NCT05289648 | Withdrawn Early Phase 1 FDA Drug

• 1 other identifier: 301014
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

Brief Summary

The study will investigate the effect of niraparib on tumor tissue in chemotherapy naïve, newly diagnosed, high-grade endometrial cancer patients. Biomarkers of cognate molecular pathways as well as investigational assays will be used to study the antineoplastic effect of the drug.

Conditions

Endometrial Cancer; Serous Adenocarcinoma; Uterine Neoplasm

Keywords

Biomarker; Chemotherapy naïve; Synthetic lethality; Phase 0

Outcome Measures

Primary Outcomes (3)

• Tumor cells proliferation before and after the treatment

  Cancer cell proliferation will be quantitatively assessed using immunohistochemical staining for cell-cycle proteins. Ki-67 (MIB) stains nuclei of cells in G1-S-G2 phases of the cell-cycle. The proliferation index will be calculated as percent of tumor positive cells. The primary outcome fold change in proliferation index after exposure to niraparib. The quantification will be done by image analysis software with pathologist supervision.

  Day 30 (day of surgery)

• Cell cycle arrest

  The levels of different cell-cycle related proteins increase and decrease throughout the cell cycle, each having its own expression pattern. Tumor specimens will be stained for Cyclin D1, Geminin and p21 proteins. The proportion of positive nuclei of each marker after exposure to niraparib will be estimated. The results will be integrated to study the effect of niraparib on endometrial cancer cells proliferation.

  Day 30 (day of surgery)

• Apoptosis marker

  Cleaved caspase-3 (cCas-3) marks cells that activated the programmed cell-death process. cCas-3 positive tumor cells will be compared before and after the exposure to niraparib.

  Day 30 (day of surgery)

Secondary Outcomes (5)

• Endometrial thickness

  Day 1 and Day 28

• CA-125 cancer tumor marker

  Day 1 and Day 28

• Adverse effects of Niraparib

  every week from day 1 and 21 days after the surgery

• Patient Reported Outcomes - General Oncology

  Day 1 and Day 28

• Patient Reported Outcomes - Endometrial Cancer

  Day 1 and Day 28

Other Outcomes (2)

• Alternation in genes expression

  Day 30 (day of surgery)

• Genomic analysis

  Day 30 (day of surgery)

Study Arms (1)

Preoperative Niraparib

EXPERIMENTAL

Single arm. Following the initial assessment and endometrial biopsy the participants will receive niraparib for 28 days. After the treatment period the patients will be surgically staged. All participants will receive the standard of care.

Drug: Niraparib oral capsule

Interventions

Niraparib oral capsule DRUG

Low dose oral niraparib capsules (2 x 100 mg) once a day for 28 days

Also known as: Zejula

Preoperative Niraparib

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients must be female ≥18 years of age, able to understand the study procedures and agree to participate in the study by providing written informed consent
• Histological and staging criteria:
• Patients must have histologically diagnosed
• Grade 3 endometrioid, serous or clear cell endometrial carcinoma, carcinosarcoma, undifferentiated carcinoma in Stage I-III according to International Federation of Gynecology and Obstetrics (FIGO) classification.
• Grade 2 endometrioid carcinoma with abnormal TP53 by immunohistochemistry.
• Surgical criteria: patients with operable disease are eligible
• Patients of childbearing potential must have a negative serum pregnancy test (beta human chorionic gonadotropin \[hCG\]) within 7 days prior to receiving the first dose of niraparib.
• Patients must be postmenopausal, free from menses for \>1 year, surgically sterilized, or willing to use adequate contraception to prevent pregnancy or must agree to abstain from activities that could result in pregnancy throughout the study, starting with enrollment through 3 months after the last dose of niraparib.
• Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Patients must have adequate organ function, defined as follows:
• Absolute neutrophil count ≥ 1,500/µL
• Platelets ≥ 100,000/µL
• Hemoglobin ≥ 10 g/dL
• Serum creatinine ≤ 1.5 x upper limit of normal (ULN) or calculated creatinine clearance ≥ 60 mL/min using the Cockcroft-Gault equation
• Total bilirubin ≤ 1.5 x ULN

You may not qualify if:

• Histology:
• Grade 1 endometrioid carcinoma OR
• Grade 2 endometrioid carcinoma with wild type TP53 OR
• Grade 2 endometrioid carcinoma with an unknown TP53 status
• Patient did not consent for the study biopsy and one of the following:
• the original endometrial biopsy tissue block could not be assessed by the study site pathologist
• the original endometrial biopsy tissue block does not contain sufficient tumor tissue
• Patient is pregnant, breastfeeding, or expecting to conceive children, while receiving study treatment and for 3 months after the last dose of study treatment;
• Patient has a known hypersensitivity to the components of niraparib or its excipients;
• Patient is simultaneously enrolled in any clinical trial of niraparib or any other investigational therapy;
• Patient has had any known ≥Grade 3 anemia, neutropenia or thrombocytopenia due to any prior medication that persisted \>4 weeks;
• Patient has any known history or current diagnosis of myelodysplastic syndrome (MDS) or acute myelocytic anemia (AML);
• Patient has undergone major surgery (per investigator judgment) within 3 weeks of starting the study or patient has not recovered from any effects of any major surgery;
• Patient has a condition (such as transfusion dependent anemia or thrombocytopenia), therapy, or laboratory abnormality that might confound the study results or interfere with the patient's participation for the full duration of the study treatment, including:
• Patient received a transfusion (platelets or red blood cells) within 2 weeks of the first dose of study treatment;

Sponsors & Collaborators

• Sir Mortimer B. Davis - Jewish General Hospital: lead

Related Publications (4)

• de Jonge MM, Auguste A, van Wijk LM, Schouten PC, Meijers M, Ter Haar NT, Smit VTHBM, Nout RA, Glaire MA, Church DN, Vrieling H, Job B, Boursin Y, de Kroon CD, Rouleau E, Leary A, Vreeswijk MPG, Bosse T. Frequent Homologous Recombination Deficiency in High-grade Endometrial Carcinomas. Clin Cancer Res. 2019 Feb 1;25(3):1087-1097. doi: 10.1158/1078-0432.CCR-18-1443. Epub 2018 Nov 9.

  PMID: 30413523 BACKGROUND

• Urick ME, Bell DW. Clinical actionability of molecular targets in endometrial cancer. Nat Rev Cancer. 2019 Sep;19(9):510-521. doi: 10.1038/s41568-019-0177-x. Epub 2019 Aug 6.

  PMID: 31388127 BACKGROUND

• Mirza MR, Monk BJ, Herrstedt J, Oza AM, Mahner S, Redondo A, Fabbro M, Ledermann JA, Lorusso D, Vergote I, Ben-Baruch NE, Marth C, Madry R, Christensen RD, Berek JS, Dorum A, Tinker AV, du Bois A, Gonzalez-Martin A, Follana P, Benigno B, Rosenberg P, Gilbert L, Rimel BJ, Buscema J, Balser JP, Agarwal S, Matulonis UA; ENGOT-OV16/NOVA Investigators. Niraparib Maintenance Therapy in Platinum-Sensitive, Recurrent Ovarian Cancer. N Engl J Med. 2016 Dec 1;375(22):2154-2164. doi: 10.1056/NEJMoa1611310. Epub 2016 Oct 7.

  PMID: 27717299 BACKGROUND

• Romero I, Rubio MJ, Medina M, Matias-Guiu X, Santacana M, Schoenenberger JA, Guerra EM, Cortes A, Minig L, Coronado P, Cueva JF, Gomez L, Malfettone A, Sampayo M, Llombart-Cussac A, Poveda A. An olaparib window-of-opportunity trial in patients with early-stage endometrial carcinoma: POLEN study. Gynecol Oncol. 2020 Dec;159(3):721-731. doi: 10.1016/j.ygyno.2020.09.013. Epub 2020 Sep 26.

  PMID: 32988624 BACKGROUND

MeSH Terms

Conditions

Endometrial Neoplasms; Cystadenocarcinoma, Serous; Uterine Neoplasms

Interventions

niraparib

Condition Hierarchy (Ancestors)

Genital Neoplasms, Female; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Uterine Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Cystadenocarcinoma; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms, Cystic, Mucinous, and Serous

Study Officials

• Shannon Salvador, MD MSc

  McGill University, Jewish General Hospital

  PRINCIPAL INVESTIGATOR

• Walter Gotlieb, MD PhD

  McGill University, Jewish General Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: NA
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: February 18, 2022
• First Posted: March 21, 2022
• Study Start: May 1, 2024
• Primary Completion: October 31, 2025
• Study Completion: January 31, 2026
• Last Updated: December 19, 2024

Record last verified: 2024-12

Data Sharing

• IPD Sharing: Will not share