Niraparib in High-grade Endometrial Cancer Trial (NIREC)

The Molecular and the Clinical Effects of Preoperative Niraparib in Patients With High-grade Endometrial Cancer: Phase 0 Exploratory Trial

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Endometrial Cancer; Uterine Neoplasm; Serous Adenocarcinoma
• Intervention / Treatment: Drug: Niraparib oral capsule

Detailed Description

Niraparib is a FDA approved Poly(ADP-ribose) polymerase inhibitor (PARPi) for the treatment of platinum-sensitive ovarian serous carcinoma. The safety profile of niraparib was established in phase III clinical trials. The therapeutic effect of niraparib on serous endometrial carcinoma is now being investigated in several clinical trials. However, the antineoplastic effect and the safety profile of niraparib in chemotherapy naïve high-grade endometrial cancer patients is unknown. By employing a phase 0 exploratory trial design, the investigators will study the niraparib's effect on endometrial cancer in chemotherapy naïve patients using molecular biomarkers as sentinels for the antineoplastic effect. Women diagnosed by endometrial biopsy with high-grade endometrial cancer will receive niraparib for 28 days. Staging surgery will be performed 4-6 weeks after the diagnosis (standard of care). The investigators will use the pre-operative biopsy and the surgical specimen to perform comparative multidimensional analysis of endometrial tumors before and after exposure to niraparib.

• Study Type: Interventional
• Enrollment (Estimated): 31
• Phase: Early Phase 1

Contacts and Locations

• Study Contact: Name: Shannon Salvador, MD MSc; Phone Number: 23114 +15143408222; Email: shannon.salvador@mcgill.ca
• Study Contact Backup: Name: David Knigin, MD PhD; Phone Number: 22797 +15143408222; Email: david.knigin@mail.mcgill.ca

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. 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

2. Histological and staging criteria:

   Patients must have histologically diagnosed

   1. 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.
   2. Grade 2 endometrioid carcinoma with abnormal TP53 by immunohistochemistry.
3. Surgical criteria: patients with operable disease are eligible
4. 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.
5. 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.
6. Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

7. Patients must have adequate organ function, defined as follows:

   1. Absolute neutrophil count ≥ 1,500/µL
   2. Platelets ≥ 100,000/µL
   3. Hemoglobin ≥ 10 g/dL
   4. Serum creatinine ≤ 1.5 x upper limit of normal (ULN) or calculated creatinine clearance ≥ 60 mL/min using the Cockcroft-Gault equation
   5. Total bilirubin ≤ 1.5 x ULN
   6. Aspartate aminotransferase and alanine aminotransferase ≤ 2.0 x ULN
8. Patients must be able to take oral medications

Exclusion Criteria:

1. Histology:

   1. Grade 1 endometrioid carcinoma OR
   2. Grade 2 endometrioid carcinoma with wild type TP53 OR
   3. Grade 2 endometrioid carcinoma with an unknown TP53 status

2. 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
3. Patient is pregnant, breastfeeding, or expecting to conceive children, while receiving study treatment and for 3 months after the last dose of study treatment;
4. Patient has a known hypersensitivity to the components of niraparib or its excipients;
5. Patient is simultaneously enrolled in any clinical trial of niraparib or any other investigational therapy;
6. Patient has had any known ≥Grade 3 anemia, neutropenia or thrombocytopenia due to any prior medication that persisted >4 weeks;
7. Patient has any known history or current diagnosis of myelodysplastic syndrome (MDS) or acute myelocytic anemia (AML);
8. 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;

9. 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:

   1. Patient received a transfusion (platelets or red blood cells) within 2 weeks of the first dose of study treatment;
   2. Patient received colony-stimulating factors (eg, granulocyte colony stimulating factor [G-CSF], granulocyte macrophage colony-stimulating factor [GM-CSF] or recombinant erythropoietin) within 2 weeks prior to the first dose of study treatment.
10. Another concurrent invasive neoplastic disease (including ovarian), diagnosis of cancer in the last 5 years (except for non-melanoma skin cancer), patient previously had cancer (> 5 years) but she is not considered cured or still treated.

11. Patient is considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease, or active, uncontrolled infection;

    - Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 90 days) myocardial infarction, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, or any psychiatric disorder that prohibits obtaining informed consent.

12. Patient is immunocompromised (patients with splenectomy are allowed).
13. Patient has known, active hepatic disease (ie, hepatitis B or C).
14. Patient has a corrected QT interval (QTc) prolongation > 470 milliseconds at screening; - If a patient has a prolonged QTc interval and the prolongation is deemed to be due to a pacemaker upon investigator evaluation (ie, the patient otherwise has no cardiac abnormalities), then the patient may be eligible to participate in the study following approval of a cardiology specialist.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Preoperative Niraparib; 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; Low dose oral niraparib capsules (2 x 100 mg) once a day for 28 days; Other Names: Zejula

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Endometrial thickness	Comparison of the thickness of endometrial lining before and after treatment	Day 1 and Day 28
CA-125 cancer tumor marker	Investigation of the effect of preoperative niraparib on CA125 levels in patients with high grade endometrial carcinoma	Day 1 and Day 28
Adverse effects of Niraparib	Assessment of adverse effects of niraparib in chemotherapy naïve patients according to CTCAE 5.0	every week from day 1 and 21 days after the surgery
Patient Reported Outcomes - General Oncology	Patients' well being will be assessed by a validated questionnaire: Functional Assessment of Cancer Therapy - General (FACT-G). https://www.facit.org	Day 1 and Day 28
Patient Reported Outcomes - Endometrial Cancer	Patients' well being will be assessed by a validated questionnaire: Functional Assessment of Cancer Therapy - Endometrial (FACT-en). https://www.facit.org	Day 1 and Day 28

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Alternation in genes expression	Gene expression profile by RNA sequencing extracted from snap-frozen tumor tissue. Unsupervised hierarchical clustering of 2-fold changed genes will be used to detect the pathways affected by niraparib treatment.	Day 30 (day of surgery)
Genomic analysis	Mutational signature and the altered genes of the DNA repair pathway will be identified by DNA next generation sequencing. Genomic findings will be correlated with molecular analysis for discovery of biomarkers for niraparib sensitivity in chemotherapy-naïve endometrial cells.	Day 30 (day of surgery)

Collaborators and Investigators

• Sponsor: Sir Mortimer B. Davis - Jewish General Hospital
• Investigators: Principal Investigator: Shannon Salvador, MD MSc, McGill University, Jewish General Hospital; Principal Investigator: Walter Gotlieb, MD PhD, McGill University, Jewish General Hospital

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Estimated): May 1, 2024
• Primary Completion (Estimated): October 31, 2025
• Study Completion (Estimated): January 31, 2026

Study Registration Dates

• First Submitted: February 18, 2022
• First Submitted That Met QC Criteria: March 15, 2022
• First Posted (Actual): March 21, 2022

Study Record Updates

• Last Update Posted (Estimated): February 1, 2024
• Last Update Submitted That Met QC Criteria: January 31, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: Biomarker; Phase 0; Synthetic lethality; Chemotherapy naïve
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Genital Neoplasms, Female; Uterine Diseases; Cystadenocarcinoma; Neoplasms, Cystic, Mucinous, and Serous; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Genital Diseases, Female; Endometrial Neoplasms; Cystadenocarcinoma, Serous; Uterine Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Poly(ADP-ribose) Polymerase Inhibitors; Niraparib
• Other Study ID Numbers: 301014

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No