Trial of Maintenance With Niraparib- Uterine Serous Carcinoma

September 20, 2023 updated by: Marina Frimer, Northwell Health

Trial of Maintenance With Niraparib in Patients With Stage III, Stage IV or Platinum-sensitive Recurrent Uterine Serous Carcinoma

Uterine serous carcinoma (USC) accounts for up to 40% of endometrial cancer-related deaths. Patients with USC share many genomic and clinical characteristics with patients who has serous ovarian cancer. The objective of this study is to evaluate the efficacy of maintenance Niraparib regimen in patients with advanced or platinum sensitive recurrent uterine serous carcinoma. Additionally, the investigators aim to further describe the safety of this regimen. The investigators hypothesize that Niraparib maintenance will be a well-tolerated treatment and show significant response in patients with uterine serous carcinoma.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

Uterine serous carcinoma (USC) accounts for up to 40% of endometrial cancer-related deaths. In contrast to the more common endometrioid histology, USC is more likely to present in advanced stage and carries a worse prognosis. USC mimics the most common serous carcinoma of the ovary and has high probability for nodal and intra-peritoneal spread. Furthermore, studies have indicated that USC harbors a high frequency of somatic TP53 mutations, germline BRCA1 mutations, and mutations within the Fanconi Anemia - BRCA pathway. Data is supportive of the USC association with hereditary breast and ovarian cancer, essentially harboring mutations in DNA repair genes. Approximately 5% of women with USC have germline mutations in 3 different tumor suppressor genes including BRCA1, CHEK2, and TP53.(1,2) The Cancer Genome Atlas Research network reported 4 groups of endometrial tumors based on integrated genomic data - including a novel POLE subtype in 10% endometrial tumors. Patients with uterine serous cancers shared many similar characteristics with basal-like breast and high grade serous ovarian cancers, suggesting a correlation with "BRCAness".(3)

Given the "BRCAness" of USC, recent multicenter prospective cohort study of 1083 women with BRCA1 and BRCA2 mutations who underwent risk reducing salpingo-oophorectomies (RRSO) without hysterectomy were noted to have increased serous/serous-like endometrial carcinoma if they harbored BRCA1 mutations.(4) The study recommended to consider this risk of uterine cancer when discussing the advantages and risks of hysterectomy at the time of RRSO in BRCA1 women. This further supports the high rates of mutations noted among USC patients. A recent systematic review and meta-analysis support the view that USC is a component of BRCA 1/2 -associated tumors. Furthermore, this analysis supports that women with USC should be offered screening for germline mutations when there is a positive family history of malignancies associated with hereditary breast and ovarian cancer syndrome(HBOCS).(5) Furthermore, the Cancer Genome Atlas Research network reported 4 groups of endometrial tumors based on integrated genomic data - including a novel POLE subtype in 10% endometrial tumors. Patients with uterine serous cancers shared many similar characteristics with basal-like breast and high grade serous ovarian cancers, suggesting a correlation with "BRCAness".(3)

Poly(ADP-ribose) polymerases (PARP1 and PARP2) play an important role in DNA repair. Upon formation of DNA breaks, PARP binds at the end of broken DNA strands helping in DNA repair of damage. The hypothesis is that treatment with PARP inhibitors will allow the killing of a subset of cancer cells with deficiencies in DNA repair pathways. For example, a tumor harboring a BRCA or Homologous Recombination gene mutation will have selective blockage by PARP inhibitors in order to maintain genomic integrity. Furthermore, the data in serous ovarian cancer has indicated that tumors arising in a non-BRCA patient that has a homologous recombination deficiency could also enhance tumor cell sensitivity to PARP inhibitors.

PARP inhibitors (PARPi) are synthetically lethal to tumor cells with homologous recombination deficiency (HRD). HRD leads to common phenotype of genome-wide loss of heterozygosity (LOH). Recent analysis of the ARIEL2 part 1 in platinum sensitive ovarian cancer trial found that patients with germline or somatic BRCA mutation or wild-type BRCA with high LOH had longer progression-free survival and improved responses with rucaparib treatment than did patients with wild-type BRCA and low LOH.(7)

The rationale for this current trial is based on significant clinical and genomic similarities of USC and epithelial ovarian carcinomas.(1,2,4) Currently the treatment for stage III and IV USC yields approximately 20-30% survival at 2 years and 10%-20% survival at 3-5 years post diagnosis with current standard therapy of chemotherapy +/-radiation depending on the sites of the disease at surgical staging/debulking. Furthermore, there is no successful second line therapy for patients with recurrent USC and no available clinical trials for patients with recurrent disease. Given the most recent findings of the multi-national, Phase 3 NOVA trial in women with platinum sensitive, recurrent ovarian cancer, Niraparib significantly prolonged the median progression-free survival - irrespective of the presence or absence of a germline BRCA mutation or the presence/absence of a homologous recombinant deficiency.(6) The investigators hypothesize that patients receiving Niraparib maintenance in addition to standard therapy for USC may lead to improved progression free survival in women with suboptimally debulked stage III, stage IV, and platinum-sensitive recurrent USC. The investigators hypothesize that this treatment will be well tolerated in this group of patients.

Study Type

Interventional

Enrollment (Estimated)

45

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • United States
    • New Jersey
      • New Brunswick, New Jersey, United States, 07103
        • Recruiting
        • Rutgers Cancer Institute of New Jersey
        • Contact:
          • Marc Bicomong
          • Phone Number: 732-235-9567
        • Principal Investigator:
          • Eugenia Girda, MD
    • New York
      • Bay Shore, New York, United States, 11706
        • Recruiting
        • Imbert Cancer Center Northwell Health
        • Contact:
          • Diane Delliliune
      • Greenlawn, New York, United States, 11740
        • Recruiting
        • Greenlawn Cancer Institute, Northwell Health
        • Contact:
        • Sub-Investigator:
          • Marisa Siebel, MD
      • New Hyde Park, New York, United States, 11042
      • New York, New York, United States, 10075
        • Recruiting
        • Cancer Institute at Lenox Hill
        • Contact:
          • Virgenmina Lugaro

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  1. Female, age at least 18 years
  2. ECOG performance status of <2
  3. Written voluntary informed consent
  4. Histologically diagnosed Uterine Serous Carcinoma.
  5. Patient must agree to undergo Foundation One testing.
  6. Patient diagnosed with advanced stage USC including stage III, stage IV, or platinum-sensitive recurrent USC
  7. If recurrent USC, patient must have platinum sensitive disease after initial treatment; defined as achieving a response (CR or PR) and disease progression >6 months after completion of their last dose of platinum chemotherapy.
  8. Patients eligible if receiving 1st or 2nd line chemotherapy for recurrence.
  9. The patient must have achieved a partial, stable, or complete tumor response following the last chemotherapy (minimal of 3 cycles) regimen of physician choice chemotherapy indicating partial, stable, complete tumor response.
  10. Patients must receive Niraparib maintenance within 12 weeks after completion of their final dose of chemotherapy regimen or within 14 weeks if received radiation therapy. CT Chest/Abd/Pelvis will be performed within 28 days of starting Niraparib.
  11. Lesions can be non-measurable or measurable by RECIST 1.1 criteria.

  12. Adequate organ function, defined as:

    1. Absolute neutrophil count ≥ 1,500/μL
    2. Platelets ≥ 100,000/μL
    3. Hemoglobin ≥ 9 g/dL
    4. Serum creatinine ≤ 1.5 x upper limit of normal (ULN) or calculated creatinine clearance ≥ 30 mL/min using the Cockcroft-Gault equation
    5. Total bilirubin ≤ 1.5 x ULN (≤2.0 in patients with known Gilberts syndrome) OR direct bilirubin ≤ 1 x ULN
    6. Aspartate aminotransferase and alanine aminotransferase ≤ 2.5 x ULN unless liver metastases are present, in which case they must be ≤ 5 x ULN
  13. Participant receiving corticosteroids may continue as long as their dose is stable for least 4 weeks prior to initiating protocol therapy.
  14. Participant must agree to not donate blood during the study or for 90 days after the last dose of study treatment.

  15. Female participant has a negative urine or serum pregnancy test within 7 days prior to taking study treatment if of childbearing potential and agrees to abstain from activities that could result in pregnancy from screening through 180 days after the last dose of study treatment, or is of non childbearing potential. Non childbearing potential is defined as follows (by other than medical reasons):

    1. ≥45 years of age and has not had menses for >1 year Patients who have been amenorrhoeic for <2 years without history of a hysterectomy and oophorectomy must have a follicle stimulating hormone value in the postmenopausal range upon screening evaluation Post-hysterectomy, post-bilateral oophorectomy, or post-tubal ligation. Documented hysterectomy or oophorectomy must be confirmed with medical records of the actual procedure or confirmed by an ultrasound. Tubal ligation must be confirmed with medical records of the actual procedure, otherwise the patient must be willing to use 2 adequate barrier methods throughout the study, starting with the screening visit through 180 days after the last dose of study treatment. See Section 6.4 for a list of acceptable birth control methods. Information must be captured appropriately within the site's source documents. Note: Abstinence is acceptable if this is the established and preferred contraception for the patient.
    2. Participant must agree to not breastfeed during the study or for 180 days after the last dose of study treatment.
    3. Able to take oral medications.

Exclusion Criteria:

  • 1. Participant must not be simultaneously enrolled in any interventional clinical trial

    2. Drainage of ascites during the last 2 cycles of last chemotherapy

    3. Radiotherapy was given within 2 weeks encompassing >20% of the bone marrow or any radiation therapy within one week prior to Day 1 of protocol therapy. Participant must not have received investigational therapy ≤ 4 weeks, or within a time interval less than at least 5 half-lives of the investigational agent, whichever is shorter, prior to initiating protocol therapy.

    4. Persistent >Grade 2 anemia, neutropenia, or thrombocytopenia from prior cancer therapy, that has persisted > 4 weeks and was related to the most recent treatment.

    5. Symptomatic uncontrolled brain or leptomeningeal metastases.

    6. Known hypersensitivity to the components of Niraparib

    7. Major surgery within 3 weeks of starting the study or patient has not recovered from any effects of any major surgery

    8. Diagnosis, detection, or treatment of invasive cancer other than uterine cancer </= 2 years prior to study enrollment (except basal or squamous cell carcinoma of the skin that has been definitively treated)

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

    10. Patients must not have received a transfusion within 4 weeks of the first dose of study treatment

    11. Participant must not have received colony stimulating factors (e.g., granulocyte colony-stimulating factor, granulocyte macrophage colony stimulating factor, or recombinant erythropoietin) within 4 weeks prior initiating protocol therapy.

    12. Participant must not have any known history of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML)

    13. Immunocompromised patients (splenectomy patients are allowed)

    14. Patients with known active hepatitis disease

    15. Prior treatment with a known PARP inhibitor

    16. Patients noted to have MSI-H mutational burden.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Niraparib

Oral niraparib

-Cohort - Uterine serous carcinoma
Drug: Niraparib
Study treatment will be administered orally Q day continuously. Up to three capsules of 100mg strength will be taken at each dose administration. Initiation dose will be defined per current FDA guidelines for Niraparib treatment in ovarian cancer. Dose interruption (no longer than 28 days) will be allowed. Dose reduction will be allowed based on treatment side effects. Dose reductions to 2 capsules daily (200mg) and subsequently to 1 capsule daily (100mg) will be allowed. No further dose reductions will be allowed. The timing of efficacy or safety evaluations should not be affected by dose interruptions or reductions.
Other Names:
  • ZEJULA

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
PFS
Time Frame: 1 year
To determine the Progression Free Survival (PFS) at 1 year in the proposed Niraparib regimen in the population of patients with stage III, all stage IV, or recurrent uterine serous carcinoma (USC).
1 year

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
PFS
Time Frame: 3 years
Progression-free survival (PFS)
3 years
Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
Time Frame: 5 years
To further describe safety and assess toxicities encountered with the use of the proposed treatment regimen in patients with stage III, all stage IV, or recurrent uterine serous carcinoma (USC).
5 years
Mutational burden
Time Frame: 3 years
To identify the prevalence of somatic mutations, HRD mutations, and overall mutational burden in patients with USC and classify tumor into loss of heterozygosity (LOH) high and low phenotype.
3 years
Quality of Life (QOL) measures using Functional Assessment of Cancer Therapy (FACT- endometrial cancer) and EQ-5D-5L Euroqol
Time Frame: 5 years
To evaluate quality of life (QOL) for the subjects undergoing this treatment, using validated tools. QOL will be assessed every 3 months during treatment course. [Functional Assessment of Cancer Therapy - Endometrial Cancer questionnaire (score range from 0 to 120 - Higher scores represent better quality of life. EQ-5D-5L Euroqol is scored 0-20, with negative values corresponding to death, full health, and health states worse than death
5 years
Overall Survival
Time Frame: 3 years
Overall Survival
3 years
ORR
Time Frame: 3 years
Overall response rate (ORR) at 2, and 3 years interval from start of treatment protocol
3 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Northwell Health

Collaborators

Tesaro, Inc.

Investigators

  • Principal Investigator: Marina Frimer, MD, Northwell Health

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

December 30, 2019

Primary Completion (Estimated)

July 1, 2024

Study Completion (Estimated)

July 1, 2026

Study Registration Dates

First Submitted

August 15, 2019

First Submitted That Met QC Criteria

September 3, 2019

First Posted (Actual)

September 6, 2019

Study Record Updates

Last Update Posted (Actual)

September 21, 2023

Last Update Submitted That Met QC Criteria

September 20, 2023

Last Verified

September 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 19-0380

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

IPD Plan Description

Individual Participant Data will be available to other researchers via REDCAP, with de-identified source documents uploaded by the site. Remote review of the CRFs will be done monthly, cross-checking with source documents. Clarification of administrative matters will be performed by study coordinator and research manager. Remote monitoring of specific data will include eligibility, adverse events, tumor response, and protocol compliance.

Data will be maintained in a password- protected secure database, secured on an ePHI. The database will contain a study identifier that is linked to the subject's medical record number. To maintain confidentiality of identifiable information, paper based records will be kept in a secured location only available to research personnel, computer based files will be made available to research personnel through the use of access privileges and passwords, and whenever feasible identifiers will be removed from study information.

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.

Yes

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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