Description:
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.
Title
- Brief Title: Trial of Maintenance With Niraparib- Uterine Serous Carcinoma
- Official Title: Trial of Maintenance With Niraparib in Patients With Stage III, Stage IV or Platinum-sensitive Recurrent Uterine Serous Carcinoma
Clinical Trial IDs
- ORG STUDY ID:
19-0380
- NCT ID:
NCT04080284
Conditions
- Endometrial Cancer
- Papillary Serous Endometrial Carcinoma
- Uterine Serous Carcinoma
- Endometrial Carcinoma
- Cancer of the Endometrium
Interventions
Drug | Synonyms | Arms |
---|
Niraparib | ZEJULA | Niraparib |
Purpose
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.
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.
Trial Arms
Name | Type | Description | Interventions |
---|
Niraparib | Experimental | Oral niraparib
-Cohort - Uterine serous carcinoma | |
Eligibility Criteria
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.
Maximum Eligible Age: | N/A |
Minimum Eligible Age: | 18 Years |
Eligible Gender: | Female |
Healthy Volunteers: | No |
Primary Outcome Measures
Measure: | PFS |
Time Frame: | 1 year |
Safety Issue: | |
Description: | 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). |
Secondary Outcome Measures
Measure: | PFS |
Time Frame: | 3 years |
Safety Issue: | |
Description: | Progression-free survival (PFS) |
Measure: | Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 |
Time Frame: | 5 years |
Safety Issue: | |
Description: | 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). |
Measure: | Mutational burden |
Time Frame: | 3 years |
Safety Issue: | |
Description: | 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. |
Measure: | Quality of Life (QOL) measures using Functional Assessment of Cancer Therapy (FACT- endometrial cancer) and EQ-5D-5L Euroqol |
Time Frame: | 5 years |
Safety Issue: | |
Description: | 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 |
Measure: | Overall Survival |
Time Frame: | 3 years |
Safety Issue: | |
Description: | Overall Survival |
Measure: | ORR |
Time Frame: | 3 years |
Safety Issue: | |
Description: | Overall response rate (ORR) at 2, and 3 years interval from start of treatment protocol |
Details
Phase: | Phase 2 |
Primary Purpose: | Interventional |
Overall Status: | Recruiting |
Lead Sponsor: | Northwell Health |
Trial Keywords
- Niraparib
- uterine Cancer
- papillary serous uterine cancer
- endometrial cancer
- serous uterine cancer
- Endometrial
- Endometrial Carcinoma
- Recurrent Uterine Carcinoma
- platinum-sensitive
Last Updated
July 26, 2021