Clinical Trials /

Trial of Maintenance With Niraparib- Uterine Serous Carcinoma

NCT04080284

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.

Related Conditions:
  • Endometrial Serous Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Trial of Maintenance With Niraparib- Uterine Serous Carcinoma
  • Official Title: Trial of Maintenance With Niraparib in Patients With Suboptimal Debulked 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

DrugSynonymsArms
NiraparibZEJULANiraparib

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, we aim to further describe the safety of this regimen. We 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) Our hypothesis is 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. We hypothesize that this treatment will be well tolerated in this group of
      patients.
    

Trial Arms

NameTypeDescriptionInterventions
NiraparibExperimentalOral niraparib -Cohort - Uterine serous carcinoma
  • Niraparib

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 sub-optimally debulked 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. 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 suboptimally debulked 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 suboptimally debulked 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.
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:Not yet 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

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