Clinical trial NCT04507841: Niraparib for the Neoadjuvant Treatment of Unresectable Ovarian Cancer
Official title: Niraparib for the Neoadjuvant Treatment of Unresectable Ovarian Cancer
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Ovarian Cancer
Lead sponsor: Tongji Hospital
Sponsor class: OTHER
Collaborators: name: West China Second University Hospital
name: Qilu Hospital of Shandong University
name: Renmin Hospital of Wuhan University
name: Sun Yat-sen University Cancer Center, Sun Yat-sen University
name: Guangdong Provincial People's Hospital Affiliated to Southern Medical University
First posted: 2020-08-11
Enrollment: 67
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This is a prospective, interventional, single-arm, open-label, phase II study to evaluate the safety and efficacy of niraparib monotherapy as neoadjuvant therapy in patients with advanced ovarian cancer, primary peritoneal cancer, fallopian tube cancer ((FIGO stage III or IV), who had low likelihood of achieving R0 cytoreduction by imaging assessment or laparoscopic evaluation, or cannot tolerate PDS by poor conditions.


Eligibility criteria: Inclusion Criteria:

1. The informed consent form must be provided before any procedure of the trial, and the informed consent form shall be filed in the research center;
2. Female patients aged between 18 and 75 years old;
3. Patients received open surgery, laparoscopic surgery, or coarse needle aspiration biopsy and confirmed as high-grade serous or endometrioid ovarian cancer, peritoneal cancer, or fallopian tube cancer (hereinafter referred to as ovarian cancer). FIGO stage III-IV;
4. BRCA1/2 gene mutation or HRD was confirmed by tissue or blood samples detected by the testing institution designated by the research center;
5. Blood and tissue samples can be obtained before, during, and after treatment, and the subjects agree to submit the blood and tissue samples to the central laboratory for the expanded research purposes of the trial, including but not limited to: I. possible gene-related research. II. Possible tumor markers related studies;
6. There is at least one lesion that can be measured by CT / MRI;
7. The professional gynecological oncologists appointed by each center should judge the patients who can not achieve R0 tumor reduction or can not tolerate surgery,

   The criteria for failure to achieve R0 tumor reduction include but are not limited to:

   i. Fagotti score ≥ 8 \[2\];

   II. When the laparoscopic evaluation method is difficult to implement, the upper abdominal CT Score ≥ 3 can be used \[3\].

   The criteria for intolerance to surgery can be considered as follows:

   III. advanced age: age ≥ 80;

   IV. body mass index: BMI ≥ 40.0;

   v. A variety of chronic diseases;

   Vi. malnutrition or hypoproteinemia;

   VII. Moderate to massive ascites;

   VIII. Newly diagnosed venous thromboembolism;

   IX. physical status: ECOG \> 2.
8. The expected survival time was more than 12 weeks;
9. The ECOG score was 0-2;
10. Good organ function, including:

    i. Bone marrow function: neutrophil count ≥ 1500 / μ L; platelet ≥ 100000 / μ L; hemoglobin ≥ 10g / dl

    II. Liver function: total bilirubin ≤ 1.5 times of the upper limit of normal value or direct bilirubin ≤ 1.0 times of the upper limit of normal value; AST and alt ≤ 2.5 times of the upper limit of normal value; when liver metastasis exists, it must be ≤ 5 times of the upper limit of normal value

    III. renal function: serum creatinine ≤ 1.5 times the upper limit of normal value, or creatinine clearance rate ≥ 60ml / min (calculated according to Cockcroft Gault formula);
11. For women with fertility potential, if blood test or urine pregnancy test is negative within one week before enrollment, effective contraceptive measures must be taken, such as physical barrier contraceptive method (condom) or complete abstinence. Oral, injectable or implantable hormonal contraceptives are not allowed. Or women without reproductive potential, defined as:

    i. Natural menopause and menopause for more than 1 year;

    II. Surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy);

    III. serum follicle-stimulating hormone, luteinizing hormone, and plasma estradiol levels were within the menopausal criteria of the research center laboratory.
12. Understand the trial process and have the ability to comply with the trial protocol for the trial duration, including any treatment, examination, inspection, follow-up, and questionnaire required for the completion of the experiment;
13. The patients were willing to complete the questionnaire survey of quality of life during the trial treatment and follow-up, and agreed that the results of the questionnaire survey could be used in clinical research;
14. The toxicity of any previous chemotherapy has returned to ≤ CTCAE 1 or baseline level, except for sensory neuropathy or alopecia with stable symptoms ≤ CTCAE grade 2.

Exclusion Criteria:

-

The enrolled patients should not contain any of the following conditions:

1. Personnel involved in the formulation or implementation of the research plan;
2. Other clinical drug experiments participated in by using other experimental research drugs at the same time as the study;
3. At the same time of this study, other neoadjuvant therapies for cancer should be used, including but not limited to chemotherapy, radiotherapy, immunotherapy, microbial therapy, traditional Chinese medicine treatment, and other experimental therapies;
4. Those who are known to be allergic to niraparib or active or inactive components of drugs with a similar chemical structure to niraparib;
5. Inability to swallow oral drugs and any gastrointestinal diseases that may interfere with the absorption and metabolism of the study drugs, such as uncontrollable nausea and vomiting, gastrointestinal obstruction or malabsorption;
6. Have received any anti-cancer treatment for ovarian cancer;
7. Have been treated with known or possible PARP inhibitors in the past;
8. Symptomatic or uncontrolled brain metastases requiring simultaneous treatment, including but not limited to surgery, radiation and / or corticosteroids, or clinical manifestations of spinal cord compression;
9. Major surgery was performed within 3 weeks before the start of the study or did not recover after the operation;
10. The subjects had other malignant diseases in the past 3 years, except skin squamous cell carcinoma, basal-like carcinoma, breast intraductal carcinoma in situ, or cervical carcinoma in situ.
11. The patient had a previous or current diagnosis of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML);
12. Patients with serious and uncontrollable diseases or the general situation of the subjects judged by the researchers to be unsuitable for joining the study, including but not limited to: active viral infection, such as human immunodeficiency virus, hepatitis B, hepatitis C, etc.; severe cardiovascular disease, uncontrollable ventricular arrhythmia, myocardial infarction in the last three months; uncontrollable epileptic grand mal seizure, no control Stable spinal cord compression, superior vena cava syndrome or other mental disorders that affect patients' informed consent; hypertension beyond drug control; immune deficiency (except splenectomy) or other diseases that researchers believe may expose patients to high-risk toxicity; and;
13. Any medical history or existing clinical evidence indicates that there may be confusion of study results, interference with patients' compliance with the trial protocol throughout the study treatment period, or not in the best interests of patients;
14. The patient received platelet or red blood cell transfusion within four weeks before the start of treatment of the study drug;
15. Patients who are pregnant or breastfeeding, or who plan to become pregnant during the study treatment.
16. Unsolved clinical toxicity (≥ grade 2, except alopecia, neuralgia, lymphopenia, and depigmentation of skin)

Primary outcomes:
measure: R0 resection rate
timeFrame: 3-month
measure: Overall Response Rate (ORR) After Neoadjuvant treatment
timeFrame: 3-month
Secondary outcomes:
measure: Disease Control Rate
timeFrame: 3-month
measure: Complete pathologic response rate
timeFrame: 3-month
measure: Progression Free Survival (PFS)
timeFrame: 3-year
measure: Overall survival (OS)
timeFrame: 5-year
measure: Quality of Life (QOL) measures using Functional Assessment of Cancer Therapy (FACT- ovarian cancer)
timeFrame: 5 years
measure: Patient report outcome, EQ-VAS
timeFrame: 3 years
measure: Rate of treatment interruption and termination
timeFrame: 5 years
measure: Number of participants with treatment-related adverse events as assessed by CTCAE v5.0
timeFrame: 5 years
measure: Overall Response Rate (ORR) during niraparib maintain treatment
timeFrame: 1 year
Other outcomes:
Locations:
city: Wuhan
country: China
facility: Tongji Hospital
state: Hubei
Study officials:
affiliation: Tongji Hospital
name: Qinglei Gao, MD. PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: Gonzalez-Martin A, Pothuri B, Vergote I, DePont Christensen R, Graybill W, Mirza MR, McCormick C, Lorusso D, Hoskins P, Freyer G, Baumann K, Jardon K, Redondo A, Moore RG, Vulsteke C, O'Cearbhaill RE, Lund B, Backes F, Barretina-Ginesta P, Haggerty AF, Rubio-Perez MJ, Shahin MS, Mangili G, Bradley WH, Bruchim I, Sun K, Malinowska IA, Li Y, Gupta D, Monk BJ; PRIMA/ENGOT-OV26/GOG-3012 Investigators. Niraparib in Patients with Newly Diagnosed Advanced Ovarian Cancer. N Engl J Med. 2019 Dec 19;381(25):2391-2402. doi: 10.1056/NEJMoa1910962. Epub 2019 Sep 28.
citation: Berek JS, Matulonis UA, Peen U, Ghatage P, Mahner S, Redondo A, Lesoin A, Colombo N, Vergote I, Rosengarten O, Ledermann J, Pineda M, Ellard S, Sehouli J, Gonzalez-Martin A, Berton-Rigaud D, Madry R, Reinthaller A, Hazard S, Guo W, Mirza MR. Safety and dose modification for patients receiving niraparib. Ann Oncol. 2018 Aug 1;29(8):1784-1792. doi: 10.1093/annonc/mdy181.
citation: Mirza MR, Avall Lundqvist E, Birrer MJ, dePont Christensen R, Nyvang GB, Malander S, Anttila M, Werner TL, Lund B, Lindahl G, Hietanen S, Peen U, Dimoula M, Roed H, Or Knudsen A, Staff S, Krog Vistisen A, Bjorge L, Maenpaa JU; AVANOVA investigators. Niraparib plus bevacizumab versus niraparib alone for platinum-sensitive recurrent ovarian cancer (NSGO-AVANOVA2/ENGOT-ov24): a randomised, phase 2, superiority trial. Lancet Oncol. 2019 Oct;20(10):1409-1419. doi: 10.1016/S1470-2045(19)30515-7. Epub 2019 Aug 29.
citation: Zhou D, Liu J, Liu R, Li H, Huang Y, Ma D, Hong L, Gao Q. Effectiveness and Safety of Niraparib as Neoadjuvant Therapy in Advanced Ovarian Cancer With Homologous Recombination Deficiency (NANT): Study Protocol for a Prospective, Multicenter, Exploratory, Phase 2, Single-Arm Study. Front Oncol. 2022 Mar 23;12:852772. doi: 10.3389/fonc.2022.852772. eCollection 2022.