Clinical trial NCT03709316: A Study of ZL-2306 (Niraparib) as Maintenance Treatment Following First-line Chemotherapy in Patients With Advanced Ovarian Cancer
Official title: A Randomized, Double-Blind, Placebo-Controlled, Multi-Center, Phase III Clinical Trial Evaluating the Efficacy and Safety of ZL-2306 (Niraparib) for Maintenance Treatment in Patients With Advanced Ovarian Cancer, Fallopian Tube Carcinoma or Primary Peritoneal Cancer (Collectively Referred to as Ovarian Cancer) Who Have Achieved Effective Response After First-line Platinum-containing Chemotherapy
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Ovarian Cancer
Lead sponsor: Zai Lab (Hong Kong), Ltd.
Sponsor class: INDUSTRY
First posted: 2018-10-17
Enrollment: 384
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Niraparib is a PARP inhibitor. This is a 2:1 randomized, double-blind, placebo-controlled study conducted in patients with advanced (FIGO Stage III or IV) ovarian cancer to evaluate Efficacy and Safety of ZL-2306 (Niraparib) for Maintenance Treatment


Eligibility criteria: Inclusion Criteria:

* 1. The written informed consent form shall be signed before proceeding with any study-related procedure.
* 2. The subject agrees to collection of blood samples for detection of gBRCA mutations (gBRCA mutation status must be known before randomization).
* 3. The subject shall be a female, aged 18 years or older.
* 4. Histologically confirmed high-grade serous/endometrioid or dominantly high-grade serous/endometrioid epithelial ovarian cancer, fallopian tube carcinoma or primary peritoneal carcinoma (no histological restriction for patients carrying germline BRCA mutations).

Note: Patients who have received neoadjuvant chemotherapy can also be enrolled if their tumors after chemotherapy cannot be pathologically graded.

* 5. FIGO staging is Stage III or IV.
* 6. Criteria for previous surgery (meeting any of these):

  * Inoperable Stage III or IV patients
  * Stage IV patients, regardless of postoperative residual lesion status
  * Stage III patients who have undergone primary tumor reductive surgery with postoperative residual lesion status of R1 (microscopic residual lesions) or R2 (macroscopic residual lesions)
  * Stage III or IV patients who have undergone intermittent tumor reductive surgery (patients who have used neoadjuvant therapy) regardless of postoperative residual lesion status
* 7. Criteria for previous chemotherapy:

  * It is allowed to enroll patients who have received intraperitoneal chemotherapy
  * Patients have completed at least 6 cycles yet no more than 9 cycles of first-line platinum-containing chemotherapy (preferably carboplatin, but cisplatin is also acceptable)
  * Patients undergoing intermittent tumor reductive surgery should respectively receive at least 2 cycles of platinum-containing chemotherapy preoperatively and postoperatively, and receive a total of at least 6 cycles yet no more than 9 cycles of chemotherapy (preferably carboplatin, but cisplatin is also acceptable) preoperatively and postoperatively
  * Patients are assessed by the investigator to have achieved complete response (CR) or partial response (PR) after first-line platinum-containing chemotherapy, and the efficacy assessment should be performed after the end of at least 3 cycles of chemotherapy
  * CA-125 level must be within the normal range after the end of chemotherapy or has decreased by more than 90% during the course of first-line chemotherapy and remains so for at least 7 days (the elevation of CA-125 prior to enrollment shall not exceed 15% compared with the CA-125 level after the end of chemotherapy)
  * Patients must be randomized within 12 weeks since Day 1 of the last cycle of chemotherapy 8. Patients must be able to submit formalin-fixed, paraffin-embedded tumor tissue samples.
* 9. ECOG physical condition score of the patient shall be 0 or 1.
* 10. Organ function is in good condition, including:

  * Neutrophil count ≥1.5×109/L
  * Platelet count ≥100×109/L
  * Hemoglobin ≥100 g/L
  * Serum creatinine is not more than 1.5 times the normal upper limit, or creatinine clearance rate is not less than 60 mL/min (calculated with Cockcroft-Gault formula)
  * Total bilirubin is not more than 1.5 times the normal upper limit, or direct bilirubin is not more than 1.0 time the normal upper limit.
  * AST and ALT are not more than 2.5 times their normal upper limit, and with existence of hepatic metastasis, these values must not be more than 5 times their normal upper limit.
* 11. Only the female patient who has been tested with pregnancy-negative result and had made a commitment to adopt effective contraption measures or to avoid sexual behavior from the start to the completion of the study and within 3 months after the last administration of study medication is eligible to be enrolled into the study. Or female patients without childbearing potential may be enrolled in the study, defined as follows:

  * A female who has undergone surgical birth control operation (e.g., hysterectomy, bilateral ovariectomy, or bilateral tubal resection); or
  * A female aged 60 years or older; or
  * A female, aged ≥40 years and \<60 years, with a period of menolipsis for 12 months or longer, whose follicle-stimulating hormone test results are within the post-menopause reference range of the study institution.
* 12. Patients must be able to take medication orally and have the ability to comply with the protocol.
* 13. Any previous toxic and side effect of the patient has restored to CTCAE grade ≤1 or the baseline level, except for CTCAE grade ≤2 symptomatically stable sensory neuropathy or alopecia.

Exclusion Criteria:

* 1. Patients diagnosed with mucinous, clear cell subtypes of epithelial ovarian cancer, carcinosarcoma, or undifferentiated ovarian cancer.
* 2. Stage III patients who have undergone primary tumor reductive surgery with postoperative status of R0-complete resection (with no residual lesion).
* 3. Patients who have undergone tumor reductive surgery more than twice.
* 4. Patients who plan to or have used bevacizumab as maintenance therapy after first-line platinum-containing chemotherapy. If the patient received bevacizumab in platinum-containing chemotherapy but did not receive bevacizumab as maintenance therapy, and the last dose of bevacizumab was used ≥ 28 days before signing the master informed consent form, the patient can be enrolled.
* 5. Patients who are known to be allergic to active or inactive ingredients of ZL-2306 (niraparib) or other drugs with similar chemical structures to ZL-2306 (niraparib).
* 6. Patients who have previously been treated with PARP inhibitors (including niraparib).
* 7. Patients who have received other study drug treatment within 4 weeks prior to the first administration or \< 5 elimination half-lives of the study drug (whichever is longer).
* 8. Patients with ≥ grade 3 anemia, neutropenia or thrombocytopenia due to prior chemotherapy for more than 4 weeks.
* 9. Patients with transfusion-dependent anemia or thrombocytopenia, including:

  * Patients who have received blood transfusion (platelet or red blood cell) within 2 weeks before the first dose
  * Patients who have received colony stimulating factor therapy (e.g., granulocyte colony-stimulating factor (G-CSF), granulocyte macrophage colony-stimulating factor (GM-CSF), or recombinant erythropoietin) within 2 weeks before the first dose
* 10. Patients who have undergone ascites drainage within 4 weeks prior to enrollment.
* 11. Brain metastases or leptomeningeal metastases that have not been treated or whose symptoms have not been controlled (e.g., new or worsening symptoms or signs, or the required dose of hormones is not yet stable). Note: It is not necessary to perform an imaging scan to confirm whether there is a brain metastasis or not; patients with spinal cord compression who have received symptomatic treatment and have evidence on clinical stable status of the disease for at least 28 days could still be considered as eligible for enrollment.
* 12. Patients who have received a major surgery 3 weeks before the start of the study, or is subject to any surgical effect that has not yet been recovered after surgery.
* 13. Patients who have received palliative radiotherapy for \> 20% of bone marrow 3 weeks prior to enrollment.
* 14. Patients suffered from invasive cancers other than ovarian cancer within 5 years prior to enrollment (except for treated carcinoma in situ of cervix, non-melanoma and ductal carcinoma in situ).
* 15. Patients who have been diagnosed previously or currently with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML).
* 16. Patients who have got other severe or uncontrollable diseases, including but not limited to:

  * Hardly controllable nausea and vomiting, inability to swallow the study drug, and any gastrointestinal disease that may interfere with the absorption and metabolism of the drug
  * Human immunodeficiency virus (HIV) infection, active hepatitis (hepatitis B, hepatitis C)
  * Uncontrolled ventricular arrhythmias, myocardial infarction that occurred within 3 months before enrollment
  * Uncontrollable grand mal epilepsy, unstable spinal cord compression, superior vena cava syndrome or other psychiatric disorders that may affect signing of the informed consent by the patient
  * Immunodeficiency (except for splenectomy), or other diseases which, as believed by investigators, could expose the patient to a high risk
* 17. Patients who are pregnant or breastfeeding currently, or expect to plan for pregnancy in the course of the study treatment.
* 18. The corrected QT interval (QTc) is more than 470 msec; if the patient has an extended QTc interval, but investigators find such a extension is caused by a cardiac pacemaker (without any other cardiac abnormality), it shall be necessary to determine whether the patient is eligible for enrollment or not based on the discussion with the study physician from the sponsor.

Primary outcomes:
measure: BICR-assessed progression-free survival (PFS)
timeFrame: Approximately 36 months since the first subject enrolled
Secondary outcomes:
measure: Overall survival (OS)
timeFrame: Approximately 36 months since the first subject enrolled
measure: Time to first subsequent anti-tumor treatment (TFST)
timeFrame: Approximately 36 months since the first subject enrolled
measure: PFS and OS assessed by BICR in patients with HRD (homologous recombination defects)
timeFrame: Approximately 36 months since the first subject enrolled
Other outcomes:
Locations:
city: Hefei
country: China
facility: Anhui Provincal Hospital
state: Anhui
city: Chongqing
country: China
facility: Chongqing Cancer Hospital
state: Chongqing
city: Fuzhou
country: China
facility: Fujian Cancer Hospital
state: Fujian
city: Guangzhou
country: China
facility: Sun Yat-sen University Cancer Center
state: Guangdong
city: Guangzhou
country: China
facility: The first affiliated hospital, Sun Yat-sen University
state: Guangdong
city: Guiyang
country: China
facility: Guizhou Cancer hospital
state: Guizhou
city: Harbin
country: China
facility: Harbin Medical University Cancer Hospital
state: Heilongjiang
city: Zhengzhou
country: China
facility: Henan Cancer Hospital
state: Henan
city: Wuhan
country: China
facility: Hubei Cancer Hospital
state: Hubei
city: Wuhan
country: China
facility: Union Hospital Affiliated to Tongji Medical College of Huazhong University of Science and Technology
state: Hubei
city: Wuhan
country: China
facility: Zhongnan hospital of wuhan university
state: Hubei
city: Changsha
country: China
facility: Hunan Cancer Hospital
state: Hunan
city: Changsha
country: China
facility: Xiangya Hospital Central South Hospital
state: Hunan
city: Nanjing
country: China
facility: Jiangsu Cancer Hospital
state: Jiangsu
city: Changchun
country: China
facility: The First Hospital of Jilin University
state: Jilin
city: Shenyang
country: China
facility: Liaoning Cancer Hospital & Institute
state: Liaoning
city: Jinan
country: China
facility: Qilu Hospital of Shandong University
state: Shandong
city: Taiyuan
country: China
facility: second hospital of Shanxi medical university
state: Shanxi
city: Chengdu
country: China
facility: West China second university hospital
state: Sichuan
city: Tianjin
country: China
facility: Tianjin Central Hospital of Gynecology Obstetrics
state: Tianjin
city: Urumqi
country: China
facility: Affiliate Cancer Hospital Xinjiang Medical University
state: Xinjiang
city: Kunming
country: China
facility: Yunnan Cancer Hospital
state: Yunnan
city: Hangzhou
country: China
facility: Woman's hospital School of medicine Zhejiang University
state: Zhejiang
city: Hangzhou
country: China
facility: Zhejiang Cancer Hospital
state: Zhejiang
city: Wenzhou
country: China
facility: the First Affiliated Hospital of Wenzhou Medical University
state: Zhejiang
city: Beijing
country: China
facility: Beijing Cancer Hospital
city: Beijing
country: China
facility: Cancer Hospital of Chinese Academy of Medical Sciences
city: Beijing
country: China
facility: Peking Union Medical College Hospital
city: Beijing
country: China
facility: Peking University People's hospital
city: Shanghai
country: China
facility: Fudan University Shanghai Cancer Center
city: Tianjin
country: China
facility: Tianjin Tumour Hospital
Study officials:
References: