Phase 2 Study of Niraparib in Recurrent or Persistent Rare Gynecologic Malignancies with Homologous Recombination Deficiency

JRCT ID: jRCT2031210264

Registered date:20/08/2021

Basic Information

• Recruitment status: Recruiting
• Health condition(s) or Problem(s) studied: uterine leiomyosarcoma, endometrial cancer(Ca), uterine sarcoma, cervical Ca, vulva vaginal Ca
• Date of first enrollment: 14/02/2022
• Target sample size: 71
• Study type: Interventional
• Intervention(s): A 200 mg dose of niraparib is orally administered once a day from the 1st day with 28 days per cycle. However, if the body weight before the first administration of this drug is at least 77 kg and the platelet count is at least 150,000/uL, 300 mg should be orally administered once a day.

Outcome(s)

Primary Outcome

*Overall response rate (ORR) in BRCA mutation-positive uLMS (Cohort A)
*ORR in BRCA mutation-negative and HR deficient uLMS (Cohort B)
*ORR in BRCA mutation-positive other gynecologic rare malignancies (Cohort C)
(Evaluate independently for each cohort)

Secondary Outcome

Efficacy outcomes
1.Progression-free survival rate at 6 months (PFS-6) in each cohort
2.Disease control rate (DCR) in each cohort
3.Duration of response (DOR) in each cohort
4.Progression-free survival (PFS) in each cohort
5.Overall survival (OS) in each cohort
6.ORR by pretreatment history in each cohort
7.Integrated analysis of ORR, PFS-6, PFS and OS for HRD positive uLMS in cohort A and B
8.ORR, DOR, DCR, PFS, OS in each primary lesion or histological type in Cohort C
* Evaluate independently for each cohort except for integrated analysis

Safety outcomes
1.Number and percentage of subjects with adverse events (AE) that occurred after administration of the investigational drug
2.Number and percentage of subjects with Grade 3 or higher AE
3.Number and percentage of subjects with serious AE
4.Number and percentage of subjects who had to discontinue the investigational drug due to AE
5.Number and percentage of subjects who were suspended from the investigational drug due to AE
6.Number and percentage of subjects whose dose of the investigational drug was reduced due to AE

Key inclusion & exclusion criteria

• Age minimum: >= 20age old
• Age maximum: Not applicable
• Gender: Female

Include criteria

Patients who meet all of the following criteria:
1. Those with uterine leiomyosarcoma (uLMS) or BRCA mutation-positive gynecologic rare malignancies receiving outpatient treatment or are hospitalized at a facility participating in this study
2. Those who are at least 20 years of age at the time of obtaining consent
3. Those who are willing to provide a written consent before undergoing clinical trial-related procedures (excluding standard medical practices) upon understanding that consent can be withdrawn at any time without being at a disadvantage in future treatments
4. Persons with advanced or recurrent solid malignancies which have been histologically diagnosed as malignant tumors, that cannot be cured and resected (if histological examination is performed at another hospital, confirmation at a registered facility is not required)
Cohort A/B: Histologically confirmed uLMS
Cohort C: Those that correspond to BRCA mutation-positive, malignancy of the uterine corpus, malignancies in the uterine cervix, and vaginal or vulvar malignancies (confirmation at enrolling facility is not required if histological test has been conducted at another hospital)
5. Those who have formalin-fixed paraffin-embedded tissue specimens of primary or recurrent tumors, or who can undergo biopsy with fresh tumor material before the start of the study
6. Those who have agreed to a cancer genome test using tumor tissue and are positive (BRCA mutation-positive or HRD-positive) in the tumor test that was performed.
Cohort A: Those with BRCA mutation-positive*2 tumor detected by HRD test*1 defined in this study. However, enrollment can proceed without performing the HRD test for cases with confirmed positive tumor BRCA mutation*2 by an insurance-covered cancer gene panel test*3 before participating in this trial. However, after enrollment, confirmation will be made by the HRD test specified in this test.
Cohort B: Those with an HRD score of at least 33 points in the HRD test*1 specified in this trial
Cohort C: Those with positive tumor BRCA mutation*2 determined by an insurance-covered cancer gene panel test*3 before participating in this study. HRD test*1 is not part of the screening for enrollment.

* 1. myChoice Plus (Myriad, US) will be used for HRD testing.
* 2. BRCA mutations do not include variants of unknown pathogenic significance. In addition, if the tumor sample is positive for pathogenic mutation, it is not essential to determine whether the sample was derived from germline or somatic cells.
* 3. The cancer gene panel test is an insurance-covered diagnostic agent such as the Foundation One CDx, OncoGuideTM NCC Oncopanel System. It is essential that the details of the variant information and the recommendations from the expert panel are available.
7. Those who have a history of chemotherapy
8. Those who have one or more measurable lesions based on RECIST (version 1.1)
9. Those who have completed the last antineoplastic drug treatment 4 weeks before the start of investigational drug administration
10. Those with 0-1 Eastern Cooperative Oncology Group (ECOG) performance status
11. Those who have proper organ function and whose latest laboratory values (the same day two weeks before the registration date is acceptable) within 14 days before registration meet all of the following criteria (however, the patient should not have received or been administered blood transfusion with granulocyte colony stimulating factor (including continuous G-CSF (PEG) preparation) within 14 days of the test date)
Absolute neutrophil count: 1500/uL
Platelet count: 150,000/uL
Hemoglobin level: 10 g/dL
The serum creatinine level is 1.5 times or less of the upper limit of the standard value (ULN), or according to the Cockcroft-Gault estimation formula, the creatinine clearance value is at least 50 mL/min
Total bilirubin value is 1.5 times or less of ULN, or direct bilirubin value is less of ULN
AST and ALT are 2.5 times or less of ULN, and if liver metastasis is present, 5 times or less of ULN
12. Those who can be orally administered the investigational drug
13. Women who meet any of the following conditions
Menopause for more than 1 year before the start of screening
Have undergone contraceptive procedures
Women at childbearing age who agree to simultaneously adhere to use two very effective contraceptive methods, constituting an effective contraceptive method and an effective barrier method from the time of consent acquisition to 180 days after the final administration of the study drug.
Agree to completely avoid sexual intercourse if this corresponds to the patient's lifestyle (does not habitually have sexual intercourse).

Exclude criteria

Subject will be excluded from the trial if they meet any of the following items.
1. Those with completely resectable lesions
2. Those who have a history of at least 4 regimens of chemotherapy
3. Those with platinum-sensitive recurrence in patients with a history of platinum-containing pretreatment in Cohort C
4. Those who received palliative radiotherapy exceeding 20% of the bone marrow within 1 week before the start of investigational drug administration
5. Those with Grade 3 or higher hematotoxicity events lasting more than 4 weeks during the latest chemotherapy session
6. Those with Grade 3 or higher fatigue lasting more than 4 weeks during the latest chemotherapy
7. Those who received pelvic radiotherapy for the purpose of clinical trials for primary or recurrent lesions within 1 year before the start of investigational drug administration
8. Those with symptomatic and uncontrolled brain metastases or leptomeningeal metastasis
Radiotherapy and surgical treatment for central nervous system lesions must be performed at least 1 month before enrollment to determine good control. There are no new or progressive clinical signs associated with CNS lesions, and steroids have been administered at a specified dosage for at least 4 weeks prior to enrollment or have not been administered at all. No diagnostic imaging is required to confirm the absence of brain metastases at baseline. Patients with compressive spinal cord lesions may be enrolled if they have received definitive treatment for the lesion and have evidence of clinical stability for 28 days.
9. Patients with hypersensitivity to components of the investigational drug or other related compounds
10. Patients who have received PARP inhibitors in the past
11. Those who received any other investigational drug within 28 days prior to the first dose
12. Those who underwent major surgery (at the discretion of the investigator) within 3 weeks prior to the first dose. The patient must have recovered from all the effects of major surgery.
13. Those who have been diagnosed, detected, or treated for malignancies other than uterine leiomyosarcoma within a period of 24 months prior to enrollment (excluding basal cell carcinoma or squamous cell carcinoma of the skin that has been definitively treated). However, patients who have previous or current medical history of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) will be excluded regardless of the time of illness.
14. Those who are considered to be at high medical risk due to serious uncontrolled disease, non-malignant systemic disease, or uncontrolled active infection. Examples include, but are not limited to:
Uncontrolled ventricular arrhythmia
Recently (within 90 days before the first dose) myocardial infarction
Major seizure epilepsy with poor control
Unstable spinal cord compression lesion
Vena cava syndrome
Intestinal obstruction or serious gastrointestinal disease
Some kind of mental disorder that prevents the subject from signing the consent form
15. Those who received blood transfusion (platelets or red blood cells) within 4 weeks before the start of administration
16. Those who received live virus and bacterial vaccines within 4 weeks before the start of study drug administration
17. Patients with any disease, treatment, or laboratory abnormalities that affect the outcome of the trial, interfere with the patient's participation in the trial for the entirety of its duration, or do not benefit the patient's participation in the trial (active or uncontrolled myelosuppression (anemia, leukopenia, neutropenia, or thrombocytopenia))
18. Patients who are addicted to any illegal substance at the time of consent (including use for recreational purposes) or have a recent (within the past year) history of substance or alcohol abuse
19. Women who are pregnant or nursing, or who plan to become pregnant within the planned clinical trial period. However, if a nursing woman stops nursing, she will be eligible for enrollment.
20. Patients in immunosuppressive condition (patients undergoing splenectomy are acceptable)
21. Patients known to be positive for human immunodeficiency virus (HIV)
22. Patients with known or suspected hepatitis B virus surface antigen (HBsAg) positive or active hepatitis C virus (HCV) infection
Note: Patients with hepatitis B core antibody (HBcAb) or hepatitis B surface antibody (HBsAb) can be enrolled, but hepatitis B virus nucleic acid testing must be below the detection limit. Patient is positive for hepatitis C virus antibody (HCVAb) must be below the detection limit of the HCV nucleic acid test.
23. Others who are judged by the principal investigator to be inappropriate as research subjects.

Related Information

• Primary Sponsor: Enomoto Takayuki
• Source(s) of Monetary Support: Takeda Pharmaceutical Company Limited.